Diffusion

Diffusion is the movement of substances down their electrochemical gradient. It is a ‘passive’ process, as it does not require any metabolic energy or carrier molecules.

Facilitated diffusion

Like diffusion, this is also passive movement of substances along their electrochemical gradient, but it relies on a carrier molecule to transport substances across the membrane. Consequently, it is much faster than diffusion.

Primary active transport

This is an energy-dependent process in which substances cross cell membranes against their concentration and electrochemical gradients. It involves the hydrolysis of adenosine triphosphate (ATP), which provides chemical energy for the transport mechanism.

The most important active transporter is the Na⁺/K⁺ ATPase pump, which is found on the basal and basolateral membranes of tubular cells. It is involved in the active transport of Na⁺ from intracellular to extracellular spaces, allowing the nephron to reabsorb over 99% of the filtered Na⁺. This maintains a low Na⁺ concentration and a high K⁺ concentration in the cell (Fig. 3.2). The other primary active transporters on the tubular cell membrane are:

Fig. 3.2 Mechanisms of active transport in the proximal tubule cells.

The ATP molecule is part of the protein structure in the primary active transporters. Energy is derived from the hydrolysis of the terminal phosphate bond of the ATP molecule to form adenosine diphosphate (ADP) and phosphate (P_i) (Fig. 3.3).

Fig. 3.3 Na⁺/K⁺ ATPase pump found in the basal membrane of the cells. It drives secondary active transport by maintaining a low Na⁺ concentration in the cells.

Secondary active transport

This process uses the energy produced from another process for transporting molecules (i.e. the transport of the solutes is coupled). The most important example of this mechanism involves the Na⁺/K⁺ ATPase pump as the driving force for the secretion and reabsorption of other solutes in which the energy is provided by the Na⁺ gradient.

The Na⁺/K⁺ ATPase pump creates an ionic gradient across the cell membrane, which allows the energy produced from the diffusion of Na⁺ into the cell as it moves along its electrochemical gradient to be used for active transport (i.e. against their electrochemical gradients) of other solutes.

Substances can move in two directions by the following processes:

These processes are carried out by specific carrier proteins embedded in the cell membrane called transporters.

Ion channels

These are protein pores found on the epithelial cell membranes. They allow rapid transport of ions into the cell. Channels that are specific for Na⁺, K⁺ and Cl^– are found on the apical membrane of all the cells lining the nephron. Although transport through these channels is very fast (10⁶–10⁸ ions/s) there are only about 100 channels per cell, compared with the slower (100 ions/s) but more numerous active transporters (10⁷ transporters per cell).

Definition

A buffer is a mixture of a weak acid (HA) and a conjugate base. It undergoes minimal pH change when either an acid or a base is added to it:

It can also be a mixture of a weak base (BH) and conjugate acid:

For example, if there is an increase in H⁺, the equations above shift to the left so that the extra H⁺ combines with the buffer and the H⁺ concentration in the body falls.

Bicarbonate buffer system

The bicarbonate buffer system is important in all body fluids. CO₂ and H₂O combine to form carbonic acid (H₂CO₃) in the presence of the enzyme carbonic anhydrase (CA). The H₂CO₃ then dissociates spontaneously to form bicarbonate ions () and H⁺:

CO₂ concentration is regulated by the lungs and concentration is regulated by the kidneys. Therefore, pH regulation depends equally on both these organs. Substituting this equation in the Henderson–Hasselbalch equation, we get:

The acid dissociation constant, pK_a, of the /pCO₂ system = 6.1.

[H₂CO₃] is determined by dissolved CO₂: [H₂CO₃] = 0.23 × pCO₂ (0.23 is the CO₂ solubility coefficient at 37 °C; pCO₂ is the pressure of CO₂ in the lungs in kPa)

This is the key equation that can be used to relate pH, [] and pCO₂. Normal values are:

reabsorption by the proximal tubule

On the apical membrane Na⁺ reabsorption down its concentration gradient drives H⁺ secretion into the lumen. H⁺ combines with ions to form H₂CO₃ (carbonic acid). Carbonic anhydrase (CA) on the brush border of the cells catalyses the dissociation of H₂CO₃ to H₂O + CO₂ within the tubular lumen. Both H₂O and CO₂ diffuse freely into the cell, where they re-form H₂CO₃, this process being catalysed by intracellular CA. and Na⁺ are actively transported out of the cell across the basolateral membrane. H⁺ is secreted out of the cell into the tubular lumen and recycled to allow continuation of this cycle (Fig. 3.5). CA inhibitors suppress H⁺ secretion, leading to a fall in Na⁺ and absorption, and thus act as a weak diuretic.

Fig. 3.5 reabsorption in the proximal tubule cells. Secreted H⁺ combines with to form carbonic acid. This is broken down by carbonic anhydrase (CA) in the brush border to CO₂ and H₂O, which diffuse freely into the cell. The process is reversed inside the cell to re-form .

reabsorption by the distal tubule

Only a small amount of can be reabsorbed by the intercalated cells of the distal tubule. The Na⁺gradient is insufficient so H⁺ is pumped into the lumen using H⁺-ATPase. Little CO₂ is produced in the lumen to enter the cell so CO₂ from the cell's own metabolism is used to create , which is moved into the plasma.

Conversion of alkaline phosphate to acid phosphate – luminal buffer

Alkaline phosphate Na₂HPO₄ and acid phosphate NaH₂PO₄ are present in the plasma in the ratio of 4:1. Both are filtered at the glomerulus. Alkaline phosphate is converted to acid phosphate, mainly in the distal tubule but also in the proximal tubule. This generates Na⁺ and binds H⁺ in the lumen. This feeds the system already described, generating for the plasma (Fig. 3.5). The buffer is more effective at a lower pH.

Ammonia secretion – luminal buffer

Deamination of glutamine in the proximal tubule yields ammonium ions () and . This is secreted into the lumen and the enters the plasma (Fig. 3.6). Fifty percent of secreted into the proximal tubule is actually reabsorbed by the thick ascending limb of the loop of Henle and accumulates in the cells of the medullary interstitium (Fig. 3.7).

Fig. 3.6 Renal secretion and handling of NH₃.

Fig. 3.7 Handling of NH₃ and by nephrons.

Acidosis increases excretion because:

Respiratory acidosis

The causes of respiratory acidosis are:

ABG results show pCO₂ > 6.0 kPa and decreased pH. Clinically, the respiratory system cannot remove enough CO₂, so CO₂ increases together with pCO₂. Therefore the following equation is shifted to the right:

This results in elevated [H⁺] and []. The extra H⁺ results in increased H⁺ secretion and increased reabsorption. This restores pH, acting as a compensatory response. The acid–base disturbance is not corrected because the pCO₂ and [] are still high. Correction requires hyperventilation to decrease pCO₂.

Respiratory alkalosis

The causes of respiratory alkalosis are:

The ABG results show a pCO₂ < 4.7 kPa and an elevated pH. Clinically too much CO₂ is removed by the respiratory system. Therefore the following equation is shifted to the left:

This causes [H⁺] to fall and hence an increased pH and a slight decrease in [HCO₃-]. The compensatory response involves reduced H⁺ secretion, increased HCO₃- excretion and decreased HCO₃- reabsorption, thus restoring pH. Correction involves rectification of the underlying respiratory defect.

Metabolic acidosis

The causes of metabolic acidosis are:

ABG results show a normal pCO₂ and decreased pH. There is an increase in [H⁺]. Therefore, the following equation is shifted to the left:

Consequently, [] falls as it is used to ‘mop up’ the excess H⁺ ions.

The decreased pH stimulates respiration to cause hyperventilation. This respiratory compensation decreases pCO₂ and returns the pH to normal, although falls further. The fall in hinders the compensatory response of the kidneys, which is to increase reabsorption and produce titratable acid.

The anion gap represents the difference between plasma anions and cations and represents unaccounted anions (e.g. phosphates, ketones, lactate):

The normal range is 8–16 mmol/L. Changes in the anion gap help define the cause of a metabolic acidosis. Metabolic acidosis due to diarrhoea or renal tubular acidosis does not alter the anion gap. Acidosis caused by renal failure, diabetes or lactic acidosis increases the anion gap.

Metabolic alkalosis

The causes of metabolic alkalosis are:

ABG results show a normal pCO₂ and an elevated pH because of a rise in plasma []. Therefore, the following equation is shifted to the right:

Consequently, [] is increased.

Respiratory compensation occurs. The increase in pH acts on chemoreceptors, which reduce the ventilatory rate and so increase pCO₂. The equation therefore shifts to the right and the pH returns to normal, but increases further. This hinders correction.

Fig. 3.9 summarizes acid–base disturbances.

Fig. 3.9 Summary of acid–base disturbances and compensatory mechanisms.

Parathyroid hormone

PTH is a polypeptide secreted by the parathyroid gland when there is a fall in plasma Ca^2 +. also affects PTH release, both directly and secondary to changes in Ca^2 + levels. Fig 3.10 illustrates mechanisms of Ca^2 + and homeostasis. Vitamin D can also affect PTH release because it alters sensitivity of the parathyroid gland to Ca^2 +.

Fig. 3.10 Mechanisms of Ca^2 + and phosphate homoeostasis. PTH, parathyroid hormone.

Vitamin D

Vitamin D refers to a group of closely related sterols obtained from the diet or by the action of ultraviolet light on certain provitamins. It is metabolized to 1,25-dihydroxycholecalciferol by the liver and kidney. This causes an increase in Ca^2 + and by:

Calcitonin

Calcitonin is a peptide produced by the parafollicular cells of the thyroid. It has the opposite effect to PTH, reducing Ca^2 + release from bone and causing a decrease in ECF Ca^2 + concentration.

Ca^2 + transport by the kidney

Only ionized Ca^2 + is filtered through the glomerulus (approximately 50% plasma Ca^2 +). Reabsorption proceeds as follows:

Phosphate

Phosphate () salts are essential for the structure of bones and teeth. Eighty per cent of the body's content is in bone and 20% is in the intracellular fluid (ICF). It is filtered easily at the glomerulus; 80% is then reabsorbed in the proximal tubule and the remaining 20% is excreted in urine.

The kidneys play an important role in the regulation of . Reabsorption of occurs with Na⁺ ions (two Na⁺ for every ion) at the apical membrane of the tubular cells. Any increase in plasma concentration (> 1.2 mmol/L) leads to an increase in the amount filtered and excreted, which is how plasma levels are controlled. A fall in GFR will result in increased plasma concentration. This hyperphosphataemia is a common cause of itching in CKD.

is an important urinary buffer for H⁺ and its excretion is influenced by:

Hypocalcaemia

Decreased Ca^2 + results in neuromuscular excitability leading to tetany with convulsions, hand and feet muscle cramps and cardiac arrhythmias.

Causes are:

Treatment is with oral or intravenous calcium and patients with chronic kidney disease will benefit from alfacalcidol, a vitamin D analogue.

Hypercalcaemia

Causes of hypercalcaemia are:

Symptoms and signs of hypercalcaemia are:

Treatment is of the underlying cause, with fluids for rehydration and bisphosphonates.

Transport of potassium

Approximately 70% of K⁺ is reabsorbed in the proximal tubule, mostly by passive paracellular reabsorption across the tight junctions between tubular cells. K⁺ can be secreted or reabsorbed in the nephron. Excretion of the filtered K⁺ can vary from 1% to 110% depending on:

K⁺ reabsorption occurs mainly in the thick ascending loop of Henle by co-transport of Na⁺/K⁺/Cl^– on the luminal membrane. Reabsorption of K⁺ occurs in the distal tubule during severe dietary depletion of K⁺.

Potassium (K⁺) is the main intracellular cation. The intracellular and extracellular [K⁺] is very important in the function of excitable tissues (e.g. nerves and muscles) as it determines the resting potentials of these tissues. Therefore, a constant [K⁺] is critical for survival. Concentration is as follows:

K⁺ transport by the kidney

K⁺ is filtered freely in the glomerulus. The proximal tubule reabsorbs 80–90%:

In the distal tubule:

Changes in the distal tubular lumen also influence the rate of K⁺ secretion. Fig. 3.11 illustrates K⁺ transport in the kidney.

Fig. 3.11 Potassium transport in the kidney.

ADH stimulates the secretion of K⁺ by the collecting ducts by enhancing Na⁺ reabsorption. Aldosterone increases K⁺ secretion. Increased plasma K⁺ concentration stimulates aldosterone production by the adrenal cortex, so plasma aldosterone concentration rises. This in turn increases K⁺ secretion and therefore K⁺ excretion.

Hypokalaemia

Causes of a decreased K⁺ concentration are:

Hypokalaemia is asymptomatic until K⁺ concentration falls below 2–2.5 mmol/L. The low K⁺ concentration results in a decreased resting potential (more negative) so the nerve and muscle cells become hyperpolarized. This means that cells are less sensitive to depolarizing stimuli and therefore less excitable, so fewer action potentials are generated and paralysis ensues. Clinical effects of hypokalaemia are:

Treatment involves treating the underlying cause, and calculated oral or intravenous administration of potassium salt may be required.

Hyperkalaemia

Hyperkalaemia can result from:

Clinical features

Very similarly to hypokalaemia, it may be asymptomatic or cause muscle weakness. Importantly it can cause cardiac arrhythmias by influencing myocardial excitability (Fig. 3.12).

Fig. 3.12 ECG changes in hyperkalaemia. There are peaked T waves, absent P waves and broad QRS complexes. Eventually the pattern looks sinusoidal and can cause arrhythmias.

Renal handling of Mg^2 +

Ionized Mg^2 + is filtered at the glomerulus. 15% is reabsorbed in the proximal tubule and 60% in the thick ascending loop of Henle.

The T_m for Mg^2 + absorption is equal to the concentration of Mg^2 + filtered. Therefore, an increase in Mg^2 + results in increased filtering, which therefore exceeds the T_m, resulting in increased excretion.

There is intrinsic regulation by cells of the thick ascending loop of Henle – if Mg^2 + decreases, cell transport of Mg^2 + increases. PTH increases reabsorption of Mg^2 + in the thick ascending loop of Henle.

Hypomagnesaemia

Causes are:

Clinical features are non-specific. A fall in Mg^2 + is followed by a decreased Ca^2 +, but the mechanism for this is unknown.

Glucose

Normal plasma glucose concentration is 2.5–5.5 mmol/L. Usually, 0.2–0.5 mmol of glucose is filtered every minute. An increase in the plasma glucose concentration results in a proportional increase in the amount of glucose filtered. Virtually all filtered glucose is reabsorbed in the proximal tubule, unless the amount of filtered glucose exceeds the resorptive capacity of the cells. Glucose is transported into the proximal tubule cells by symport against its concentration gradient. It is driven by the energy released from the transport of Na⁺ down its electrochemical gradient because the Na⁺/K⁺ ATPase pump on the basolateral membrane maintains a low Na⁺ concentration and negative potential within the cell (Fig. 3.13). This is an example of secondary active transport. The transport ratio is:

Fig. 3.13 Active transport of glucose in the proximal tubule (pars convoluta). This occurs against a concentration gradient.

T_m is the maximum tubular resorptive capacity for a solute (i.e. the point of saturation for the carriers), and this value can be calculated for glucose. There is a limited number of Na⁺/glucose carrier molecules, so glucose reabsorption is T_m limited. Fig. 3.14 shows that the lowest renal threshold of glucose is at a plasma glucose concentration of 10 mmol/L. At this level, filtered glucose will begin to be excreted in the urine (glycosuria). If the plasma glucose concentration increases further even those nephrons with highest resorptive capacity become saturated, and glucose is excreted. Urinary glucose increases in parallel with plasma glucose.

Fig. 3.14 Relation between plasma concentration, filtration, reabsorption and excretion of glucose (glomerular filtration rate = 100 mL/min). T_m is exceeded in nephrons with plasma glucose > 10 mmol/L and for all nephrons when plasma glucose > 20 mmol/L (nephron heterogeneity gives rise to ‘splay’ on the curve).

Glycosuria occurs if:

Amino acids

Amino acids are the basic unit of proteins and are absorbed constantly from the gut. The plasma concentration of amino acids is 2.5–3.5 mmol/L. They are small molecules that filter easily through the glomerulus, with most reabsorption occurring in the proximal tubule. The transport is a secondary active process (by symport with Na⁺) and is driven by Na⁺/K⁺ ATPase, as with glucose. There are at least five different transport systems coupled with Na⁺ and these are responsible for the movement of different types of amino acid residue. This is a T_m-limited process, so amino aciduria results if the reabsorption mechanism is saturated or if the reabsorption mechanism is defective (e.g. in Fanconi's syndrome).

Urea

Urea is the end-product of protein metabolism, which occurs in the liver. Urea is transported to the kidneys via the blood. It is a small molecule that is filtered freely at the glomerulus. The normal plasma concentration of urea is 2.5–7.5 mmol/L. Urea concentration increases in the filtrate as a result of Na⁺, Cl^– and water reabsorption. This allows passive reabsorption of 40–50% of urea along its concentration gradient; 50–60% of the filtered urea is excreted in the urine. ADH increases the permeability of the inner medullary collecting ducts to urea. The distal tubule and the outer medullary ducts are impermeable to urea.

Sulphate

The normal plasma concentration of sulphate is 1–1.5 mmol/L. Sulphate reabsorption is T_m limited and this is an important mechanism in regulating its plasma concentration.

Thin descending limb

The thin descending limb is lined by thin, flat cells that have minimal cytoplasmic specialization. It is permeable to water, Na⁺ and Cl^–. Water is reabsorbed passively down a concentration gradient caused by the hypertonic interstitium of the medulla. NaCl moves into the lumen and water moves out of the lumen into the interstitium, allowing the tubular fluid to come into equilibrium with the interstitium.

Thin ascending limb

The thin ascending limb has a similar structure to the thin descending limb but is impermeable to water and has minimal NaCl transport occurring within the cells.

Thick ascending limb

The thick ascending limb consists of large cells with mitochondria, which generate energy for the active transport of Na⁺ (20% of filtered Na⁺ is reabsorbed in the loop of Henle) and Cl^– ions from the tubular fluid into the interstitium. As a result, the filtrate becomes progressively diluted (this part of the tubule is impermeable to water). There is co-transport (symport) of Na⁺, Cl^– and K⁺ (in the ratio 1:2:1 – so the pump is electrochemically neutral) on the apical membrane. This transport process is driven by the Na⁺ gradient across the cell membrane. Na⁺ is removed from the cell by the Na⁺/K⁺ ATPase pump on the basolateral membrane and K⁺ and Cl^– diffuse passively out as a result of Na⁺ movement; however, most of the K⁺ leaks back into the cell and tubular lumen. Overall, NaCl accumulates in the medullary interstitium. Fig. 3.15 shows the transport processes in the loop of Henle; the inset shows the transport of ions in the cells in the thick ascending limb of the loop of Henle.

Fig. 3.15 (A) Transport processes in the loop of Henle. (B) Transport of ions in the thick ascending limb.

Role of vasa recta and urea

The countercurrent mechanism requires an environment in which the waste products and water are cleared without disturbing the solutes that maintain the medullary hypertonicity. This exchange is provided by the vasa recta capillary system derived from the efferent arterioles of the longer juxtaglomerular nephrons. It does not require metabolic energy.

The capillaries have a hairpin arrangement surrounding the loop of Henle and are permeable to water and solutes. As the descending vessels pass through the medulla they absorb solutes such as Na⁺, urea and Cl^–. Water moves along its osmotic gradient out of the capillaries. At the tip of the loop the capillary blood has the same osmolality as the interstitium, and an osmotic equilibrium is reached. The capillaries that ascend with the corresponding loop of Henle contain very viscous concentrated blood as a result of the earlier loss of water from the capillaries. A consequent increase in oncotic pressure because of the concentration of plasma proteins favours the movement of water back into the blood vessel from the interstitium. However, most of the NaCl is retained in the interstitium to maintain the hypertonic medullary environment.

The collecting tubules pass through the cortex and medulla. They consist of two functionally different parts:

Both parts are impermeable to NaCl. The permeability to water and urea (only in the inner medullary collecting ducts) varies according to the presence of ADH. ADH increases the permeability to water and thus controls the concentration of the urine produced. ADH acts to increase water uptake in the cortical collecting tubules resulting in the production of a more concentrated urine.

The water reabsorbed in the medullary part of the collecting ducts is taken up by the vasa recta to prevent dilution of the medullary interstitium, which is crucial to the function of the distal nephron and the concentration of urine.

Although about 20% of the initial glomerular filtrate enters the distal nephron, only 5% enters the medullary collecting ducts. This is mainly due to water reabsorption in the cortical tubules.

Fig. 3.17 shows the countercurrent exchanger and the collecting duct as it passes through the medulla.

Fig. 3.17 Countercurrent exchanger as it passes through the medulla. The descending vessels of the vasa recta lose water as they pass through the hypertonic medulla. As a result of increasing oncotic pressure in the ascending vessels, water is reabsorbed passively back into the blood vessels from the interstitium as water uptake occurs in the collecting ducts under the influence of antidiuretic hormone (ADH). Because of this uptake of water by the vasa recta, the high osmolality of the medullary interstitium is maintained and this hypertonic environment allows continued concentration of the tubular fluid in the collecting duct.

Although urea is impermeable in the cortical collecting tubules, ADH affects the permeability of urea within the medullary cortical tubules. Urea, along with NaCl, helps maintain medullary hypertonicity as follows

A high-protein diet increases the amount of urea in the blood for excretion as a result of increased metabolism. Consequently, there is more urea in the medullary interstitium, resulting in a higher urine osmolality.

Concepts of osmolality

The normal plasma osmolality (P_osm) is 285–295 mOsmol/kg H₂O. This is strictly regulated and an increase or decrease of 3 mOsmol/kg H₂O will stimulate the body's osmolality regulation mechanism.

Osmoreceptors

Osmoreceptors detect changes in the plasma osmolality and are located in the supraoptic and paraventricular areas of the anterior hypothalamus. Their blood supply is the internal carotid artery. They have two functions:

Fig. 3.18 illustrates the role of ADH in maintaining osmolality.

Fig. 3.18 Role of antidiuretic hormone (ADH) in maintaining osmolality. The lateral preoptic area of the hypothalamus regulates thirst. The supraoptic and paraventricular nuclei are involved in ADH release from the posterior pituitary. ECF, extracellular fluid.

Sensitivity of osmoreceptors to osmotic changes caused by different solutes

Na⁺ and other associated anions are the main constituents that determine plasma osmolality. Water loss alters the Na⁺ concentration. Other solutes without the addition or loss of water can also change the osmolality. Not all solutes stimulate the osmoreceptors to the same degree – this depends on how easily they can cross the cell membrane (i.e. their ability to cause cellular dehydration).

Synthesis and storage

ADH is a peptide hormone synthesized in the supraoptic nucleus of the hypothalamus as a large precursor molecule. It is transported to the posterior pituitary gland, where its synthesis is completed and it is stored until release (Fig. 3.19).

Fig. 3.19 Synthesis and storage of antidiuretic hormone (ADH). CNS, central nervous system.

Release

A rise in plasma osmolality triggers ADH release. Action potentials in the neurons from the hypothalamus (which contains ADH) depolarize the axon membrane, resulting in Ca^2 + influx, fusion of secretory granules with the axon membrane and the release of ADH and neurophysin into the bloodstream.

Cellular actions

ADH has two functions:

Aquaporins

When present on the peritubular side of the collecting tubule cell (Fig. 3.20), ADH causes intracellular water channels (aquaporins) to fuse with the luminal membrane. There are at present 11 known members of the mammalian aquaporin gene family which encode for proteins involved in the transport of water or small molecules. In the kidney, aquaporin 2 (AQP2) resides in intracellular vesicles and is trafficked to the luminal membrane on stimulation. ADH triggers this by binding to V₂ receptors on the basal membrane. These are G-protein-coupled receptors, which on activation cause fusion of the inactive vesicles with the luminal membrane. The relation between urine osmolality (mOsmol/kg) and plasma ADH concentration is shown in Fig. 3.21.

Fig. 3.20 Actions of antidiuretic hormone (ADH) in the collecting tubule. AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase; AQP2, aquaporin 2 water channel.

Fig. 3.21 Urine osmolality in relation to plasma antidiuretic hormone (ADH) concentration.

(From Berne RM, Levy MN, 1996. Physiology, 3rd edn. Mosby Year Book.)

Drugs affecting ADH release

Drugs can:

Water clearance and reabsorption

Dehydration leads to a rise in plasma osmolality. Thus, the kidneys reabsorb ‘solute-free’ water from the tubules. This produces a more dilute plasma and a concentrated urine.

Excessive water intake lowers plasma osmolality. Thus, the kidneys excrete ‘solute-free’ water from the tubules, producing dilute urine. Dilute urine has a lower osmolality than plasma, concentrated urine has a higher osmolality than plasma, isotonic urine has the same osmolality as plasma. The osmotic clearance (C_osm) (Fig. 3.22) is the rate at which osmotically active substances are cleared from the plasma. If urine is isotonic, C_osm = urine flow.

Fig. 3.22 Osmotic clearance. ADH, antidiuretic hormone.

Effect of solute output on urine volume

The concentrating ability of the kidneys is limited, with a maximum urinary osmolality of 1400 mOsmol/kg. Thus, the amount of urine excreted per day depends on the:

At maximum ADH concentration, large amounts of solutes can still cause a dieresis.

Mannitol is an osmotic diuretic that cannot be reabsorbed. It alters the kidney's concentrating ability and produces isotonic urine. In diabetes mellitus, the excess blood glucose causes an osmotic diuresis.

Adrenal steroids and urinary dilution

Adrenal insufficiency leads to impaired water excretion (i.e. mineralocorticoid and/or glucocorticoid deficiency):

Causes

The causes of hyponatraemia are:

The diagnostic approach to hyponatraemia is shown in Fig. 3.23.

Fig. 3.23 Diagnostic approach to hyponatraemia. ECF, extracellular fluid; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TURP, transurethral resection of the prostate.

Syndrome of inappropriate ADH secretion (SIADH)

Occasionally ADH is secreted inappropriately by the pituitary or other areas in the body. Causes are given in Fig. 3.24. Signs and symptoms are:

Fig. 3.24 Causes of syndrome of inappropriate antidiuretic hormone secretion (SIADH)

The diagnosis should be considered in hyponatraemic patients in the absence of hypovolaemia, oedema, endocrine dysfunction, renal failure and drugs, all of which can impair water excretion.

Causes

The causes of hypernatraemia are:

A diagnostic algorithm is given in Fig. 3.25.

Fig. 3.25 Diagnostic approach to hypernatraemia.

Diabetes insipidus

This is the inability to reabsorb water from the distal part of the nephron, due to the failure of secretion or action of ADH. Symptoms are:

The causes of diabetes insipidus are:

Diabetes insipidus can be mistaken for psychogenic polydipsia, in which large volumes of dilute urine are produced secondary to compulsive water drinking. This causes a decrease in the urine-concentrating ability because of loss of medullary tonicity.

Ischaemic acute tubular necrosis

This is caused by hypotension and hypovolaemic shock following trauma, infections, burns or haemorrhage. There is a rapid fall in blood pressure, which causes hypoperfusion of the peritubular capillaries with consequent tubular necrosis along the entire length of the nephron. The kidneys appear pale and swollen. Histological examination reveals:

Non-steroidal anti-inflammatory drugs (NSAIDs) can increase the risk of ATN following other renal insults by preventing the synthesis of prostaglandins (PGs). PGs are vasodilators, which protect the kidney from ischaemic injury by dilating blood vessels and increasing blood flow.

Toxic acute tubular necrosis

This disorder is caused by agents with specific nephrotoxic activity causing damage to the epithelial cells. Such substances include:

These substances cause the cells to come away from the basement membrane and consequently collect in and obstruct the tubular lumen. The effect is limited because there is regeneration of the epithelial cells in 10–20 days, which permits clinical recovery and is confirmed by the presence of mitotic figures on biopsy. Damage by nephrotoxic substances is limited to the proximal tubules. The kidneys appear swollen and red.

Rhabdomyolysis

Muscle breakdown leads to the release of myoglobin into the blood. This is filtered freely by the glomerulus. If the filtrate is acidic myoglobin precipitates to form casts which block the normal flow of urine through the tubules. The muscle damage can be caused by:

Investigations will reveal a very high creatine kinase (> 10 000) and hyperkalaemia from release from muscle cells. The urine will be dark and give a false positive for blood on a dipstick test.

Treatment involves stopping the damage to muscle tissue if possible. Intravenous fluids are given to promote high urine production alongside alkalinisation of the urine with sodium bicarbonate to help to decrease the precipitation of myoglobin in the tubules.

Pyelonephritis

This is a bacterial infection of the kidney and results in inflammation and damage to the renal calyces, parenchyma and pelvis. It can be acute or chronic.

Acute pyelonephritis

This occurs because of infection in the kidney and is spread via two routes:

The predisposing factors of acute pyelonephritis are:

Patients present with general malaise, fever, loin pain, tenderness and often rigors with or without symptoms of lower UTI. Infection spreads into the renal pelvis and papillae and causes abscess formation throughout the cortex and medulla.

With retrograde ureteric spread the kidney characteristically contains areas of wedge-shaped suppuration especially at the upper and lower poles. In septicaemia there is haematogenous seeding within the kidney and minute abscesses are distributed randomly in the cortex. On histological examination there is:

Uncomplicated cases resolve with antibiotic treatment and high fluid intake. The important complications of acute pyelonephritis are:

Chronic pyelonephritis

This condition is characterized by long-standing parenchymal scarring, which develops from tubulointerstitial inflammation. It is the end-result of various pathological processes. There are two main types:

Fig. 3.26 Normal and refluxing (abnormal) junction.

The disease process usually begins in childhood and has a silent, insidious onset. Reflux of urine into the renal pelvis occurs during micturition and this increases the pressure in the major calyces. The high intrapelvic pressure forces urine into the collecting ducts with intraparenchymal reflux further distorting the internal structure. This is most predominant at the poles of the kidney and results in deep irregular scars on the cortical surface. The tubulointerstitial inflammation heals with the formation of corticomedullary scars that overlie the deformed and dilated calyces, which are characteristic of chronic pyelonephritis (Fig. 3.27).

Fig. 3.27 Differences between (A) acute and (B) chronic pyelonephritis.

On histological examination there is interstitial fibrosis and dilated tubules containing eosinophilic casts; 10–20% of patients requiring dialysis have chronic pyelonephritis.

Ultrasonography is used to diagnose chronic pyelonephritis and may show distortion of the calyceal system and contraction of the kidney because of cortical scarring. Intravenous pyelography may be more sensitive but requires exposure to X-rays which should be avoided, especially in children.

Toxin- and drug-induced tubulointerstitial nephritis

Heavy metals (mercury, gold, lead) and drugs (ampicillin, rifampicin, NSAIDs) can cause T-cell-mediated inflammation in the interstitium. This reaction usually occurs 2–40 days after exposure to the toxin. Clinical features include fever, skin rash, haematuria, proteinuria and ARF. Withdrawal of the causative agent leads to recovery.

On histological examination there is interstitial oedema and tubular degeneration with eosinophil infiltration. In chronic analgesic abuse with phenacetin, and to a lesser extent aspirin, PG synthesis is inhibited, causing ischaemia (as described on p. 50 for ischaemic ATN). This causes papillary necrosis and a secondary tubulonephritis (analgesic nephropathy). It is associated with an increased risk of developing transitional cell carcinomas with chronic analgesic abuse.

Acute urate nephropathy

If there is an increased blood urate concentration, urate crystals are precipitated in the acidic environment of the collecting ducts, causing inflammatory obstruction and dilatation of the tubules. This is called acute urate nephropathy and causes acute kidney injury. A typical cause is tumour lysis syndrome. This involves rapid cell turnover in those patients with haematological or lymphatic malignancy who are receiving chemotherapy. There is excess cell breakdown and release of nucleic acids, which results in acute urate nephropathy and presents as Acute Kidney Injury.

Hypercalcaemia and nephrocalcinosis

A persistently high blood Ca^2 + level causes Ca^2 + deposition in the kidneys. The hypercalcaemia can be due to:

Renal insufficiency occurs in these patients because of stones (nephrolithiasis) or focal calcification in the renal parenchyma (nephrocalcinosis).

In nephrocalcinosis the Ca^2 + accumulates in the tubular cells and the basement membrane, resulting in interstitial fibrosis and inflammation. Hypercalcaemia also causes a renal concentrating defect, which leads to polyuria, nocturia and dehydration.

Multiple myeloma

Approximately 50% of patients with multiple myeloma develop renal insufficiency, which can cause AKI or CKD. Histological changes include: