Introduction
Glycosuria is a term that defines the presence of reducing sugars in the urine, such as glucose, galactose, lactose, fructose, etc. Glucosuria connotes the presence of glucose in the urine and is the most frequent type of glycosuria, which is the focus of this review. It happens when the glomerulus filters more glucose than the proximal tubule can reabsorb. In normal individuals, glucosuria can be up to 0.25 mg/ml. More than 0.25 mg/ml in random fresh urine is considered increased glucosuria and can be due to elevated plasma glucose, renal glucose absorption impairment, or both.[1][2] Physiologic glucosuria is a condition where individuals consume an excessive amount of carbohydrates.
Small amounts of glucose in the urine are considered normal, but glucosuria usually refers to pathologic conditions where the amounts of urine glucose are more than 25 mg/dl in random fresh urine. The renal tubule normally reabsorbs almost all (leaving less than 25 mg/dl urine glucose) in the normal glomerular filtrate. When the glucose filtrated by the glomerular exceeds the capacity of the renal tubule to absorb it, the loss of balance occurs. It can happen due to elevated plasma glucose, as in diabetes mellitus, or when the ability of the tubule to absorb glucose is impaired, eg, Fanconi syndrome with impairment in the absorption of phosphate, amino acids, or isolated glucosuria as an inherited disorder termed Familial Renal glucosuria.
Issues of Concern
One limitation of urine glucose testing is the ability of most commercial semiquantitative urine tests to detect glucose in the urine only until it reaches a level of 50 to 250 mg/dl. Also, errors can stem from an altered renal threshold. There are known variations in the renal threshold among individuals that can lead to significantly misleading data.
Organ Systems Involved
The renal tubule plays a significant role in glucose reabsorption. If the plasma glucose rises, renal tubular glucose reabsorption increases linearly until it reaches its maximum tubular resorptive capacity. The capacity of the proximal tubule to reabsorb glucose to prevent its passing to the urine is known as the renal threshold.[2][3] Membrane proteins responsible for glucose reabsorption in the proximal convoluted tubule (PCT) from the glomerular filtrate are sodium-glucose cotransporters SGLT1 and SGLT2, located in the apical membrane of proximal tubular cells, and GLUT2, a uniporter, located in the basolateral membrane. The first stage is glucose being transported across the apical membrane by SGLTs. These transporters bind to Na before binding to glucose; the electrochemical sodium gradient generated by the Na/K-ATPase drives the symporter activity, leading to glucose accumulation in the epithelium. It causes a glucose concentration gradient between the cell and plasma, driving to the second stage, a passive glucose exit through the basolateral membranes via GLUT2. SGLT1 functions in segments 1 and 2 of the PCT, and SGLT1 functions in segment 3.[4][5]
Mechanism
The renal system filters approximately 180 g of glucose daily in healthy individuals. The glucose entering the tubular system is reabsorbed along with the PCT segments. In diabetic patients, as a result of the increase in plasma glucose, the filtered glucose exceeds the capacity of the tubular system and results in glucosuria. Most glucose uptake of over 90% occurs in the proximal tubule, mediated by SGLT2, a low-affinity/high-capacity transporter. The proximal tubule's distal parts reabsorb the remaining glucose via the high-affinity/low-capacity SGLT1.[6] Kidneys play a significant role in maintaining glucose homeostasis and preventing an individual from developing hypoglycemia. Maintaining glucose homeostasis by the kidney includes glucose reabsorption in the PCT, gluconeogenesis, and the clearance of important hormones such as insulin.[7]
Related Testing
In a patient with glucosuria, diabetes is confirmed by measuring fasting or random plasma glucose and glycated hemoglobin (HbA1c). In Fanconi syndrome, a generalized defect of the PCT, there is hypophosphatemia with metabolic acidosis (due to bicarbonate wasting) in the presence of phosphaturia, aminoaciduria, and glucosuria.
Pathophysiology
Glucose filters through glomeruli, which is reabsorbed by the proximal renal tubule. Less than 0.1% of glucose is not reabsorbed by the kidneys (less than 0.25 mg/ml), and most of the standard tests do not detect this level. The causes of glucosuria can be grouped under 2 classes: the inability of PCT to reabsorb glucose and an increase in glucose concentration in the circulating blood.[8] Defects in the PCT, either primary or secondary, can result in glucosuria. Examples include pregnancy, Fanconi syndrome, and acute tubular necrosis. In a normal condition, when the plasma glucose level increases, renal tubular glucose reabsorption rises linearly until its maximum is reached (ranges from 0.9 to 2.0 mmol/min).[2] As mentioned, SGLT1, SGLT2, and GLUT2 are the membrane proteins responsible for glucose reabsorption; mutations in 1 of these membrane proteins cause glucosuria. A mutation in SGLT1 is associated with glucose-galactose malabsorption, a mutation in SGLT2 is associated with familial renal glucosuria, and a mutation in GLUT2 is associated with Fanconi-Bickel syndrome.[5]
Glucosuria can also occur in increased glucose concentration in the circulating blood. This phenomenon can also occur in normal individuals who consume excess carbohydrates, known as ‘alimentary glycosuria.’ It also presents in diabetic patients.[8] In diabetes mellitus, glomeruli can be damaged with increasing duration, resulting in albuminuria and a decrease in the glomerular filtration rate. In diabetic patients, the kidneys are more susceptible to the effects of hyperglycemia; many of the kidney cells cannot decrease glucose transport rates and prevent intercellular hyperglycemia in an increased glucose concentration state.[7]
Some conditions are known to raise the renal threshold for glucose, such as age, renal disease (diabetic glomerulosclerosis), heart failure, and chronic hyperglycemia. Also, some conditions are known to decrease it, such as hyperthyroidism, pregnancy, fever, and exercise. Normal aging and glomerulosclerosis in long-standing diabetes are associated with an increased renal threshold for glucose, and because of that, urine glucose testing becomes of little value, if any. Several substances are also known for their capability to cause glucosuria, such as chloride, iodide, bromide, and nitrate of sodium. Glucosuria can also occur when there is a lack of oxygenation of the PCT.[8]
Clinical Significance
A study comparing the urine and plasma response 60 minutes after a 50 g oral glucose challenge for patients with potential gestational diabetes mellitus screening showed that post-load glycosuria is a poor predictor of gestational diabetes mellitus, pre-eclampsia, and newborn size at birth. It has a limited clinical benefit.[9] In diabetes mellitus type 2, there appears to be a maladaptive upregulation of SGLT2 that contributes to hyperglycemia. A significant advance in diabetes treatment is the ushering in of the SGLT2 inhibitor class of drugs. These drugs have been demonstrated to improve glycemic control with weight loss by inducing glycosuria with calorie loss. They also promote natriuresis, which results in a decrease in blood pressure. However, they can increase the risk of genital and urinary tract infections and dehydration.[10]
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Disclosure: Maria Nataly Liman declares no relevant financial relationships with ineligible companies.
Disclosure: Ishwarlal Jialal declares no relevant financial relationships with ineligible companies.
