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. Treatment (cid:2) High-dose bicarbonate merely i HCO 3 \200\223 wasting and increases Na + delivery to the distal nephron (and so worsens d K + ). Aim to allow mild acidosis: potass ium bicarbonate 1.5 \200\223 3g/day in three divided doses (KHCO 3 \200\223 is less calci uric, replenishes K + and Na + load). Thiazide diuretics may also be helpful. Fanconi syndrome A descriptive term for generalized proximal tubular dysfunction. It is mar ked by failure of proximal reabsorption of many \201 ltered substances and classically de scribes glucosuria, aminoaciduria, and phosphaturia. Excretion of uric acid and LMW protein s is also increased. Commonly seen in association with type 2 RTA. \200 May present with bone pain 9 osteomalacia. Causes as for proximal RTA. Investigations: metabolic acidosis, d s-phosphate, d s-urate. Glycosuria and proteinuria (amino acids), i u-phosphate, and i u-citrate. Drug-induced Fanconi Occurs with antivirals (tenofovir, adefovir, and cidofovir), didano- s ine, out-of-date tetracyclines, aminoglycosides, sodium valproate, or ifosfamide. Hyperkalaemic distal RTA (type 4) Is much more common than proximal RTA or distal RTA and i s due to hypoaldosteronism, usually hyporeninaemic hypoaldosteronism. Aldosterone promotes urinary K + loss, so its absence l hyperkalaemia. i K + impairs NH 3 secretion, limiting ne t acid excretion l acidosis. Causes include: \200 Diabetes mellitus (often with mild rena l impairment). \200 Drugs (NSAIDs, ciclosporin, heparin, co-trimoxazole). \200 Obstruct ive uropathy. \200 Chronic tubulointerstitial disease of any cause ( b p. 582) 9 CKD. \200 Addison \200\231s or selective aldosterone de \201 ciency. CHAPTER 10 Fluids and electrolytes 826 Investigations \200 i K+, d HCO 3 \200\223 (rarely <16mmol/L). \200 Normal AG ( i Cl \200\223 ), negative u-AG ( b p. 820), d u-citrate. Urine pH variable but often <5.3. Treatment If due to hypoadrenalism, mineralocorticoid replacement ( \202 udrocortisone 100 \200\223 300 micrograms/day) will rapidly reverse the problem. (cid:2) Often revealed in patients taking ACE-I and increasingly spironol- actone for treatment of heart failure. Adv ise low K + diet ( b p. 259). Mineralocorticoids rarely useful because of signi \201 cant Na + retention in at-risk patients (CKD, heart failure). Trial of furosemide 40 \200\223 1 20mg od. Review drugs. Table 10.5 RTA by numbers Type Distal RTA Proximal RTA Hyperkalaemic distal Defect Impaired net acid excretion Impaired HCO 3 \200\223 uptake d Hypoaldosteronism K + d i Bicarbonate <10 12 \200\223 20 >16 <5.3, i + bicarbonate Urine pH >5.3 Variable UAG Positive Negative Positive d i or normal i or normal Urine citrate Nephrocalcinosis Yes No No RENAL TUBULAR ACIDOSIS 827 CHAPTER 10 Fluids and electrolytes 828 Lactic acidosis L-lactate is an end-product of anaerobic glucose metabolism: glucose is met abolized to pyruvate. In hypoxic tissue, oxidative regeneration of NAD + cannot occur, so p yruvate is used with NADH and H + by lactate dehydrogenase to produce NAD + (crucial earlie r for glycolysis) and lac- tate. In health, lactate is usually rapidly oxidized by the live r. The normal plasma concentration is between 0.5 and 1.5mmol/L. Signi \201 cant lactic ac i- dosis is present if blood lactate is >3.5mmol/L, with an increased anion gap. Convention ally, lactic acidosis is divided into: Type A lactic acidosis Secondary to increased O 2 demand or inadequate O 2 delivery (tissue underperfsuion), causes of which include: \200 Shock: Cardiogenic. \200 Septic. \200 Hypovolaemic. Severe anemia. \200 Localized tissue or organ ischaemia (infarcted gut, muscle). \200 i energy-dependent work (usually in skeletal muscle): Seizures. \200 Extreme exercise. \200 Malignant hyperthermia. Respiratory failure with severe hypoxaemia. \200 Carbon monoxide poisoning. Type B lactic acidosis Secondary to abnormal lactate metabolism, the underproduction or ove r-utilization of ATP or other causes of defective gluconeogenesis (drugs!). Causes include: \200 Mitochondrial dysfunction, either congenital or drug-induced ( b p. 829). \200 Th iamine de \201 ciency. \200 Metabolic derangements involving oxidation: Diabetes mellitus \200\224 especially when poorly controlled. \200 Ethanol poisoning. Liver impairment. D-lactic acidosis is a rare cause of an increased anion gap metabolic acidosis where bacter ial overgrowth in intestinal blind loops leads to increased lactate absorption \200\224 th e proliferating organisms (and not humans) are capable of producing the D-isomer. Management of lactic acidosis Treat the underlying cause \200\224 there is no role for sys temic NaHCO 3 . So the treatment of type A lactic acidosis involves improving oxygenation: resus- citate shock; restore blood \202 ow, and/or improve gas exchange. LACTIC ACIDOSIS 829 Drugs and lactic acidosis Metformin has long been thought to cause a type B lactic acidosis , par- ticularly in diabetics with renal impairment. There is some doubt about this associa tion. However, current NICE recommendations are to stop metformin if SCr >150 mol/L (1.7 mg/dL) or eGFR <30mL/min/1.73m 2 . Recently, reverse transcriptase inhibitors have also bee n found to cause an often severe lactic acidosis as a result of mitochondrial injury \200 \224 in life-threatening cases (lactate >10mmol/L), consider L-carnitine. Other drugs recognized as causes of type B lactic acidosis: Ethanol, cocaine, paracetamol, salicylate. \200 Zidovudine, didanosine, stavudine, lamivu dine, zalcitabine. \200 Propofol, isoniazid. \200 Niacin, nitroprusside, cyanide. \200 Sorbitol and fructose. CHAPTER 10 Fluids and electrolytes 830 Alkalosis Metabolic alkalosis Metabolic alkalosis is common (as might be expected from its causes) and, if severe (pH >7.55), is associated with mortality as high as 45%. Either rete ntion of base or loss of acid in the ECF leads to a rising serum bicar- bonate and pH. To b uffer such changes, patients can hypoventilate to i pCO 2 to as much as 7kPa ( x 7.5 for kP a l mmHg). For each 1mmol/L rise in serum HCO 3 \200\223 above normal, the pCO 2 will rise by 9 0.08kPa to buffer the alkalosis (e.g. to buffer a serum HCO 3 \200\223 of 34mmol/L, the pCO 2 will need to rise by 0.8kPa). Causes of a metabolic alkalosis include: With low chloride: Gastric losses (vomiting, NG suction, self-induced vomiting). \200 Diuretics (thiazide, l oop diuretics). \200 Diarrhea (esp. chloride-secreting villous adenoma). \200 Cystic \201 brosis. Chloride-losing alkaloses With vomiting or NG losses, the stomach generates replacement gas tric HCl, in the process returning HCO 3 \200\223 to the ECF. NaCl loss into gastric \202 uids l volume contraction as well. Diuretics block NaCl uptake, with ECF depletion ( s hyperaldoster- onism) and i salt delive ry to the DCT ( 6 i exchange of Na + for K + and H + ). Diuretic-induced d K + exacerbates alkalosis further. With low potassium: p hyperaldosteronism (and, less commonly, s ). \200 Drugs (carbenoloxone, liquorice, laxa tive abuse). \200 Bartter \200\231s, Liddle \200\231s, and Gitelman \200\231s syndromes ( b p. 800). Hypokalaemic alkalosis Hyperaldosteronism leads to i Na + retention at the expense of K + a nd H + . d K + may increase net acid excretion. The intracellular acidosis found with d K + leads to i HCO 3 \200\223 retention in the kidney. Other: Milk-alkali syndrome (or hypercalcaemia of other causes usually s to calcium and vitamin D- containing preparations, occasionally in association with thiazide diuretic use, the so-cal led calcium-alkali syndrome). Overzealous bicarbonate therapy (esp. if with CKD). \200 Penicillins (cation load l uHCO 3 \200\223 wasting). \200 Massive transfusion (citrate load). ALKALOSIS 831 Symptoms and signs Often due to associated hypovolaemia or hypokalaemia. With severe alka- losis, d cerebral and myocardial blood \202 ow: headaches, confusion, seizures, angina, a rrhythmias. Compensatory hypoventilation and hypocapnoea may be important in critically ill patients (failure to wean off ventilator). O 2 delivery to tissues is reduced (through alkalosis-induced vaso- constriction and reduce d O 2 release \200\224 the dissociation curve is shifted leftwards). Investigations Only consider ABG if evaluating respiratory contribution to a mixed acid \200\223 base disorder. \200 U&E ( d K+, d Cl \200\223 ). ? i Ca 2+ . \200 Urinary ele ctrolytes: u-Cl \200\223 <10mmol/L if gastric losses ( 2 surreptitious vomiting). \200 u-Cl \200 \223 >30mmol/L if diuretic therapy (abuse), Bartter \200\231s, Gitelman \200\231s. \200 u -K + >30mmol/L if diuretics, hyperaldosteronism. \200 u-K + <20mmol/L if extrarenal K + l osses. Diagnosis usually obvious: urinary diuretic/laxative screen, renin and aldos- terone, if in dicated. Treatment Depends on the cause: \200 Treat d Cl \200\223 alkalosis with chloride. Replacement of lost Cl \200\223 is the mainstay of treatment. \200 If volume-deplete: 0. 9% saline (NaCl) 3 \200\223 5L/day IVI. \200 If volume-overloaded: KCl, rather than NaCl (unless i K + ). Treat d K + alkalosis with KCl ( b p. 799). \200 Reverse the underlying cause: Stop alkali therapy. \200 Stop diuretics, if possible, or add K + -sparing agent, esp. if hyperaldosteronism present (spironolactone). \200 Antiemetics (e.g. metoclopramide 10mg I MI/IVI). \200 If NG drainage needed, H 2 receptor antagonist or proton pump inhibitor. Acetazolamide 250 \200\223 500mg daily will cause NaHCO 3 \200\223 wasting. Particularly useful in those with chronic lung disease (and need their respiratory drive) o r with acute unstable cardiac syndromes. Respiratory alkalosis Always a result of overventilation (due to mechanical ventilation), i ncreased central respiratory drive (anxiety, pregnancy, stroke, or CNS infection), or hypox aemia (mild asthma, pulmonary oedema, or emboli). Treatment can be dif \201 cult if alkalo sis severe. CHAPTER 10 Fluids and electrolytes 832 Urgent reversal of severe metabolic alkalosis (in ITU) Indications \200 Bicarbonate >45mmol/L (or pH >7.55), and \200 Hepatic encephalopathy, or \200 Arrhythmias (including digoxin toxicity), or \200 Confusion, seizures. Correct K + IVI hydrochloric acid (HCl) via central line: body weight (in kg) x 0.5 (bicarb onate space = 50% body weight) x required d HCO 3 \200\223 (mmol/L) = mmol HCl infused at 0.2mmol/kg/h. Example: in a 70kg male, to d HCO 3 \200\223 by 10mmol/L, 0.1M HCl solution (10 x 70 x 0.5 = 350mmol) at 35mmol/h for 10 hours to reduce plasma bicarbonate by 10mmol/L. Alternatives include NH 4 Cl or arginine HCl. HD or CVVHF also provide rapid correction of severe alkal osis. ALKALOSIS 833 CHAPTER 10 Fluids and electrolytes 834 Mixed disturbances As a rule of thumb, pH will rise or fall by 0.1 if: \200 [HCO 3 \200 \223 ] changes by 6mmol/L, or \200 pCO 2 changes by 1.58kPa. For example, a fall in [HCO 3 \200\223 ] from 24 to 12 = pH from 7.4 to 7.2, or a rise in pCO 2 from 5.5 to 7.9 = pH from 7.4 to 7.25. See Table 10.6 for normal ranges. Table 10.6 Normal ranges pH pO 2 pCO 2 HCO 3 \200\223 7.38 \200\223 7.42 10 \200\223 13kPa (1kPa = 7.6mmHg) 4.7 \200\223 5.9kPa (mixed venous pCO 2 usually 1kPa h igher) 22 \200\223 26mmol/L Table 10.7 Characteristics of pure acid \200\223 base disturbances [HCO 3 \200\223 ] d pH pCO 2 d d Metabolic acidosis i i i Metabolic alkalosis d i i Respiratory acidosis i d d Respiratory alkalosis Circled arrows = compensatory mechanism. Mixed acid \200\223 base disturbances are not uncommon in hospitalized patients: the key t o diagnosis is recognizing when compensation is inap- propriate. Using Table 10.7, the foll owing should be expected: \200 Metabolic acidosis: pCO 2 falls by [24 \200\223 actual HC O 3 \200\223 ] x 0.17. \200 Metabolic alkalosis: pCO 2 rises by [actual HCO 3 \200\223 \200\223 24] x 0.08. \200 Acute respiratory alkalosis: [HCO 3 \200\223 ] falls to not l ess than 18mmol/L. \200 Acute respiratory acidosis: [HCO 3 \200\223 ] rises by [0.75 x p CO 2 \200\223 5.3] 9 3. \200 Chronic respiratory alkalosis: [HCO 3 \200\223 ] falls to not less than 14mmol/L. \200 Chronic respiratory acidosis: [HCO 3 \200\223 ] rises by [3 x pCO 2 \200\223 5.3] 9 4. If compensation does not fall roughly within these limits, the re is likely to be a mixed component to the disturbance: \200 What is the pH (acidotic or alkalotic)? \200 Is predominant cause metabolic or respiratory? \200 Is compensation a ppropriate? \200 If not, a mixed acid \200\223 base disturbance is present. See Fig. 10.2 for the acid \200\223 base nomogram. MIXED DISTURBANCES 835 30 7.6 7.4 7.5 7.7 M 20 C R 7.3 ) M m 10 Metabolic alkalosis Metabolic acidosis ( E B S 7.2 AR AR 0 c i l o b a t e M 7.1 R \200\22310 C 7.0 pH \200\22320 M Respiratory acidosis Respiratory alkalosis \200\22330 2 3 4 5 7 Respiratory PaCO2 (kpa) 6 8 9 10 11 12 Fig. 10.2 The acid \200\223 base nomogram. Plot PaCO 2 on the x-axis. The left-hand scale predicts the base excess/de \201 cit from the intersection with the measured pH. Changes i n PaCO 2 (i.e. in ventilation) will lead to horizontal shifts, whilst changes in bicarbonat e (i.e. administration) will lead to vertical shifts from the original intersection. Metabo lic and respiratory changes move the patient along the appropriate axis without altering th e other. Adapted from Schlichtig R, Grogono AW, Serveringhans JW (1998) Current status of a cid \200\223 base quantitation in physiology. Anesthesiology Clinics of North America 16 : 211 \200\223 13, with permission from Elsevier. CHAPTER 10 Fluids and electrolytes 836 Tubular rarities Cystinuria (see b p. 719) Defective uptake of \201 ltered cystine and ot her dibasic amino acids from the urine leads to cystine stone formation. Autosomal recessiv e inheritance of genes encoding tubular amino acid transporter proteins presents in child- hood or adolescence with \202 ank pain 9 haematuria (calculi). Urine microscopy shows characteristic hexagonal crystalluria (see Fig. 10.3). i 24h urinary cystine excretion (>2mmol/day, NR <0.15), radio-opaque calculi on plain KUB or USS. Aim to increase oral \202 uids for UO of >3 \200\223 4L/day. If u-cystine remains >1mmol/L (cy stine is insoluble much above this), add in penicillamine 1 \200\223 2g/day in four divide d doses. Alternatives include tiopronin up to 400mg daily or captopril. All work by increas ing cystine solubility. For managing stones, see b p. 722. Cystinosis (cid:2) Is not the same disease as cystinuria Presents in childhood with growth failure, Fanconi syndrome, and progres- sive renal impairment. Eye involvement, hepatomegal y, hypothyroidism, and diabetes develop, as cystine deposits impair organ function. An ado- lescent variant with normal stature and tubular function, but renal impair- ment, offers a better renal prognosis. An autosomal recessively inherited defect in cystine export from i ntracellular lysosomes leads to accumula- tion and local injury. Oral cysteamine forms a co mplex with cystine that can leave lysosomes, ameliorating disease. Hyperoxaluria An autosomal recessive condition presenting in childhood marked by i u-oxalat e excretion, calcium oxalate calculi, and nephrocalcinosis. Defective synthesis or targeting of the enzyme AGXT, which converts glyoxalate to glycine, leads to compensatory shuttling of glyoxalate to oxalate. Heavy oxalate deposition in the h eart, blood vessels, and joints causes signi \201 cant morbidity. The treatment of choice is combined liver \200\223 kidney transplantation, although high-dose pyridoxine offers in terim ben- e \201 t. Rarely, hyperoxaluria and nephrocalcinosis may be associated with Cro hn \200\231s disease. See Fig. 10.4 for radiography of the abdomen Dent \200\231s disease An X-linked inherited defect in the gene encoding CLC-5, a chloride chan- nel responsible for endosomal acidi \201 cation in the proximal tubule and elsewhere . This leads to impaired endocytosis and uptake of urinary pro- teins. Presents predominant ly in \231\202 ( \231\200 may have urinary abnormalities) as Fanconi syndrome ( b p. 825) , hypercalciuria, nephrocalcinosis, and renal impairment. Rickets and osteomalacia are comm on. Renal transplantation is the treatment of choice for ESRD, and patients generally do we ll. Other syndromes, such as X-linked recessive nephrolithiasis, X-linked recessive hypopho sphataemic rickets, and idiopathic low molecular weight pro- teinuria of Japanese children, are now known to be due to similar defects. 837 Fig. 10.3 Characteristic hexagonal urinary crystals of cystine. Reproduced from M http://th iola.com/Kidney_Stone_Photos/Photo27-Cystine-Crystals.aspx , with permission from Mission P harmacal Co. Fig. 10.4 Plain abdominal radiograph demonstrating the cortical pattern of calcium oxalate crystal deposition seen in hyperoxaluria. Reproduced from Phang Boon Lim et al. , Nephrolog y Dialysis Transplantation , 19 : (5) 1325 (2004) with permission from Oxford University Pr ess. 839 Chapter 11 Pregnancy and the kidney Physiological changes during pregnancy 840 Urinary tract infection 842 AKI during pregnancy 844 Hypertension during pregnancy 846 Pre-eclampsia: pathophysiology 850 Pre-eclampsia: ma nagement 852 Pre-existing renal disease 856 Disorders of the urinary tract in pregnancy 860 Pregnancy on dialysis 862 Pregnancy after renal transplantation: introduction 864 Transpla nt function and pregnancy 865 Pregnancy after renal transplantation: management 866 CHAPTER 11 Pregnancy and the kidney 840 Physiological changes during pregnancy Systemic changes \200 Signi \201 cant changes to cardiovascular function and volume homeostasis begin early in pregnancy. \200 Increased cardiac output (up to 50%). \200 Increased pla sma volume (up to 30 \200\223 40%). \200 Increased peripheral vasodilatation, with corre sponding decrease in systemic vascular resistance ( l fall in BP and widening of pulse pres sure during 1st and 2nd trimesters that normalizes during 3rd trimester). The fall in BP is actually modest, in comparison to the increase in CO and intravascular vo lume, as there is a signi \201 cant concomitant increase in vascular compliance. Renal changes \200 Increased renal blood \202 ow, up to 70 \200\223 80% in 2nd trimest er (under the in \202 uence of NO, vasodilator prostaglandins and relaxin). Trans-glomerular capilla ry pressure remains the same, with matching dilatation of both afferent and efferent arteri oles. Marked stimulation of RAAS. \200 Increased GFR (40% by end of 1st trimester). \200 Incr ease in proteinuria. \211 300mg/24h is not signi \201 cant in pregnancy. \200 It is important to quantify b aseline pre-existing proteinuria at the start of pregnancy (uACR/uPCR). Pre-existing proteinuria is likely to double. Renal function (See Table 11.1.) \200 1 eGFR is not validated in pregnancy: MDRD underest imates, and Cockcroft \200\223 Gault overestimates, true GFR. 2 SCr >80 mol/L (0.9mg/dL) or Ur >5mmol/L (14mg/dL) during pregnancy may indicate renal impairment and warrant further evaluation. 24h urinary creatinine clearance ( b p. 33) remains the gold standard for the measurement o f renal function during pregnancy (NR: 125 \200\223 150mL/min; 30% above range for non-pre gnant women). Table 11.1 Renal function in pregnancy Mean serum creatinine values Non-pregnant Average 72 mol/L (0.8mg/dL) 1st trimester 52 \200\223 68 mol/L (0.58 \200\2230.77mg/dL) 2nd trimester 44 \200\223 64 mol/L (0.5 \200\2230.72mg/dL) 3rd trimester 55 \200\223 73 mol/L (0.62 \200\2230.82mg/dL) PHYSIOLOGICAL CHANGES DURING PREGNANCY 841 Tubular function \200 Glycosuria does not necessarily indicate impaired glucose tolerance during pregnancy. If persistent, measure blood glucose. \200 Tubular handling of bicarbon ate and acid is unchanged, but hyperventilation in pregnancy leads to d pCO 2 , a mild respiratory alkalosis ( i pH from 7 .4 to 7.43). HCO 3 \200\223 excretion increases and serum HCO 3 \200\223 falls to 18 \200\223 22mmol/L to compensate. Urinary calcium excretion is increased. \200 Serum urate falls in early pregnancy: as a r ough guide the intrapartum urate should be 0 (gestational age in weeks), i.e. at 26 weeks, urate will be 7 0.26mmol/L. Plasma osmolality is reduced: Women gain an average 9 \200\223 14kg during pregnancy, with up to 8L as i total body water. The threshold for arginine vasopressin (AVP or ADH) release is lowered, resulting in sustai ned AVP release in the face of plasma dilution and 6 a true fall in plasma osmolality ( 7 1 0mOsmol/kg). \200 Serum Na + falls to 132 \200\223 140mmol/L ( 1 Na + >140mmol/L may indicate hypernatraemia in pregnancy). Rarely, transient diabetes insipidus of pregnancy (with polyuria) may develop in the 3rd tr imester (the result of either incomplete cranial DI in susceptible women or increased AVP d egradation). Anatomical changes \200 Increased kidney volume, size, and weight. \200 Renal length in creases by 7 1cm. \200 Collecting system dilatation: May begin at 8 weeks. Apparent in 90% of women by 20 weeks \200\231 gestation ( 7 2cm above normal diameter). More obvious on right (uterine veins, enlarging uterus, and iliac artery compress the right ureter l \200\230 iliac sign \200\231 on IVU, with abrupt urete ric cut-off at the pelvic brim). Assessments made during pregnancy should be interpreted with caution. Collecting system dilatation usually resolves within 48h of delivery in 50% of cases but ca n still be present up to 12 weeks post-partum. CHAPTER 11 Pregnancy and the kidney 842 Urinary tract infection Introduction Anatomical, functional, and hormonal changes in the ur inary tract make UTI more common in pregnancy. Pyelonephritis is the most common renal comp lication of pregnancy, occurring in 1 \200\223 2% of all pregnancies. In addition, preterm labor or low birthweight infants may be associ- ated with asymptomatic bacteriuria or UTI (mechanism: possible amnio- nitis l i in \202 ammatory cytokine synthesis, provoking uteri ne contraction). Untreated UTI may be associated with subsequent developmental delay in the child and even increased risk of fetal death. Bacteriology 80 \200\223 90% due to E. coli . Proteus spp., Klebsiella spp., or Gram +ve o rgan- isms may also be implicated. Group B Streptococcus (GBS) infection near delivery may lead to vaginal colonization and serious neonatal sepsis, so penicillin prophylaxis should be given during labor. Risk factors \200 Asymptomatic bacteriuria (>10 5 cfu/mL urine) occurs in 4 \200\223 7% of women and, in pregnancy, is associated with pyelonephritis in 30% of cases, if untreated. \200 Send urine for culture at \201 rst antenatal visit. \200 If asymptomatic bacteriu ria is present, send a second sample. \200 If second sample positive, l treat. The absence of bacteriuria at antenatal booking is associated with <2% chance of UTI through pregnancy. Further risk factors for bacteriuria or frank UTI prior to delivery include: \200 UTI before falling pregnant or UTI in previous pregnancies. \200 An abnor mal urinary tract. \200 Diabetes mellitus, HIV positivity, or sickle cell disease. \200 Prolonged labor, Cesarean section, pre-eclampsia, placental abruption, and urinary catheters are all risk factors for post-partum UTI. Diagnosis \200 Dysuria, frequency, urgency, or offensive urine suggests UTI. \200 Loin pain, backache, vomiting, and fevers often occur in pyelonephritis. \200 Suprapubic or re nal angle tenderness may be present. \200 Dipstick for leucocytes or nitrites may suggest UTI but will often miss asymptomatic bacteriuria. 2 Send MSU for M,C+S. If pyelonephritis suspected: blood cultures, FBC, U&E, CRP. Consider USS renal tract. Fetal well-being should be assessed. 3 Acute pyelonephritis Pyelonephritis is more common in the second half of pregnancy and is a signi \201 cant cause of fetal mortality and maternal morbidity. The increasing size of the uterus may cause ureteral obstruction and impaired urinary \202 ow (particularly on the right), encouraging stasis and sepsis. URINARY TRACT INFECTION 843 Recurrent UTIs in pregnancy 2 After more than one UTI (or a single episode in 5 with an abn ormal urinary tract), women should be offered prophylactic antibiotics for the duration of the pregnancy. Post-coital cefalexin 500mg PO stat or cefalexin 500mg nocte for 1 month, alternating with nitrofurantoin 100mg nocte, have proved safe and effective. Antimicrobial choice should ide ally re \202 ect sensitivities of organisms cultured. Post-partum investigation is recomme nded ( b p. 708). Treatment of UTI in pregnancy Asymptomatic bacteriuria or cystitis \200 First line, prior to sensitivities becoming available: \200 Nitrofurantoin 50mg PO qds x 7 days, or \200 Cefalexin 500mg PO bd (or 250mg qds) x 7 days. \200 Trimethoprim 200mg bd PO ( 1 but giv e a folic acid supplement during the 1st trimester, and avoid if patient is folate-de \201 cient or taking a folate antagonist, or if trimethoprim has been used in the preceding yea r). Amoxicillin 250mg qds PO x 7 days (often \201 rst choice if sensitivities known). Ampicillin 500mg PO qds x 7 \200\223 10 days for group B Streptococcus infections \200\224 and inform the patient s antenatal service, as prophylactic antibiotic s may be indicated during labor and delivery. Repeat MSU for M,C+S monthly to con \201 rm eradication. Pyelonephritis \200 Admit. \200 IV access and rehydration with 0.9% NaCl, as required. \200 Ceftriaxone 1g IV od or cefotaxime 1 \200\223 2g IV qds. \200 Alternative: ampicillin 1g IV qds + gentamicin 1. 5mg/kg tds. \200 If the patient is immunocompromised and/or has incomplete urinary drainage, then seek urgent microbiological advice. 1 Fluoroquinolones, such as cipro \202 oxacin, should be avoided, unless resistant organis ms are cultured. Co-trimoxazole needs to be used with caution (sulfonamides should not be u sed in the 3rd trimester). Safe antibiotics in pregnancy \200 Penicillins. \200 Cephalosporins. \200 Nitrofurant oin (a recent large Norwegian population study suggests low teratogenic potential but incre ased risk of neonatal jaundice if used within 30 days of delivery). Trimethoprim ( 1 safe after 1st trimester ( b p. 843)). CHAPTER 11 Pregnancy and the kidney 844 AKI during pregnancy Introduction AKI during pregnancy remains a signi \201 cant problem i n the developing world, accounting for up to 20% of all AKI (usually in circumstances where there is no access to safe and sterile termination). 2 In the developed world, pre-eclamps ia is the commonest pregnancy-related cause of AKI. Causes Pre-renal \200 Volume depletion: Esp. s to hyperemesis gravidarum during the 1st trimester. Placental abruption: Presents with abdominal pain and PV bleeding in 2nd or 3rd trimester. A classical cause of cortical necrosis ( b p. 845). \200 Post-partum hemorrhage (see also cortical necrosis, b p. 845). \200 Septic abortion ( b p. 845). Common in the developing world. Presents with abdominal pain, fever, and shock. Renal \200 Pre-eclampsia ( b p. 850). \200 Acute fatty liver of pregnancy: 3rd trimester. Presents with coagulopathy, abnormal LFTs, hypoglycaemia, and lactic acidosis. AKI common. HUS/TTP ( b p. 845): May present in either the antenatal or post-natal period. Exacerbation of existing renal disease, e.g. SLE: Renal biopsy may be required to con \201 rm diagnosis and is safe in early pregnancy in expert hands. \200 Acute interstitial nephritis ( b p. 580): Often drug-related, e.g. NSAIDs, antibiotics, proton pump inhibitors. Nephrotoxic drugs ( b p. 898). Post-renal \200 Acute urinary retention: 3rd trimester. Relates to bulk of expanding uterus. \200 Also occurs following combined k idney/pancreas transplantation where the transplanted kidney is placed in an intraperitonea l location (unusual in renal transplantation alone where the transplant is in the false pel vis). Investigations SCr ( 2 a SCr of >80 mol/L (0.9mg/dL) may indicate of renal impairment in p regnancy). FBC, U&E, LFTs, calcium, clotting, urate, haemolysis screen, G&S, infection scre en (MSU, blood cultures, vaginal swabs, as appropriate). Management Similar to non-pregnant patients. Careful assessment of \202 uid status, with correction of volume depletion. Treat underlying cause. AKI DURING PREGNANCY 845 Septic abortion Sudden onset (over hours) after attempted abortion. Fever (often >40 * C), rigors, myalgia, vomiting, and diarrhea (may be bloody). Abdominal pain is common, but vagi nal discharge is often absent. Progression to septic shock, with d BP, i HR, peripheral vas odilatation, oliguria, and DIC is rapid. Culpable organisms include E. coli and Clostridia . Investigations Blood cultures, Hb (haemolysis), d Plt (DIC) G&S, clotting, D-dimers, U&E, L FT. Perform VE for high vaginal swabs ( l M,C+S). Plain AXR may show intrauterine or intra \200\223 abdominal gas. Consider USS or CT to exclude pyometrium. Management Transfer to critical care. O 2 , resuscitate with IV \202 uids and blood prod- ucts ( b p. 168). 2 Benzylpenicillin 1.2 \200\223 2.4g IVI qds, metronidazole 500mg IVI t ds + Gram \200\223ve cover (e.g. cefuroxime 1.5g stat, followed by 750mg IVI tds or cipro \202 oxacin 200mg IVI bd, adjusted for SCr). Acute fatty liver of pregnancy Occurs late in pregnancy or immediately post-partum. Part of a spectrum of pregnancy-related diseases characterized by endothelial dysfunction with end -organ damage (which also includes pre-eclampsia). Presents with nausea, vomiting, jaundice , encephalopathy, acute hepatitis, and DIC. AKI is common. Management is supportive. Expedi te delivery, if possible. Cortical necrosis Common historically, especially after placental abruption and post-partum hemorrhage. Sudden and profound renal vasospasm (often with marked d BP) causes patchy inf arction of the renal cortex. Causes severe AKI (often with persistent anuria) and often irr eversible renal failure. Contrast-enhanced CT scanning, Doppler USS or MAG-3 isotope scan- ning will demonstrate the perfusion defects. HUS/TTP ( b p. 574) Very rare ( 7 1 in 100,000 pregnancies). Presents with AKI (often requiring RRT), usually in the 3rd trimester or ear ly puerperium (up to 10 weeks post-partum), but can occur throughout pregnancy. Endothelial dysfunc- tion, with microangiopathic haemolytic anemia, thrombocytopenia (both typically s evere), and coagulopathy are present. i BP (>70%) and pro- teinuria (>80%) are common. May follow an otherwise unremarkable (normotensive and non-proteinuric) pregnancy. Easily (and 6 commonly) confused with other diagnoses, such as pre-eclampsia, HELLP, acute fatty liver of pregnancy, and antiphospho- lipid antibody syndrome. It is important to cons ider the diagnosis, as early treatment (FFP/plasmapheresis) is helping to improve historica lly poor outcomes for maternal morbidity and mortality. Pregnancy d ADAMTS13 levels (as doe s HELLP) \200\224 but they will be much lower in TTP and many cases of HUS (although usual ly not available to assist immediate manage- ment). Relapse may occur in subsequent pregnan cies. CHAPTER 11 Pregnancy and the kidney 846 Hypertension during pregnancy Introduction Blood pressure falls in the early stages of a no rmal pregnancy and returns to pre-pregnancy baseline by term.