The major function of the tubule is the selective reabsorption or excretion of water and various cations and anions to keep the volume and electrolyte composition of body fluid normal. The active reabsorption from the glomerular filtrate of compounds such as glucose and amino acids also takes place. Within the normal range of blood concentrations these substances are completely reabsorbed by the proximal tubule. However, if blood levels are elevated above the normal range, the amount filtered (filtered load = GFR x plasma concentration) may exceed the maximal absorptive capacity of the tubule and the compound ‘spills over’ into the urine. Examples of this occur with hyperglycaemia in diabetes mellitus or elevated plasma phenylalanine in phenylketonuria.
Conversely, inherited or acquired defects in tubular function may lead to incomplete absorption of a normal filtered load, with loss of the compound in the urine (a lowered ‘renal threshold’). This is seen in renal glycosuria, in which there is a genetically determined defect in tubular reabsorption of glucose. It is diagnosed by demonstrating glycosuria in the presence of normal blood glucose levels. Inherited or acquired defects in the tubular reabsorption of amino acids, phosphate, sodium, potassium and calcium also occur, either singly or in combination. Examples include cystinuria and the Fanconi syndrome . Tubular defects in the reabsorption of water (nephrogenic diabetes insipidus) or. bicarbonate (proximal renal tubular acidosis) and defective acidification of the urine (distal renal tubular acidosis) are dealt. Investigation of tubular function in clinical practice.
Proximal tubular function
Five tests of proximal tubular function are employed in clinical practice: measurement of serum potassium and serum phosphorus concentrations, and detection of glycosuria, generalized aminoaciduria and ‘tubular’ proteinuria.
Hypokalaemia in the face of a normal or increased urinary potassium excretion (>40 mmol in 24 hours) is indicative of proximal tubular failure of potassium reabsorption. Unless other explanations exist such as treatment with thiazide diuretics or hyperaldosteronism, the defect can be assumed to lie in the proximal tubule. Similarly, hypophosphataemia may be attributed to a proximal tubular abnormality, provided alternative explanations, such as the use of gut phosphorus binders and primary hyperparathyroidism, can be ruled out. Glycosuria in the absence of hyperglycaemia and generalized aminoaciduria are also indicative of failure of proximal tubular reabsorption of glucose and amino acids, respectively. Proteins derived from tubular cells, such as f32- microglobulin, are reabsorbed in the proximal nephron.
If proteinuria is present, and urine electrophoresis shows the characteristic ‘tubular’ as distinct from ‘glomerular’ pattern (i.e. albumin) a proximal tubular defect is demonstrated.
Distal tubular function
Two tests of distal tubular function are commonly applied in clinical practice: measurement of urinary concentrating capacity in response to water deprivation, and measurement of urinary acidification.
The juxtaglomerular apparatus is made up of specialized arteriolar smooth muscle cells that are sited on the afferent glomerular arteriole as it enters the glomerulus. These cells secrete renin, which converts angietensinogen in blood to angiotensin I. Renin release is controlled by:
• Pressure changes in the afferent arteriole
• Sympathetic tone
• Chloride and osmotic concentration in the distal tubule via the macula densa
• Local prostaglandin release
Angiotensin II is generated from angiotensin I by angiotensin- converting enzyme (ACE). Angiotensin II is both a vasoconstrictor and the most important stimulus for the release of aldosterone by the adrenal cortex. It also modifies intrarenal blood flow.
Erythropoietin is a glycoprotein produced principally by the kidney and is the major stimulus for erythropoiesis. Loss of renal substance, with decreased erythropoietin production, results in a normochromic, normocytic anaemia. Conversely, erythropoietin secretion may be increased, with resultant polycythaemia, in patients with polycystic renal disease, benign renal cysts or renal cell carcinoma.
Recombinant human erythropoietin has now been biosynthesized and is available for clinical use, particularly in patients with renal failure.
Prostaglandin E2 is the primary prostaglandin produced by the kidney and is known to be a powerful vasodilator agent. Its precise role in regulating intrarenal blood flow and its interaction with renin release remains unclear. It may also have some direct or indirect role in the renal handling of sodium and water.
The role of this system is not fully understood but it probably also plays a part in the control of the distribution of renal blood flow and in salt and water excretion.
There is considerable evidence that atrial tissue contains a group of pep tides that contribute to the regulation of sodium balance-atrial natriuretic peptides (ANP). Intravenous infusion of one of these is followed by a marked natriuresis with a rise in GFR and a fall in blood pressure. These pep tides appear to oppose the reninangiotensin system in four ways: reduced renin secretion, reduced aldosterone secretion, opposition to the action of angiotensin II and to the sodium-retaining action of aldosterone on the renal tubule. Their role in the long-term regulation of sodium balance and blood pressure in humans remains to be clarified.
Endopeptidase inhibitors are becoming available and show therapeutic promise as potent new diuretic agents. Vitamin D metabolism.
Naturally occurring vitamin D requires hydroxylation in the liver and again by a Ie-hydroxylase enzyme in the kidney to produce the powerfully metabolically active 1,25-dihydroxycholecalciferol (1,25-(OH)2D3)’ Reduced l o-hydroxylase activity in diseased kidneys results in relative deficiency of 1,25-(OH)2D3′ As a result, gastrointestinal calcium absorption is reduced and bone mineralization impaired. Receptors for 1,25-(OH)2D3 exist in the parathyroid glands and reduced occupancy of the receptors by the vitamin alters the set-point for release of parathyroid hormone (PTH) in response to a given decrement in plasma calcium concentration. Gut calcium malabsorption, which induces a tendency to hypocalcaemia, and relative lack of 1,25-(OH)2D3 contribute therefore to the hyperparathyroidism seen regularly in patients with renal impairment, even of modest degree.
Protein and polypeptide metabolism
It is clear that the kidney is a major site for the catabolism of many small molecular-weight proteins and polypeptides, including many hormones such as insulin, PTH and calcitonin. In renal failure the metabolic clearance of these substances is reduced and their half-life is prolonged. This accounts, for example, for the reduced insulin
requirements of diabetic patients as their renal function declines.