Clinical Note

Differential Diagnosis of Glucosuria

In normal individuals, no glucose is detectable in the urine by clinical tests. Mild glucosuria is usually not accompanied by any clinical signs, but if the excretion of glucose becomes significant, the presenting symptom is often complaints of thirst, frequent voiding, and nocturia (waking at night to urinate). Why? When glucose is not completely reabsorbed, it acts like an osmotic diuretic. Glucose has the same molecular size and polar hydroxyl groups as mannitol. Thus, the only reason that glucose is normally reabsorbed is that there is a special transporter for glucose but not for mannitol. The osmotic diuresis produced by hyperglycemia is the cause of the frequent voiding and nocturia, and the thirst is a consequence of persistent water loss in the urine, which can be confirmed by the demonstration of significant glucose in the urine.

The physician must next determine the cause of the glucosuria. Pregnancy may produce an apparent glucosuria (more accurately termed glycosuria) because of the presence of lactose and galactose in the urine. Also, in pregnancy a normal increase in GFR may raise the filtered load of glucose beyond the Tm. Other than pregnancy, Fig. 13 shows there are two potential reasons for the abnormal appearance of glucose in the urine: a plasma glucose concentration exceeding the plasma threshold of 200 mg/dL (which is often indicative of diabetes mellitus) or an abnormality in the glucose transporter such that significant amounts of glucose appear in the urine even at normal plasma concentrations. In the latter case, there may be a decreased renal plasma threshold for glucose, possibly in combination with a decreased Tm. This condition is referred to as renal glucosuria—that is, glucose appearance in the urine due to a renal defect. Most glucosuria is a consequence of elevated plasma glucose concentrations, LCA in although renal glucosuria is a rare hereditary disorder, it should be ruled out as a cause of glucosuria. A diagnosis of diabetes mellitus, on the other hand, can be confirmed by additional clinical laboratory tests.

A further note: Intestinal glucose intolerance and renal glucosuria provide an interesting side light on the genetics of glucose transport abnormalities. Glucose is also absorbed in the small intestine by a Na+ cotransport mechanism, but two different Na+/glucose cotransporters are encoded by separate genes. The first, SGLT1, is the more common and is found in the intestine as well as in the kidney. It has a relatively high affinity for glucose, and an even higher affinity for galactose. Mutations in SGLT1, which are inherited as an autosomal recessive trait, lead to a combination of mild glucosuria (due to increased splay) and an intestinal malabsorption of galactose and glucose, which produces severe and even fatal diarrhea in neonates. A rarer mutation in the second transporter, SGLT2, leads to severe glucosuria because of a reduction in Tm. SGLT2 is a low-affinity, high-capacity transporter that is present in the proximal convoluted tubule and the early proximal straight tubule, whereas SGLT1 is present only in the late proximal straight tubule. Because most of the filtered glucose is reabsorbed in the proximal convoluted tubule, it is not surprising that a defect in SGLT2 leads to severe glucosuria but no significant effects on intestinal sugar absorption.

The gradual rise in the rate of excretion with increasing glucose concentration is referred to as splay. In other words, the renal plasma glucose threshold is lower than the plasma glucose concentration at which maximal reabsorption is achieved. The reasons for this are twofold: (1) Various nephrons have different capacities to reabsorb glucose. Some reach their maximum at relatively low plasma glucose concentrations and others at high concentrations, but glucose will begin to appear in the urine as soon as the nephrons with the lowest capacity are saturated. However, it requires higher filtered loads to saturate all carriers. (2) The transporters are known to demonstrate enzyme-like kinetics; they require high luminal glucose concentrations to be fully saturated, but before they are saturated they let measurable amounts of glucose pass to the urine.

Amino Acids

Separate but similar transporters reabsorb all the organic solutes mentioned previously. Depending on the particular solute, the normal filtered load may or may not exceed the Tm. There are several different transporters for various groups of amino acids such as neutral, acidic, and basic, and subgroups of these. However, the reabsorption of most amino acids is not complete and, depending on the amino acid, 0.5-2% of the filtered load normally appears in the urine. This incomplete reabsorption does not indicate that the Tm for the amino acid transport systems are exceeded but rather that the plasma concentrations of the amino acids exceed their renal plasma thresholds. The filtered loads of the amino acids are normally much less than their Tm but the transport mechanisms exhibit considerable splay, meaning that the renal plasma amino acid thresholds occur at concentrations lower than the plasma concentrations at which the filtered loads exceed the Tm. There are several known congenital abnormalities in the reabsorption of various groups of amino acids that result from a lack of expression or mutation of the gene for specific transporters. This can result in the excretion of large amounts of those amino acids that are normally reabsorbed by the affected transporter.

Organic Acids

Most of the filtered weak organic acids that are useful metabolic substrates are reabsorbed by the proximal tubule. These include acetate, lactate, citrate, oxalate, and mono- and dicarboxylic acids such as the

Krebs cycle intermediates. These organic acids are normally present at very low concentrations in the plasma, resulting in low filtered loads that are completely reabsorbed. However, under abnormal metabolic conditions such as diabetic ketoacidosis [in which the plasma contains high concentrations of acetoacetate and (3-hydroxybutyrate)] and lactic acidosis (in which the plasma has high concentrations of lactate), the filtered load of these particular solutes exceeds the renal plasma threshold and the Tm, resulting in excretion of a large amount of the solutes. This incomplete reabsorption can produce an osmotic diuresis, but has a salutary effect in delivering a large amount of buffer anions to the more distal nephron segments so that more buffered protons (titratable acidity; see Chapter 31) can be excreted in the urine, thus counteracting the acidosis.

Proteins and Peptides

Tm-limited transporters in the proximal tubule also reabsorb proteins and small peptides. Although the glomerular filtration barrier is impermeable to proteins with molecular weights in excess of 60,000 Da, a finite but small amount of albumin still remains in the glomerular filtrate. The concentration of albumin in the filtrate is normally less than 30 mg/dL, that is, less than 1% of the plasma concentration. Nevertheless, if the filtered load of albumin were not reabsorbed, up to (30 mg/dL • 180 L/day) = 54 g

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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