Renal Physiology Flashcards
Buffers
The kidneys aid in acid–base balance regulation via excretion of hydrogen ions (H+) in urine. In the proximal convoluted tubule, secretion of H+ occurs via passive sodium–hydrogen exchange down the concentration gradient (a passive electroneutral process). In contrast, H+ secretion in distal convoluted tubules and collecting ducts occurs via active hydrogen extrusion by proton ATPase against the concentration gradient (an active electrogenic process). Urinary buffers are essential for H+ excretion to avoid significant reduction in urinary pH. The bicarbonate buffer system acts mainly at the proximal tubules, whereas the phosphate and ammonia buffer systems act at distal tubules and collecting ducts. Many factors can affect hydrogen excretion (e.g. aldosterone). Aldosterone acts on the alpha type of intercalated cells in the distal convoluted tubules and collecting duct, and results in absorption of potassium and excretion of hydrogen into urine.
There is disagreement in physiology textbooks about which buffering system is more important in the kidney. Some say phosphate, others, ammonia. Depending on the physiological state, both play an important role. The pK of the bicarbonate system is 6.1, the phosphate system 6.8 and ammonia system 9.0.
Large amounts of bicarbonate are filtered and reabsorbed. This reabsorption is essential in maintaining acid–base balance and 80% occurs in the proximal convoluted tubule. Potassium is 90% reabsorbed in the proximal convoluted tubule. Aldosterone increases the reabsorption of sodium and the excretion of potassium.
The acid–base balance is a multisystemic and complex process that permits blood and other bodily fluids to regulate a narrow pH range. The kidneys play a significant role in the regulation of acid–base balance. H+ ions are secreted and then buffered by HCO3 in the proximal tubule. It is estimated that approximately 50–80 mmol of H+ ions are excreted every day under normal conditions. However, they are secreted into the distal tubule in increased amounts in the presence of aldosterone.
The urinary buffer systems are the body’s first line of defence to maintain a physiological pH. Buffers can reversibly bind to, or release, free H+. Common urinary buffer systems include bicarbonate, phosphate and ammonia. Each of these buffers has its specific pKa. The pKa of the bicarbonate system is 6.1. The pKa of the phosphate system is 6.8, and the pKa of the ammonia system is 9.0 (the highest).
Water reabsorption
The proximal tubule has a very high permeability to water. Very small differences in osmolality (less than 1 mOsm/L) is enough to drive water reabsorption of large quantities of water, normally about 65% of the filtered water. The descending limb of the loop of Henle is more permeable to water than the ascending limb. The distal convoluted tubule is very low and similar to the ascending loop of Henle. The water permeability of the collecting duct system, both cortical and medullary portions, is under the control of antidiuretic hormone. The inner medullary collecting duct has a finite permeability even in the absence of ADH. The outer medullary and cortical collecting duct have an extremely low permeability without ADH.
The ionic gradients that facilitate secondary transport have been created across the cell membrane of the nephron by ATPases that enable the secretion of reabsorption of several solutes. If this primary active transport didn’t occur, the secondary transport would not occur either. Sodium entry into tubular cells is a passive process. The sodium/potassium ATPase pump extrudes sodium against electrical and chemical gradients. There is no active reabsorption of water in the proximal tubule. Water is reabsorbed osmotically following solute reabsorption. 90% of filtered bicarbonate and 60%–70% of filtered water is reabsorbed in the proximal tubule.
Aldosterone
Aldosterone is produced by the zona glomerulosa of the adrenal cortex. Its effects are to increase retention of sodium and water and to increase intravascular volume. It mainly acts on the collecting ducts (and to some extent, the distal convoluted tubules) of the kidneys, where it acts on nuclear mineralocorticoid receptors to increase the number of basolateral sodium/potassium channels. More sodium is pumped out of the cells in exchange for potassium in the extracellular fluid, and this sets up a concentration gradient which causes the movement of sodium out of the tubular lumen and into the tubule cells across the apical membrane. Thus, sodium is retained. Aldosterone also increases the number of epithelial sodium channels (ENaCs) in the collecting ducts and the colon, increasing the permeability of the apical membrane to sodium. Other effects include secretion of potassium and protons (H+) into the tubular fluid, increasing loss of these two ions, and retention of sodium in exchange for potassium in the sweat and salivary glands.
Aldosterone secretion is stimulated by hyperkalaemia, a rise in angiotensin II or ACTH, increased discharge of renal nerves or decreased blood pressure (detected by atrial stretch receptors). Increased secretion is seen in pregnancy, trauma, burns and blood loss. Reduction of dietary sodium will increase aldosterone secretion. Glucocorticoids can exert significant mineralocorticoid activity, not the other way around.
Reabsorption of sodium in the collecting ducts is via the Na⁺ channel which is regulated by aldosterone. Reabsorption of sodium in the thick ascending limb and the proximal tubule is primarily through passive paracellular movement and is not regulated by aldosterone. Reabsorption in the distal tubule is mostly via the Na+/Cl- co-transporter and this is also not regulated by aldosterone.
Carbonic anyhydrases
Carbonic anhydrases (CAs) are enzymes that catalyse the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid (i.e. bicarbonate and hydrogen ions). They play an important role in the HCl production process by the parietal cells. In the nephron, especially in the proximal tubules, carbonic anhydrase plays a vital role, since 85% of filtered HCO3- is reabsorbed there. In the proximal tubule, filtered H+ and HCO3- will become H2CO3, and CA will catalyse a reaction of H2CO3 into H2O and CO2. In the cells, CA will catalyse both back to H2CO3. In cells of the distal nephron, CA catalyses the formation of H2CO3 from H2O and CO2. They will split into H+ and HCO3-. CA doesn’t have a big contribution inside the distal nephron lumen because those cells are capable of absorbing and secreting HCO3- and Cl+ from and into the lumen without converting them into H2O and CO2.
Carbonic anhydrase inhibitors limit the secretion of hydrogen ions which causes less reabsorption of sodium and bicarbonate in the proximal tubule. Water follows the sodium which results in the diuretic effect. The major site of action is the proximal convoluted tubule. Carbonic anhydrase is also present in the cells of the thick ascending limb of the loop of Henle and in the collecting duct but the diuretic action is due to the effects in the proximal tubule. This is because one-third of the reabsorption of sodium ions in the proximal tubule occurs in exchange for hydrogen ions through the sodium-hydrogen antiporter and thus depends on the activity of carbonic anhydrase
Natriuretic peptides
Natriuretic peptides are peptide hormones released by several organs, including the brain and heart, to maintain blood pressure, blood volume and vascular resistance. Natriuretic peptides maintain blood pressure via several mechanisms. They improve glomerular filtration rate, cause diuresis, increase sodium excretion (natriuresis), inhibit renin release (via reducing aldosterone and angiotensin II), reduce arterial and venous blood pressure, reduce pulmonary capillary wedge pressure and increase capillary permeability and systemic vasodilation.
Atrial natriuretic peptide, combined with afferent arteriolar dilation and efferent arteriolar vasoconstriction, increases the net filtration pressure. It is a potent vasodilator, improving renal blood flow. It is released from the atrial myocytes in response to atrial stretch.
Renin is fundamental to the renin–angiotensin–aldosterone system (RAAS). The RAAS is a mechanism used to maintain our blood pressure. Renin is produced by renal juxtaglomerular cells in response to low renal blood pressure. The secretion of renin is directly inhibited by atrial natriuretic factor/atrial natriuretic peptide. Atrial natriuretic peptide (ANP) is a hormone that is synthesized, stored, and released by atrial myocytes. ANP directly inhibits renin release by juxtaglomerular cells.
Vasopressin
After significant haemorrhage and subsequent vasopressin secretion:
S. Serum sodium may be low because R. the osmotic response curve is shifted left, favouring water retention over sodium.
Osmoreceptors are mostly located in the tissues surrounding the third ventricle and have neural connections to the hypothalamic cells which release ADH. Antidiuretic hormone will increase the permeability of the collecting ducts to water. Baroreceptors detect changes in arterial pressure and via neural connection to the hypothalamus, alter the ADH secretion. Extracellular fluid osmoregulation is purely achieved by modulating the volume of extracellular fluid free water and does not involve active modulation of solutes.
Vasopressin secretion is regulated via several mechanisms. Hypovolemia leads to a reduction in atrial pressure. Low atrial pressure results in reduced firing of specialized stretch receptors localized within the atrial wall and the walls of large veins (i.e. vena cava and pulmonary vessels). This is transmitted to the medulla (nucleus tractus solitarius), then to the hypothalamus which increases vasopressin secretion. Hypovolemia is the overriding stimulus to vasopressin secretion. Increased osmolality detected by hypothalamic osmoreceptors results in increased vasopressor release. Angiotensin II increases vasopressin secretion by binding to vasopressin receptors on the circumventricular organs around the third and fourth ventricles of the brain.
Antidiuretic hormone (ADH), or vasopressin, is a hormone that decreases diuresis. ADH has two main functions: to increase water reabsorption in the kidney and constrict arterioles to increase blood pressure. The constriction in renal arterioles will decrease the blood flow in the renal medulla. ADH has three main effects. First, to increase the water permeability of initial and cortical collecting tubules (ICT & CCT), as well as the outer and inner medullary collecting ducts (OMCD & IMCD) in the kidney. Second, to increase the permeability of the inner medullary portion of the collecting duct to urea. Third, to increase sodium absorption across the ascending loop of Henle.
Vasopressin is a hormone of the posterior pituitary that is secreted in response to high serum osmolarity (normal serum osmolarity in adults: 285–295 mOsm/kg) and also in response to hypovolemia, for example, in the state of acute severe blood loss. Vasopressin has receptors in the anterior pituitary gland where it has a role in the neuroregulation of the secretion of adrenocorticotropin (ACTH), beta-endorphin, and prolactin (PRL).
Vasopressin, or antidiuretic hormone, is a peptide hormone secreted from the pituitary gland. Its main function is regulation of body fluids’ tonicity. Changes in osmolality or volume of the plasma or extracellular volume are the main stimuli of vasopressin secretion. Increased plasma or extracellular fluid volume inhibits vasopressin secretion. Vomiting results in loss of body fluids and consequently stimulation of vasopressin secretion. Other factors affecting vasopressin secretion include central nervous system diseases, hypoglycaemia, angiotensin II and certain medications. Alcohol, lithium and norepinephrine reduce vasopressin secretion. Angiotensin II, nicotine, opiates, hypoglycaemia and pain stimulate vasopressin secretion.
Renal drugs
For some drugs, although the size of the maintenance dose is reduced it is important to give a loading dose if an immediate effect is required. This is because it takes about five times the half-life of the drug to achieve steady-state plasma concentrations. It can take many doses for the reduced dosage to achieve a therapeutic plasma concentration.
Digoxin and lithium may accumulate in renal failure without appropriate dose adjustment and both should be therapeutically monitored. Polydipsia and polyuria are signs of lithium toxicity. Metformin dose should be reduced in renal failure to reduce the incidence of lactic acidosis.
In patients with conditions that cause renal hypoperfusion, prostaglandin production may be increased to maintain adequate renal blood flow. The adverse renal effects associated with NSAIDs are mainly mediated via inhibition of prostaglandin-induced vasodilation and can result in reduced renal blood flow.
ATPase
The sodium–potassium ATPase pump on the basolateral membrane of the tubular cell pumps 3 sodium ions into the interstitial fluid and 2 potassium ions into the tubular cell, thus producing a net positive gradient outside the cell. Glucose is reabsorbed by co-transport with sodium across the apical membrane of epithelial cells. It then diffuses out of the cells into the peritubular interstitium. Water reabsorption occurs due to osmotic pressure differences.
Tubuloglomerular feedback
In renal physiology, tubuloglomerular feedback (TGF) regulates tubular flow through detecting and correcting renal GFR. If the macula densa (MD) cells detect that chloride concentration is above the target value, the feedback will constrict the afferent arteriole to decrease glomerular flow. This is achieved by the binding of adenosine to A1 receptors. Angiotensin II does constrict both afferent and efferent arterioles, though the efferent by a greater degree.
Raised anion gap metabolic acidosis
Metabolic acidosis with a raised anion gap occurs due to the reduction of the level of cations rather than sodium and potassium. The common mnemonic for metabolic acidosis with raised anion gap is “CAT MUDPILES”. This stands for: cyanide poisoning, carbon monoxide poisoning, congenital heart failure, aminoglycoside toxicity, toluene or theophylline toxicity, methanol toxicity, uraemia, diabetic ketoacidosis, paracetamol toxicity, paraldehyde toxicity, iron toxicity, isoniazid toxicity, inborn errors of metabolism, lactic acidosis, ethanol or ethylene glycol intoxication, and salicylates toxicity.
Indications for dialysis
The main indications for dialysis in acute renal failure are life-threatening conditions such as metabolic acidosis, electrolyte abnormality (e.g. hyperkalaemia), intoxication, overload (e.g. pulmonary oedema) or uraemia complications (e.g. encephalopathy, seizures, pericarditis, or GIT bleeding). The mnemonic for these indications is “AEIOU”. Metabolic acidosis is an indication for dialysis when it is intractable or when correction by bicarbonate is not possible (e.g. it may result in fluid overload). Hyperkalaemia is an indication for dialysis when the level of K exceeds 6.5 or 7 mmol/L or when the ECG changes result. Intoxication that necessitates dialysis includes salicylates, lithium, isopropranolol, magnesium, and ethylene glycol (“SLIME”).
Diuretics
Diuretics act via several mechanisms at the kidney. Carbonic anhydrase inhibitors inhibit water, sodium and bicarbonate reabsorption at the proximal convoluted tubule. Loop diuretics inhibit the sodium–potassium–chloride cotransporter at the thick ascending limb of the loop of Henle. Thiazides inhibit the sodium–chloride transporter at the proximal distal convoluted tubules. Potassium-sparing diuretics inhibit aldosterone-sensitive potassium pump at the distal part of the distal convoluted tubules and the collecting ducts, leading to potassium and hydrogen reabsorption, and water and sodium excretion.
Carbonic anhydrase inhibitors are a type of diuretic that act on renal tubules by inhibiting the action of carbonic anhydrase. Under normal physiological conditions, H2CO3 is transported from the lumen to the renal tubules’ cells, and converted to water and CO2 via carbonic anhydrase IV. Water and CO2 are then transformed to H+ and HCO3-. H+ is secreted to the tubular fluid (via Na+/H+ exchange) and HCO3- is reabsorbed into the blood. Upon the inhibition of carbonic anhydrase, reabsorption of bicarbonate is impaired, leading to lower Na+/H+ exchange, and diuresis.
Erythropoietin
Erythropoietin is a glycoprotein hormone that is essential for the production of red blood cells. It is secreted mainly by the kidneys, but extrarenal tissues also participate in erythropoietin secretion (e.g. liver, brain and uterus). Erythropoietin secretion is stimulated by several factors such as hypoxia, alkalosis, beta-adrenergic stimulants, adenosine, androgens and cobalt salts. Hypoxia is the major stimulant of erythropoietin secretion. Alkalosis that occurs with acclimatization to high altitude also stimulates erythropoietin secretion.
Renal insufficiency
Renal insufficiency results in inadequate renal function. During renal insufficiencies, such as in chronic kidney disease or acute kidney disease, the glomerular filtration rate is decreased. Renin secretion will be stimulated when the sodium level in the distal tubules is decreased, in this case, due to a low GFR. Renin will then start the renin–angiotensin–aldosterone system. Angiotensin II then stimulates the brain to produce antidiuretic hormone. ADH increases water reabsorption and consequently urea reabsorption in the nephron.
Glucose reabsoprtion
The maximum tubular transport of glucose is not exceeded at normal plasma glucose concentrations. Glucose is cotransported with sodium in the proximal convoluted tubule. There is heterogenicity in the ability of nephrons to reabsorb the glucose load. Above plasma glucose concentrations of 11 mmol/L (200 mg/dL), nephrons with the lowest capacity for glucose reabsorption reach their limit and glucose begins to be excreted. As plasma glucose continues to rise, more and more nephrons reach their limits. Above plasma glucose concentrations of 22 mmol/L (400 mg/dL) no nephrons can reabsorb their entire filtered load. The maximum tubular transport rate for glucose is 380 mg/min.
Diabetic nephropathy
90% of diabetic nephropathy occurs in those with type 2 diabetes compared to type 1. Thickening of the glomerular and tubular basement membrane can be detected at an early stage and is diagnostic of diabetic nephropathy. Microalbuminuria and proteinuria indicate that lesions are far advanced and reductions in GFR may progress rapidly. Changes in tubular function take place early in diabetes and are related to glycaemic control.
