Mitchell L. Halperin

Lesson of the week: Acute hyponatraemia in children admitted to hospital: retrospective analysis of factors contributing to its development and resolution.

Do not infuse a hypotonic solution if the plasma sodium concentration is less than 138 mmoVl

The transtubular potassium concentration in patients with hypokalemia and hyperkalemia.

It is advantageous to make an independent assessment of the potassium (K) secretory process and the luminal flow rate in the renal cortex to evaluate K handling by the kidney during hypokalemia or hyperkalemia. The transtubular potassium concentration gradient (TTKG) is a semiquantitative index of the activity of the K secretory process. The purpose of this study was to define expected values for the TTKG in normal subjects with hypokalemia or following an acute K load. During hypokalemia of non-renal origin, the TTKG was 0.9 +/- 0.2; in contrast, the TTKG was significantly higher during the hypokalemia of hyperaldosteronism, 6.7 +/- 1.3. The TTKG was 11.8 +/- 3.6, 2 hours after normokalemic subjects received 0.2 mg 9 alpha-fludrocortisone (9 alpha-F). To obtain expected values during hyperkalemia, normal subjects ingested 50 mmol potassium chloride; 2 hours later, the TTKG was 13.1 +/- 3.8. Therefore, the expected value for the TTKG must be interpreted relative to the concentration of K in the plasma. Circumstances were also defined where the TTKG is low despite hyperaldosteronism, namely, during a water diuresis and pre-existing hypokalemia.

The urine anion gap: a clinically useful index of ammonium excretion

In patients with a normal plasma anion gap type of metabolic acidosis, knowledge of the rate of ammonium excretion can provide valuable information to determine if there is a renal cause for the disorder. Unfortunately, few hospital biochemistry laboratories offer routine determination of the urine ammonium concentration. Data are presented that demonstrate a direct linear relationship between the urine anion gap (Na+ +K+ - CI−) and the urine ammonium concentration. In a 24-hour urine collection, the relationship is urine ammonium equals - 0.8 (urine anion gap) + 82 (r = 0.97 p less than 0.01). The applications of this index of ammonium excretion are discussed.

Effect of 2-methylcitrate on citrate metabolism: implications for the management of patients with propionic acidemia and methylmalonic aciduria.

Extract: 2-Methylcitrate was tested in vitro on enzymes which interact with citrate and isocitrate. It was found to inhibit citrate synthase, aconitase, the NAD+- and NADP+-linked isocitrate dehydrogenase. This inhibition was competitive in nature except in the case of aconitase, and the Ki for all the enzymes was in the range of 1.5-7.6 mM. Phosphofructokinase was also inhibited by 2-methylcitrate with 50% inhibition achieved at 1 mM. ATP-citrate lyase and acetyl-CoA carboxylase were not inhibited by this compound. 2-Methylcitrate was not a substrate for ATP-citrate lyase. Acetyl-CoA carboxylase was activated by 2-methylcitrate with a Ka of 2.8 mM. The apparent Km (3.3 mM) for 2-methylcitrate for the mitochondrial citrate transporter was about 10-fold higher than the apparent Km (0.26 mM) for citrate. The tricarboxylate carrier can also be inhibited by low concentrations (0.2 mM) of 2-methylcitrate when the concentration of citrate is close to the apparent Km. Accumulation of 2-methylcitrate inside the mitochondrion, therefore, might lead to inhibition of enzymes in the citric acid cycle and thereby contribute to the ketogenesis and hypoglycemia seen under these conditions.Speculation: Treatment of patients with propionic aciduria and methylmalonic aciduria with alkali therapy would be advantageous with respect to the acidemia but also would cause a more rapid exit of 2-methylcitrate from the mitochondrion. Alkalinization with sodium citrate might be even more beneficial if this citrate could enter the liver and allow more rapid removal of 2-methylcitrate and methylmalonate from liver mitochondria since increased cytosolic levels of these intermediates would facilitate more rapid diffusion to the extracellular space and eventual excretion in the urine. This therapy does not exclude the low protein diet and for the vitamin-responsive form of methylmalonic aciduria, B12 treatment.

Tonicity balance, and not electrolyte-free water calculations, more accurately guides therapy for acute changes in natremia

The usual way to decide why hyponatremia or hypernatremia has developed and to plan goals for its therapy is to analyze events in electrolyte-free water (EFW) terms. We shall demonstrate that an EFW balance does not supply this information. Rather, one must calculate mass balances for water and sodium plus potassium separately (a tonicity balance) to understand the basis for the change in natremia and the proper goals for its therapy. These points are illustrated with a clinical example.

Renal tubular acidosis (RTA) : Recognize The Ammonium defect and pHorget the urine pH

To maintain acid-base balance, the kidney must generate new bicarbonate by metabolizing glutamine and excreting ammonium (NH4+). During chronic metabolic acidosis, the kidney should respond by increasing the rate of excretion of NH4+ to 200–300 mmol/day. If the rate of excretion of NH4+ is much lower, the kidney is responsible for causing or perpetuating the chronic metabolic acidosis. Thus, the first step in the assessment of hyperchloraemic metabolic acidosis is to evaluate the rate of excretion of NH4+. It is important to recognize that the urine pH may be misleading when initially assessing the cause of this acidosis, as it does not necessarily reflect the rate of excretion of NH4+. If proximal renal tubular acidosis (RTA) is excluded, low NH4+ excretion disease may be broadly classified into problems of NH4+ production and problems of NH4+ transfer to the urine; the latter being due to either interstitial disease or disorders of hydrogen ion secretion. The measurement of the urine pH at this stage may identify which problem predominates. This approach returns the focus of the investigation of RTA from urine pH to urine NH4+.

The Plasma Potassium Concentration in Metabolic Acidosis: A Re-evaluation

The purpose of these investigations was to describe the mechanisms responsible for the change in the plasma [K] during the development and maintenance of hyperchloremic metabolic acidosis. Acute metabolic acidosis produced by HCI infusion resulted in a prompt rise in the plasma [K], whereas no change was observed during acute respiratory acidosis in the dog. After 3 to 5 days of acidosis due to NH4Cl feeding, dogs became hypokalemic; this fall in the plasma [K] was due largely to increased urine K excretion. Despite hypokalemia, aldosterone levels were not low, and the calculated transtubular [K] gradient was relatively high, suggesting renal aldosterone action. Thus, rather than anticipating hyperkalemia in patients with chronic metabolic acidosis due to a HCl load, the finding of hyperkalemia should suggest that the rate of urinary K excretion is lower than expected (ie, there are low aldosterone levels or failure of the kidney to respond to this hormone).

Chronic lactic acidosis in a patient with cancer: Therapy and metabolic consequences

Lactic acidosis is a life‐threatening disorder in some cases. Treatment should be directed at the primary cause. Sodium bicarbonate should be added if the acidosis is very severe, or if the rate of hydrogen ion production is very rapid and not controlled. In contrast, with moderate degrees of steady state lactic acidosis and poor dietary intake, the risks of therapy with sodium bicarbonate or dichloro‐acetate may actually outweigh the benefits in a cachectic patient unless a dietary glucose and/or protein load is given.

Renal tubular acidosis and osteopetrosis with carbonic anhydrase II deficiency : pathogenesis of impaired acidification

Abstract. Renal tubular acidosis with osteopetrosis is an autosomal recessive disorder due to deficiency of carbonic anhydrase II (CAII). A 3.5-year-old Egyptian boy with osteopetrosis and cerebral calcification had a persistent normal anion gap type of metabolic acidosis (plasma pH 7.26) and a mild degree of hypokalemia. A baseline urine pH was 7.0; ammonium (NH4+) excretion was low at 11 μmol/min per 1.73 m2; fractional excretion of bicarbonate HCO3 (FEHCO3) was high at 9%, when plasma HCO3 was 20 mmol/l; citrate excretion rate was high for the degree of acidosis at 0.35 mmol/mmol creatinine. Intravenous administration of sodium bicarbonate led to a urine pH of 7.6, a FEHCO3 of 14%, a urine-blood PCO2 difference of 7 mmHg, NH4+ excretion fell to close to nil, and citrate excretion remained at 0.38 mmol/mmol creatinine. Intravenous administration of arginine hydrochloride caused the urine pH to fall to 5.8, the FEHCO3 to fall to 0, the NH4+ excretion rate to rise to 43 μmol/min per 1.73 m2, and citrate excretion to fall to <0.01 mmol/mmol creatinine. These results show that our patient had a low rate of NH4+ excretion, a low urine minus blood PCO2 difference in alkaline urine, and a low urinary citrate excretion, but only when he was severely acidotic. He failed to achieve a maximally low urine pH. These findings indicate that his renal acidification mechanisms were impaired in both the proximal and distal tubule, the result of his CAII deficiency.

Factors contributing to the degree of polyuria in a patient with poorly controlled diabetes mellitus.

Polyuria due to a glucose-induced osmotic diuresis is common in patients with hyperglycemia. This diuresis usually abates when the plasma glucose level approaches its renal threshold; the usual time course is less than 8 hours after commencing therapy. A 69-year-old man with non-insulin-dependent diabetes mellitus maintained hyperglycemia (540 mg/dL) and polyuria (4.7 L/24 hr) for 40 hours. Because there was no external supply of glucose, a balance study was conducted between the third and 40th hour after commencing treatment. In this interval, the overall concentration of glucose in the urine was less than 100 mmol/L and the urine osmolality was 378 mOsm/kg H2O. To evaluate the expected composition of the urine during a glucose-induced osmotic diuresis, urine was analyzed in normal rats infused with glucose plus urea and in untreated BB diabetic rats (plasma glucose and urea similar to that in our patient) as well as in 29 patients with hyperglycemia and polyuria. Glucose accounted for 60% of the urinary osmoles in rats and humans. Two subgroups of patients had a much lower urine glucose: one had an impaired concentrating ability (n = 6) and the other had an increased rate of renal glucose reabsorption (n = 5). In conclusion, in polyuria caused by hyperglycemia, the urine glucose should be 300 to 400 mmol/L with normal renal function. In the case we report, both the concentration of glucose and its excretion rate were much lower than expected with steady-state hyperglycemia (540 mg/dL) due to the high rate of excretion of NaCl, a concentrating defect, and excessive renal reabsorption of glucose.