Biological Chemistry - Berezov T. T., Korovkin B. F. 1998

Kidneys and Urine
The Mechanism of Urine Formation

Three main processes take place within the nephron: Glomerular Filtration, tubular reabsorption, and tubular secretion.

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Fig. 18.1. Structure of juxtamedullary (a) and cortical (b) nephrons.

I - cortex; II - medulla; A - outer zone of the medulla; B - inner zone of the medulla; 1 - glomerular capillary tuft; 2 - glomerular capsule (Bowman's capsule); 3 - proximal convoluted tubule; 4 - proximal straight tubule; 5 - descending thin limb of the nephron loop; 6 - ascending thin limb of the nephron loop; 7 - ascending thick limb of the nephron loop; 8 - Distal convoluted tubule; 9 - connecting tubule; 10 - collecting duct; 11 - papillary collecting tubule.

Glomerular filtration. The initial stage of Urine Formation is filtration: the liquid component of Blood is filtered from the capillary tuft into the capsular space within the renal corpuscle. Glomerular filtration is a passive process. Under resting conditions, an adult human receives about ¹/₄ of the Cardiac Output pumped into the aorta by the left ventricle into the renal Arteries. In other words, about 1,300 mL of blood passes through both Kidneys per minute in an adult man, and slightly less in women. The total filtration surface area of the renal glomeruli is approximately 1.5 m². Ultrafiltration of Blood Plasma occurs from the blood capillaries into the lumen of the renal corpuscle capsule in the glomeruli, resulting in the Formation of primary urine (glomerular filtrate), which is virtually protein-free. Normally, Proteins, being colloidal substances, do not pass through the Capillary Wall into the capsular space of the renal glomerulus. In A number of pathological conditions, the permeability of the renal filter membrane increases, leading to an altered ultrafiltrate composition. Increased permeability is the primary cause of proteinuria, notably albuminuria. Under normal conditions, the glomerular filtration rate (GFR) averages 125 mL/min, which is 100 times greater than The production of final urine. The filtration rate is driven by the net filtration pressure, which can be expressed by the following formula:

NFP = CP - (OP + CCSP),

where NFP is the net filtration pressure; CP is the capillary pressure; OP is the oncotic pressure; and CCSP is the capsular (hydrostatic) pressure. Consequently, to sustain the filtration process, the hydrostatic pressure of the blood in the capillaries must exceed the sum of the oncotic and intracapsular pressures. Normally, this value is about 40 hPa (30 mm Hg). Substances that enhance renal blood flow or increase the number of functioning glomeruli (e.g., theobromine, theophylline, juniper berries, bearberry leaves, etc.) exhibit diuretic properties.

Capillary pressure in the kidneys depends not so much on ARTERIAL BLOOD PRESSURE as on the lumen ratio of the afferent and efferent arterioles of the glomerulus. The efferent arteriole is approximately 30% smaller in diameter than the afferent arteriole, and their lumen regulation is primarily mediated by the kinin system. Constriction of the efferent arteriole increases filtration. Conversely, constriction of the afferent arteriole decreases filtration.

The glomerular filtration rate serves as an index of the filtration capacity of the kidneys. If a substance that is filtered in the glomeruli but neither reabsorbed nor secreted by the nephron tubules is introduced into the bloodstream, its clearance is numerically equal to the glomerular filtration rate. The clearance of any compound is conventionally expressed as the volume of plasma (in milliliters) that is completely cleared of a given substance per minute as it passes through the kidneys. The substances most commonly used to determine glomerular filtration are inulin and mannitol. To calculate clearance (e.g., of inulin), the minute diuresis must be multiplied by K_M/K_cr (The ratio of the concentrations of the given substance in the urine and blood plasma):

where C is clearance; K_M is the concentration of the given compound in the urine; K_cr is the concentration in blood plasma; and V is the urine volume per minute in mL. For instance, calculating normal inulin clearance yields a glomerular filtration rate of 100–125 mL/min*.

Reabsorption and secretion. The daily volume of ultrafiltrate exceeds the total body fluid volume by a factor of 3. Naturally, as primary urine flows along the renal tubules, it returns the majority of its constituents—especially Water—back into the blood. Only 1% of the fluid filtered by the glomeruli is converted into urine.

* It is generally accepted that in a normal human with a body weight of 70 kg, the glomerular filtration rate is 125 mL/min, or 180 L/day.

The tubules reabsorb 99% of water, sodium, chlorine, bicarbonate, Amino Acids, 93% of potassium, 45% of urea, etc. Through reabsorption, primary urine is transformed into secondary, or definitive, urine, which then flows into the renal calyces and pelvis, and via the Ureters reaches the Urinary Bladder.

The functional role of individual renal tubules in urine formation varies. The Cells of the proximal segment of the nephron reabsorb glucose, amino acids, Vitamins, and electrolytes that have entered the filtrate; ⁶/₇ of the fluid making up the primary urine is also reabsorbed in the proximal tubules. The water of the primary urine is partially reabsorbed in the distal tubules. These same tubules effect additional sodium reabsorption, and can secrete potassium, ammonium, hydrogen ions, and others into the nephron lumen.

At present, the MOLECULAR MECHANISMS OF substance reabsorption and secretion by renal tubular cells have been largely elucidated. For example, it has been established that during reabsorption, sodium passively enters The Cell from the tubular lumen, travels through it to the basal Plasma Membrane, and is pumped into the extracellular fluid via the "sodium pump." Up to 80% of ATP energy in renal tubular cells is consumed by the sodium pump. Water reabsorption in the proximal segment occurs passively as a consequence of active sodium reabsorption; in this case, water "follows" sodium. Incidentally, water reabsorption in the distal segment occurs independently of sodium ion reabsorption, a process regulated by the antidiuretic hormone.

Unlike sodium, potassium can undergo not only reabsorption but also secretion. During secretion, potassium moves from the intercellular fluid across the basal plasma membrane into the tubular cell via the action of the "sodium-potassium pump," and is subsequently excreted passively into the nephron lumen through the apical cell membrane. Secretion, much like reabsorption, is an active process tied to the function of tubular cells. The mechanisms of secretion mirror those of reabsorption, except that all processes operate in the reverse direction—from the blood to the tubule.

Substances that are not only filtered through the glomeruli but also reabsorbed or secreted in the tubules have a clearance that reflects overall renal performance (mixed clearance). Depending on whether filtration is combined with reabsorption or secretion, Two Types of mixed clearance are distinguished: filtration-reabsorption and filtration-secretion clearance. The value of mixed filtration-reabsorption clearance is lower than the glomerular clearance because a portion of the substance is reabsorbed from the primary urine in the tubules. This value is smaller the more efficient tubular reabsorption is. For instance, in the case of normal glucose, it is equal to 0. Maximum glucose reabsorption in the tubules is 350 mg/min. The maximum tubular reabsorptive capacity is denoted as T_m (transport maximum). Occasionally, patients with Kidney disease are encountered who, despite high blood plasma glucose levels, do not excrete glucose in their urine because the filtered glucose load is below the T_m value. Conversely, in congenital disorders, renal glucosuria may be caused by a reduced T_m value.

Fig. 18.2. Regulation of reabsorption in the kidney (diagram according to A.P. Zilber). Explanations in the text.

For urea, the mixed filtration-reabsorption clearance value is 70. This means that out of every 125 mL of ultrafiltrate or blood plasma, 70 mL are completely cleared of urea per minute. In other words, a specific amount of urea—namely, the amount contained in 55 mL of ultrafiltrate or plasma—is reabsorbed.

The value of mixed filtration-secretion clearance can exceed glomerular clearance because additional amounts of a substance secreted in the tubules are added to the primary urine. This clearance is greater when tubular secretion is more robust. The clearance of certain substances secreted by the tubules (e.g., Diodrast, p-aminohippuric acid) is so high that it practically approaches the renal plasma flow rate (the volume of blood passing through the kidneys per minute). Thus, the clearance of these substances can be used to determine blood flow.

The reabsorption and secretion of various substances are regulated by the Central Nervous system and hormonal factors. For example, severe pain stimuli or negative emotions can trigger anuria (cessation of urine formation). Water reabsorption increases under the Influence of the antidiuretic hormone vasopressin. Aldosterone increases sodium reabsorption in the tubules, and consequently water reabsorption as well. Calcium and phosphate reabsorption is modulated by parathyroid hormone. Parathormone stimulates phosphate excretion, whereas vitamin D inhibits it.

The regulation of sodium and water reabsorption in the kidney is illustrated in Fig. 18.2. When Blood supply to the renal glomeruli is insufficient, accompanied by slight stretching of the arteriolar walls (decreased pressure), the juxtaglomerular apparatus (JGA) cells located in the walls of the arterioles are stimulated. They begin to intensively secrete renin, a proteolytic enzyme that catalyzes the initial stage of angiotensin formation. The substrate for the enzymatic action of renin is angiotensinogen (a glycoprotein), which belongs to the a₂-globulins and is present in blood plasma and Lymph.

Renin cleaves a peptide bond in the angiotensinogen molecule formed by two leucine residues, thereby releasing the decapeptide angiotensin I, which exhibits negligible biological activity in a near-neutral environment.

It is believed that under METABOLISM/18.html">The Influence of a special peptidase found in blood plasma and Tissues—angiotensin-converting enzyme (dipeptidyl carboxypeptidase I)—angiotensin I is converted into the octapeptide angiotensin II. The Lungs are the primary site for this conversion.

In 1963, V.N. Orekhovich et al. isolated a proteolytic enzyme from bovine kidneys that differed in its catalytic Specificity from all tissue proteases known at the time. This enzyme cleaves dipeptides from the carboxyl terminus of various Peptides, with the exception of peptide bonds formed involving the imino group of Proline. The enzyme was named carboxycathepsin. Its optimal activity is observed in a nearly neutral medium; it is activated by Cl^- ions and classified as a metalloenzyme. V.N. Orekhovich hypothesized that carboxycathepsin is the very enzyme responsible for converting angiotensin I (Asp—Arg—Val—Tyr—Ile—His—Pro—Phe—His—Leu) into angiotensin II by cleaving the His—Leu dipeptide from angiotensin I. Given the broad specificity of carboxycathepsin, V.N. Orekhovich and co-workers suggested that this enzyme might also be involved in the inactivation of bradykinin, an antagonist of angiotensin. Work published in 1969–1970 confirmed these propositions. At the same time, it was demonstrated that The conversion of angiotensin I into angiotensin II occurs not only in lung tissue but also in the kidneys (it is now known that carboxycathepsin is present in virtually all tissues).

Unlike its precursor (angiotensin I), angiotensin II exhibits extremely high biological activity. Specifically, angiotensin II stimulates the adrenal cortex to secrete aldosterone, which enhances sodium reabsorption in the renal tubules, accompanied by water reabsorption. As a result, circulating blood volume increases, arteriolar pressure rises, and systemic balance is restored.

When blood filling in the atria and, presumably, the carotid vessels decreases, volume receptors (volumoreceptores) are triggered; their signals are transmitted to the Hypothalamus, where antidiuretic hormone (ADH, or vasopressin) is produced. Via the hypophyseal portal system, this hormone reaches the neurohypophysis (posterior pituitary), where it is concentrated and released into the bloodstream. The primary target of ADH action appears to be the walls of the distal renal tubules, where it increases hyaluronidase activity. By depolymerizing hyaluronic acid, hyaluronidase increases the permeability of the tubular walls. Water passively diffuses across cell membranes driven by the osmotic gradient between the hyperosmotic body fluid and hypoosmotic urine; in other words, ADH regulates the reabsorption of free water. Thus, ADH lowers the osmotic pressure in body tissues, whereas aldosterone raises it.

The kidneys also play a crucial role as an endocrine (internal secretion) organ. As noted earlier, renin is produced in the cells of the juxtaglomerular apparatus (JGA), located near the vascular pole of the glomerulus. Renin is known to influence systemic blood pressure via the angiotensin pathway. A number of researchers believe that excessive renin production is a major factor in the Pathogenesis of certain forms of Hypertension.

The kidneys also produce Erythropoietin, which stimulates Bone Marrow hematopoiesis (erythropoiesis). Erythropoietin is a proteinaceous substance. Its renal Biosynthesis is significantly upregulated during various stress conditions, such as Hypoxia, Hemorrhage, and Shock. In recent years, it has also been established that the kidneys synthesize Prostaglandins, which are capable of altering the sensitivity of renal cells to the Introduction/43.html">Action of Certain Hormones.