Nephrol Dial Transplant (2003) 18: 2442–2448 DOI: 10.1093/ndt/gfg333

Teaching Point (Section Editor: K. Ku¨hn) Supported by an educational grant from

Metabolic alkalosis in patients with renal failure Maria E. Ostermann, Yvonne Girgis-Hanna, Stephen R. Nelson and John B. Eastwood Department of Renal Medicine, St George’s Hospital Medical School, London, UK

Keywords: alkalosis; anion gap; metabolic acidosis; renal failure

hyponatraemia;

Introduction Alkalosis is most unusual in patients with advanced renal failure. When patients are also hyponatraemic, hypochloraemic and hypokalaemic, management can be a considerable challenge. The purpose of this report is to illustrate by means of three patients the potential for diagnostic uncertainty and therapeutic error in these metabolic settings and to outline some simple principles in diagnosis and management.

Cases Patient 1 A 38-year-old man presented to the A&E department giving a history of vomiting and intermittent diarrhoea for 2 weeks. He could keep nothing down other than cider and water, and his urine output had fallen. His alcohol intake was excessive and he smoked heavily but he denied taking recreational drugs. His only medication was ranitidine. A known epileptic he had had a seizure 1 week previously. On several occasions in the past he had been admitted with drug overdoses. On examination his breath smelt of alcohol. He was restless but orientated with a Glasgow Coma Score (GCS) of 15/15. His blood pressure (BP) was 140/80 mmHg with a pulse of 90 beats/min in sinus rhythm. His jugular venous pressure (JVP) was visible 1 cm above the level of the manubrio–sternal joint. His respiratory and

Correspondence and offprint requests to: Maria E. Ostermann, Department of Renal Medicine, St George’s Hospital Medical School, Cranmer Terrace, London SW17 0QT, UK. Email: [email protected]

abdominal systems were unremarkable and neurological examination revealed only truncal ataxia. Blood results are shown in Table 1. In addition, his liver enzymes, amylase and thyroid hormones were within the normal range; calcium 2.33 mmol/l, phosphate 2.12 mmol/l, magnesium 0.77 mmol/l, creatine kinase 1111 U/l, random cortisol 1207 U/l, total cholesterol 3.4 mmol/l. Arterial blood revealed: pH 7.59, pO2 12.06 kPa (on air), pCO2 5.2 kPa, HCO3– 38.4 mmol/l and lactate 0.7 mmol/l. Serum was negative for opiates, benzodiazepines, cocaine, cannabinoids, salicylate and paracetamol. The patient was treated with i.v. saline 0.9%, Kþ supplements and antiemetics. His nausea and diarrhoea settled within 48 h. The electrolyte abnormalities improved with i.v. fluid (Table 1) and he did not need dialysis. Computer tomography (CT) of his head demonstrated generalized cerebral atrophy with no evidence of a focal intracranial lesion. Upper gastrointestinal endoscopy was recommended but the patient declined it. When discharged 12 days after admission he was back to his usual self. Patient 2 A 48-year-old builder was admitted to hospital complaining of abdominal pain and vomiting for 10 days and of not passing urine for 2 days. He was known to have type II diabetes mellitus, hyperlipidaemia, ischaemic heart disease and hypertension. He had suffered episodes of depression and had had acute pancreatitis. He smoked 30 cigarettes a day and had drunk alcohol on a regular basis until 12 months before presentation. On admission he was afebrile, peripherally vasoconstricted and intravascularly volume deplete. His BP was 120/80 mmHg; pulse 100 beats/min in sinus rhythm. Abdominal examination revealed tenderness in the epigastrium and fullness around the umbilicus. Examination of the respiratory and nervous systems was unremarkable.

Nephrol Dial Transplant 18(11) ß ERA–EDTA 2003; all rights reserved

36 13.5

498

280 44 17.9 23 81 12.5

44 17.6 36 14.3 37 13.6 41 15.1

41 19.9 241

34 9.8 102

6.8 107

34 2.0 77

125 2.5 59 44 19 280 8.3 139 3.8 134 3.3 137 3.2

31 28 10.1 31 16

25 6.2 127 26 15.3 482

30 11.1 31 11.6

28 10.9

138 3.8

111 3.8 68 28 22.4 1201

103 3.1 49 38 20.2 1230 5.9 248 35 13.0 15 18 5.9 154

108 3.4 62 35 22.3 1269 5.6

128 4.0 86 29 20.2 1039

131 4.4

135 4.2 96 24 3.0 96

130 3.1 76 38 24.3 577 8.8

131 2.7

35 14.6

37 19 265

126 2.8 74 40 21.6 288

132 3.4

133 4.2 99 33 13.5 226

133 4.5 101 27 9.8 203

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Naþ (mmol/l) Kþ (mmol/l) Cl– (mmol/l) HCO3– (mmol/l) Urea (mmol/l) Creatinine (mmol/l) Glucose (mmol/l) Serum osmolality (mosmol/kg) Albumin (g/l) Hb (g/dl) Urine Naþ (mmol/l) Urine Kþ (mmol/l) Urine pH Urine osmolality (mosmol/kg)

2 21 15 10 6 3 2

Table 1. Serial blood and urine measurements in the three patients

121 2.2 58 44 23 336

3 2 1 7 1 1

3

Patient 2, day in hospital Patient 1, day in hospital

4

Patient 3, day in hospital

4

5

6

Metabolic alkalosis in patients with renal failure

Blood results are shown in Table 1. In addition, liver enzymes and amylase were within the normal range, calcium 2.24 mmol/l, phosphate 2.21 mmol/l, white blood cells 23.1
109/l and platelets, 277
109/l. Arterial blood revealed: pH 7.79, pO2 10.1 kPa (on air), pCO2 3.3 kPa and HCO3– 36 mmol/l. Electrolytes were not measured in the urine. Following resuscitation with i.v. saline 0.9% and Kþ supplementation the patient started to pass urine, and his renal function improved without the need for dialysis. Upper gastrointestinal endoscopy revealed pyloric obstruction. At laparotomy he was found to have duodenal obstruction due to a pancreatic mass. Roux-en-Y bypass to the common bile duct with gastroenterostomy was performed and he made an uneventful recovery. Histology of the pancreatic mass was benign. Patient 3 A 48-year-old man was brought to the A&E department following a witnessed Grand mal seizure. His girlfriend reported that he had suffered from nausea and vomiting for 3 days. His alcohol intake was usually excessive but for 3 days he had abstained. Four years previously he had been admitted to the intensive care unit of another hospital with alcohol-related hepatitis and renal failure and had required haemofiltration. He made a good recovery and was discharged without further follow-up. On admission on this occasion he was disorientated and restless with a GCS of 15/15. His BP was 115/65; pulse 90 beats/min in sinus rhythm. His JVP was just visible above the level of the manubrio–sternal joint. Examination of his respiratory and abdominal system was unremarkable. He had a broad-based gait but no focal neurological abnormality. Blood results are shown in Table 1. In addition, liver enzymes were within the normal range; calcium 2.37 mmol/l, white blood cells 11.1
109/l and platelets 274
109/l. Arterial blood was not taken; urine electrolytes were measured on the day after admission. A CT scan of his head was normal. He was treated with regular benzodiazepine, thiamin and potassium, and asked to restrict his fluid intake to 1.5 l a day. This decision was reversed 24 h later on review of the history, clinical status and blood results. Instead, i.v. saline 0.9% was commenced which was later changed to NaCl tablets, as he refused further i.v. cannulation. He had no more seizures and self-discharged 5 days after admission.

Discussion Vomiting can lead to metabolic alkalosis and volume depletion. It is also well known that advanced renal failure is usually associated with a metabolic acidosis. In patients presenting with a combination of advanced renal failure and metabolic alkalosis, it can be difficult

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M. E. Ostermann et al.

Fig. 1. Acid–base regulation in the gastrointestinal tract.

to discern a clear picture of the underlying physiological processes. 1. Pathophysiological processes relevant to our patients a. Metabolic alkalosis. Metabolic alkalosis can be generated by loss of Hþ, administration of HCO3–, movement of Hþ into the cells or volume depletion associated with Cl– loss. The kidney is normally able to excrete excess HCO3– in the urine. However, in situations where either glomerular filtration rate (GFR) is reduced or tubular HCO3– reabsorption increased, renal HCO3– excretion is impaired and metabolic alkalosis is maintained. Loss of gastric juices leads to loss of Hþ, Cl–, Kþ and volume, all of which can contribute to the development of metabolic alkalosis. Loss of Hþ. Gastric HCl is formed in gastric cells where H2O and CO2 combine to form HCO3– and Hþ ions. HCO3– diffuses into the extracellular fluid in exchange for Cl– which then binds to Hþ. Usually acidic gastric

fluid enters the small intestine and stimulates pancreatic secretion of HCO3– into the gut (to bind HCl) and of Hþ into the blood (to buffer HCO3– from the stomach) (Figure 1). Lack of acid in the fluid entering the small intestine reduces the stimulus for pancreatic secretion with the result that HCO3– generated during the process of gastric HCl production will remain unbuffered. The more severe the vomiting the greater will be the systemic gain of HCO3–. Loss of Cl–. HCO3– and Cl– are the main anions involved in maintaining ionic equilibrium with Naþ and Kþ. Tubular Naþ reabsorption is usually linked to Cl– reabsorption, Hþ secretion and Kþ exchange. With less filtered Cl– available for reabsorption along with Naþ, Naþ reabsorption is accompanied by either Hþ or Kþ secretion resulting in metabolic alkalosis (Figure 2). Loss of Kþ. Loss of gastric secretions is commonly associated with hypokalaemia. The main reason is Kþ loss in the urine as a consequence of hypovolaemiainduced secondary hyperaldosteronism; relatively little

Metabolic alkalosis in patients with renal failure

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Fig. 2. Tubular physiological processes related to acid–base maintenance.

Kþ is lost in the gastric juice itself. Loss of extracellular Kþ leads to movement of Kþ out of cells into the extracellular space, and Hþ and Naþ into the cells (to maintain electroneutrality). An increased Hþ concentration in renal tubular cells enhances Hþ secretion into the tubular lumen and subsequent reclamation of HCO3– (Figure 2) [1]. Loss of volume. Volume depletion is associated with increased HCO3– reabsorption, usually through the action of angiotensin II and aldosterone. Combined loss of Hþ, Kþ and Cl– and volume (e.g. diuretics, vomiting) represents a particularly potent

stimulus to the development of metabolic alkalosis. Correction of only one of these components does not usually correct the alkalosis. b. Hyponatraemia. Hyponatraemia is often a diagnostic dilemma (as in our patients), where the difficulty lies in ascertaining whether the patient has an excess of water in relation to Naþ or a lack of Naþ in relation to water or a combination of the two. From a single measurement of plasma Naþ on its own it is not possible to draw conclusions as to volume status. (In contrast, hypernatraemia is usually due to loss of water rather than excess Naþ.) It is ADH that plays an important

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Table 2. Equations for analysis of acid–base disorders a. Expected respiratory response to metabolic acid–base disorders Metabolic acidosis For every mmol/l fall in plasma [HCO3–] below 24 mmol/l, the arterial pCO2 can be expected to fall by an average of 0.15 kPa from 5.3 kPa Metabolic alkalosis For every 10 mmol/l increase in plasma [HCO3–] above 24 mmol/l, the arterial pCO2 can be expected to increase by an average of 0.93 kPa (range 0.33–1.33 kPa) above 5.3 kPa to a maximum of 7.5 kPa b. ‘Anion gap’ Conventional equation: [(Naþ þ Kþ)  (Cl þ HCO3)] Equation to correct for hypoalbuminaemia: [(Na þ Kþ)  (Cl þ HCO3)] þ [0.25
(40  albumin)] Upper limit of normal: 15 mmol/l (observed anion gap – 15) / (24 – observed [HCO3–]) c. ‘
anion gap/
plasma HCO3– ratio’ Normal: 1–2

role in the generation of hyponatraemia. ADH is secreted principally in response to hyperosmolality and depletion of circulating volume. The latter is a particularly strong stimulus and operates even in the presence of a low plasma osmolality. Other potent stimuli that are not directly related to osmolar or volume balance—such as nausea—can also stimulate ADH release [2]. The major renal effect of ADH is to promote water reabsorption by increasing water permeability in collecting tubules. Thirst stimulated by volume depletion, often leads to ingestion of water or hypotonic fluid resulting in a further fall of plasma Naþ. In our three patients it was presumably ADH release (induced by nausea and vomiting) coupled with continued ingestion of water that led to hyponatraemia. The management of Patient 3 demonstrates how the misconception of hyponatraemia being an indicator of water overload can be dangerous for patients. In this man, restriction of fluid led to loss of circulating volume, a fall in urine volume and a fall of GFR but did not correct the hyponatraemia. Careful clinical assessment of volume status revealed that he was volume deplete and in need of saline replacement. This patient illustrates the point that plasma Naþ concentration gives no useful information on volume status. Hyponatraemia can be associated with hypo-, eu- or hypervolaemia and should always be interpreted in the context of careful clinical examination. 2. Assessment of complex metabolic acid–base and electrolyte disorders For the analysis of any acid–base disorder it is important to assess whether compensatory mechanisms (metabolic or respiratory) have occurred as expected; also, whether patients have more than just one acid– base disorder. Measurement of arterial blood gases and urinary electrolytes with calculation of the ‘anion gap’ and ‘
anion gap/
plasma HCO3– ratio’ can be useful in unmasking complex acid–base disorders [3]. a. Respiratory response to evolving metabolic alkalosis. Respiratory suppression is the physiological response to metabolic alkalosis (Table 2) [4]. In practice the

maximum pCO2 achievable is 7.5 kPa; more pronounced hypoventilation leads to hypoxia. In Patients 1 and 2 respiratory correction of the metabolic alkalosis failed (arterial blood gases were not measured in Patient 3). Patient 1 with a HCO3– of 37 mmol/l was expected to have a pCO2 of 5.7–7.0 kPa (in fact it was 5.2 kPa). Presumably his restlessness and agitation impaired his ability to hypoventilate. With a HCO3– of 38 mmol/l, the second patient was expected to have a pCO2 of 5.8–7.2 kPa (it was 3.3 kPa). In his case, hypoventilation may have been impossible because of pain. b. ‘Anion gap’. Calculation of the anion gap is usually performed in patients with metabolic acidosis but it is an equally useful measurement in patients with metabolic alkalosis who might also be retaining acids. The anion gap represents those anions other than HCO3– and Cl–, which, although not measured, counterbalance the positively charged cations among which Naþ predominates (Table 2). The upper limit of normal of the anion gap is 15 mmol/l; this is lower than sometimes quoted because of recent changes in laboratory Cl– measurements. As the normal anion gap is largely a result of the charge on albumin, the reference range for the anion gap must be adjusted downwards in patients with hypoalbuminaemia. For every 10 g/l decline in the plasma albumin concentration the reference range for anion gap falls by 2.5 mmol/l. In order to avoid missing an increased concentration of ‘unmeasured’ anions in the presence of hypoalbuminaemia, the equation for anion gap has recently been revised (Table 2) [5]. In patients with metabolic acidosis the anion gap helps to distinguish between anion gap acidosis and normal-anion gap acidosis. Similarly, in patients with metabolic alkalosis calculation of the anion gap gives a clue to whether they are also retaining acids (in addition to being alkalotic). Patient 1 had an anion gap of 20 mmol/l; it was 19 in the second and 24 mmol/l in the third patient, confirming occult retention of acids. Without calculation of the anion gap the presence of two metabolic acid–base disorders would not have been obvious.

Metabolic alkalosis in patients with renal failure –

c. ‘
anion gap/
plasma HCO3 ratio’. In the context of complex metabolic disorders the ‘
anion gap/
plasma HCO3– ratio’ deserves mention. Just as patients with metabolic alkalosis may have occult retention of acids, patients with anion gap acidosis may have occult retention of HCO3–. Normally, when unmeasured anions are retained, the plasma HCO3– falls to the same degree (although in practice, the elevation in the anion gap will usually exceed the fall in the plasma HCO3– concentration slightly). Sometimes, this change in plasma HCO3– is significantly less (or greater) than expected according to the anion gap. The resulting discrepancy between the expected and measured HCO3– concentration is due to an occult metabolic acid–base disorder which can be calculated as the ‘
anion gap/
plasma HCO3– ratio’. For patients with straightforward anion gap acidosis the ratio is 1.0–2.0 (Table 2). A value above 2.0 suggests hidden HCO3– retention. Similarly, a value below 1.0 indicates that there must be HCO3– loss (renal or gastrointestinal) in addition to that consumed by the buffering of retained acid. All three patients had increased plasma HCO3– concentrations and were also retaining acid as a consequence of reduced GFR. Had they not had renal failure and had some of the reclaimed HCO3– not been buffered by the retained acids, the serum HCO3– and pH would have been even higher. The combination of metabolic alkalosis and metabolic acidosis can sometimes prevent a significant change in the ultimate serum pH, so disguising the severity of the acid–base disturbance. d. Urine anions and cations. The concentrations of ions in the urine are a reflection of the systemic environment. There are no ‘normal’ values for urine electrolytes, just expected values in a given clinical setting. Urinary electrolytes can be useful in the assessment of volume depletion or metabolic alkalosis, but some caution is necessary. Sodium. The urine Naþ concentration can help to distinguish between volume depletion (urine Naþ usually 40 mmol/l). However, in patients with chronic renal failure or in those taking diuretics, tubular Naþ reabsorption is impaired so Naþ excretion can be high even when patients are volume deplete. Chloride. Cl– is usually reabsorbed with Naþ throughout the nephron. Measurement of urinary Cl– is useful in the diagnosis of volume depletion and in the differential diagnosis of metabolic alkalosis. Conditions associated with Naþ and volume loss lead to maximally increased renal Cl– conservation and a urinary Cl– concentration of 40 mmol/l (chloride resistant metabolic alkalosis). Although generally useful, the urine Cl– concentration may be misleading in patients with a defect in tubular reabsorption, such as that associated with severe hypokalaemia, where the tubules are unable to maximally conserve Cl– even in the presence of a low plasma Cl– concentration. Potassium. In the steady-state urinary Kþ excretion varies with intake, virtually all regulation taking place in the cortical collecting duct. Provided that renal function is normal, urinary Kþ excretion can increase in response to a high Kþ intake without any significant elevation of the serum Kþ level. In patients with hypokalaemia, measurement of the urinary Kþ is important in distinguishing renal from extra-renal loss. Renal Kþ loss leading to hypokalaemia is most often due to hyperaldosteronism, increased urinary flow of water and Naþ to the distal secretory site (an effect of diuretics) or low Cl– concentrations in the luminal fluid (so that Naþ reabsorption occurs in association with Kþ secretion). In contrast, extra-renal Kþ loss should enhance Kþ reabsorption and lead to urinary Kþ losses of 25 mmol/day even when hypokalaemia is due to extra-renal losses. Hydrogen and pH. The ultimate urine pH is a product of the retention and excretion of substances involved in maintaining a physiological plasma pH. The lowest pH achievable is 4.5. Interestingly, in patients with metabolic alkalosis secondary to depletion of Naþ, Cl– and water, HCO3– reabsorption is increased and urine pH falls to 7.0. 3. Circumstances in which metabolic alkalosis and renal failure occur together The combination of metabolic alkalosis and renal failure is unusual but may occur in patients who are both volume deplete and reclaiming endogenous HCO3– (as in our patients). It can also occur where there is gain of exogenous HCO3– in a patient with renal impairment. Ingestion of calcium-containing preparations. Patients taking large amounts of calcium carbonate have been reported to develop hypercalcaemia (as well as high HCO3–) and as a consequence acute renal failure [6]. Indeed, this risk is higher in patients with pre-existing renal dysfunction in whom urinary excretion of both Ca2þ and HCO3– might be impaired. Patients who are also taking laxatives and diuretics (i.e. patients with anorexia nervosa) are at particular risk.

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Ingestion of antacids. In patients with chronic renal failure taking aluminium or magnesium hydroxide, the hydroxide component buffers gastric Hþ, whereas Mg2þ and Al3þ bind to pancreatic HCO3–. Some of the Mg2þ also binds to other constituents in the intestinal lumen, such as fat and phosphate. As a result some of the secreted pancreatic HCO3– remains unbuffered and is absorbed. As long as renal function is normal this is not a problem. However, in patients with renal failure who are taking cation-exchange resins in addition to Al or Mg hydroxide, some of the Mg2þ or Al3þ binds to the resin, which leaves more HCO3– in the intestinal lumen available for absorption [7]. Ingestion of HCO3– containing preparations. Patients with chronic renal failure taking large amounts of HCO3–, for example as NaHCO3 or baking soda, can become significantly alkalotic. Hypoventilation leading to daytime fatigue and sleepiness has been reported [8]. Treatment with continuous veno-venous haemofiltration (CVVH). Metabolic alkalosis can occur in patients with renal failure undergoing bicarbonate-based CVVH.

Management Patients with metabolic alkalosis are often asymptomatic. On the other hand they may have symptoms related to the underlying derangement (volume depletion, hypokalaemia). Although alkalosis can have potentially adverse consequences (depression of ventilation, compromise of myocardial perfusion, shift of the oxyhaemoglobin dissociation curve to the left), these effects are usually more pronounced in respiratory than in metabolic alkalosis [9]. This is why metabolic alkalosis is often well tolerated provided the underlying disorder is corrected. Full recovery has been reported in a patient with a pH of 7.95 secondary to vomiting in the context of pyloric stenosis [10].

M. E. Ostermann et al.

Teaching point Renal failure can present with electrolyte and acid–base abnormalities extending from life-threatening hyperkalaemia to hypokalaemia, from hypernatraemia to significant hyponatraemia, and from severe acidosis to marked alkalosis. There are two mechanisms by which renal failure and metabolic alkalosis can be associated. (i) Metabolic alkalosis developing in the context of loss of Naþ, Cl–, Hþ and volume by vomiting or diuretic therapy resulting in increased (endogenous) HCO3– reclamation in the tubules, the marked hypovolaemia sometimes leading to renal failure. (ii) Patients with known chronic renal failure ingesting or being treated with a base thereby inducing a metabolic alkalosis. Conflict of interest statement. None declared.

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