Osmolality measurements in plasma and urine

The renal tubules perform a bewildering array of functions. However, in practice, the urine osmolality serves as a proxy or general marker of tubular function. This is because of all the tubular functions, the one most frequently affected by disease is the ability to concentrate the urine. If the tubules and collecting ducts are working efficiently, and if AVP is present, they will be able to reabsorb water. Just how well can be assessed by measuring urine concentration. This is conveniently done by determining the osmolality, and then comparing this to the plasma. If the urine osmolality is 600 mmol/kg or more, tubular function is usually regarded as intact. When the urine osmolality does not differ greatly from plasma (urine : plasma osmolality ratio ~1), the renal tubules are not reabsorbing water.

The water deprivation test

The causes of polyuria are summarized in Table 15.1. Renal tubular dysfunction is one of several causes of disordered water homeostasis. Where measurement of baseline urine osmolality is inconclusive, formal water deprivation may be indicated. The normal physiological response to water deprivation is water retention, which minimizes the rise in plasma osmolality that would otherwise be observed. The body achieves this water retention by means of AVP, the action of which on the renal tubules may be inferred from a rising urine osmolality. In practice, if the urine osmolality rises to 600 mmol/kg or more in response to water deprivation, diabetes insipidus is effectively excluded. A flat urine osmolality response is characteristically seen in diabetes insipidus where the hormone AVP is lacking. In compulsive water drinkers, a normal (rising) response is usually seen.

It should be noted that the water deprivation test is unpleasant for the patient. It is also potentially dangerous if there is severe inability to retain water. The test must be terminated if more than 3 L of urine is passed or there is a fall of >3% in body weight. An alternative approach, which is sometimes used first (or instead of), is to fluid restrict overnight (8 pm–10 am) and measure the osmolality of urine voided in the morning. If the urine osmolality fails to rise in response to water deprivation, desmopressin (DDAVP), a synthetic analogue of AVP, is administered. The subsequent urine osmolality response allows central diabetes insipidus to be distinguished from nephrogenic diabetes insipidus. In the former, the renal tubules respond normally to the DDAVP and the urine osmolality rises. Nephrogenic diabetes insipidus is characterized by failure of the tubules to respond; the urine osmolality response remains flat.

Urine pH and the acid load test

Urine pH measurements may be useful as a first step in the diagnosis of Renal tubular acidosis (RTA), which typically gives rise to hyperchloraemic metabolic acidosis. RTA may be characterized as follows:

The first step in making a diagnosis of RTA is to establish the presence of a persistent unexplained metabolic acidosis. If RTA is suspected after other diagnoses have been considered and excluded, a fresh urine specimen should be collected for measurement of urine pH. (If the specimen is not fresh, urease-splitting bacteria may alkalinize the specimen post collection giving a falsely high urine pH.) The normal response to a metabolic acidosis is to increase acid excretion, and a urine pH of less than 5.3 makes diagnosis of RTA unlikely as the cause of the acidosis. Where the urine pH is not convincingly acidic, an acid load test may be indicated. This involves administering ammonium chloride (which makes the blood more acidic) and measuring the urine pH in serial samples collected hourly for about 8 hours afterwards. Rarely, the excretion rates of titratable acid and ammonium ion, and the serum bicarbonate concentration, may have to be measured in order to make the diagnosis. This test should not be performed in patients who are already severely acidotic or who have liver disease.

In addition, because ammonium chloride can give rise to abdominal pain and vomiting, it is preferable to perform the furosemide test first. Furosemide reduces the reabsorption of chloride and sodium from the loop of Henle, resulting in an increased delivery of sodium ions to the distal tubule. Normally, the sodium is reabsorbed in exchange for hydrogen ions, thereby resulting in production of an acidic urine. In either test, failure to produce at least one urine sample with a pH <5.3 is consistent with RTA.

Specific proteinuria

Mention has already been made of protein in urine as an indicator of leaky glomeruli (p. 29). β₂-microglobulin and α₁-microglobulin are small proteins that are filtered at the glomeruli and are usually reabsorbed by the tubular cells. An increased concentration of these proteins in urine is a sensitive indicator of renal tubular cell damage. Proteinuria is discussed in detail on pages 34–35.

Glycosuria

The presence of glucose in urine when blood glucose is normal usually reflects the inability of the tubules to reabsorb glucose because of a specific tubular lesion. Here, the renal threshold (the capacity for the tubules to reabsorb the substance in question) has been reached. This is called renal glycosuria and is a benign condition. Glycosuria can also present in association with other disorders of tubular function – the Fanconi syndrome.

Aminoaciduria

Normally, amino acids in the glomerular filtrate are reabsorbed in the proximal tubules. They may be present in urine in excessive amount either because the plasma concentration exceeds the renal threshold, or because there is specific failure of normal tubular reabsorptive mechanisms. The latter may occur in the inherited metabolic disorder cystinuria, or more commonly because of acquired renal tubular damage.

The Fanconi syndrome

The Fanconi syndrome is a term used to describe the occurrence of generalized tubular defects such as renal tubular acidosis, aminoaciduria and tubular proteinuria. It can occur as a result of heavy metal poisoning, or from the effects of toxins and inherited metabolic diseases such as cystinosis.

Renal stones

Renal stones (calculi) produce severe pain and discomfort, and are common causes of obstruction in the urinary tract (Fig 15.1). Chemical analysis of renal stones is important in the investigation of why they have formed. Types of stone include: