The renal system and associated diseases are considered complex, even by many more senior doctors. This is probably due to the unique development and multiple functions of the urinary tract in comparison with other organ systems. An understanding of the first principles of the urinary tract, however, will make the understanding of the diseases and their management readily accessible to even the preclinical medical student.
1.1 Overview of the renal system
The urinary tract consists of two kidneys, two ureters and the single, centrally located bladder and urethra (Figure 1.1). Each kidney contains over a million nephrons, the functional units of the kidney. These are composed of glomeruli and tubules. The tubules join up as the renal collecting system to establish continuity with the rest of the renal tract. They are responsible for the physiological function of the renal tract, that is, regulation of the volume and composition of our body fluids. Tubules have several distinct epithelial cell types requiring precise positioning during fetal development in order to form an optimally functional urinary tract.
The urinary tract's main roles include excretion of waste products from the system (i.e. urine formation) and homeostasis of the extracellular environment by regulation of fluid balance and electrolyte concentration within the extracellular and intracellular compartments. The kidney is also responsible for the production of hormones such as erythropoietin, involved in the formation of red blood cells; the enzyme renin, a key player in blood pressure control and sodium reabsorption; and conversion of vitamin D to its active form dihydroxycholecalciferol, required for bone health.
1.2 Anatomy and embryology
The kidneys are bean-shaped with concave hila (Figures 1.2 and 1.3). They are located retroperitoneally in the posterior abdominal wall at the level of T11 to L3 or L4 at either side of the lumbar vertebrae.
The relations of the kidney are:
- The diaphragm, quadratus lumborum, psoas, transversus abdominis, the 12th rib and the subcostal (T12), iliohypogastric and ilioinguinal nerves (L1) lie posteriorly
- The second part of the duodenum, ascending colon and the liver lie in front of the right kidney, while the left lies behind the stomach, pancreas, spleen and the descending colon
- Superiorly, both kidneys are closely capped by the adrenal glands
- The medial aspect of the hilum receives the renal vein, renal artery and pelvis of the ureter in that order as well as lymphatics and nerves
The surface anatomy of the kidneys is shown in Figure 1.4.
In adulthood, each normal kidney usually measures between 10 cm and 14 cm long and 6 cm wide depending on height and sex. The right kidney lies about 12 mm lower than the left, as it is displaced downwards by the liver. The kidneys are surrounded by perirenal fat, which has a protective role in supporting and cushioning the kidney.
The nerve supply is particularly important in the kidney because it is essential for function in terms of regulation of vasomotor tone, which in turn regulates renal blood flow. The kidneys have a sympathetic supply arising from the lower splanchnic nerves, which travel through the lumbar ganglion to the kidney.
Sympathetic stimulation leads to intrarenal vasoconstriction and hence reduced blood flow along side enhanced sodium reabsorption and stimulation of the local renin–angiotensin system.
The kidneys receive just over 20% of the cardiac output. Blood enters the kidney via the renal artery at the hilum. Renal lymph vessels begin in the cortex and they return the protein reabsorbed from the tubular fluid back to the blood.
The vasculature of the kidney is highly variable. Each kidney is usually supplied by a single artery, though multiple arteries are not uncommon. These can be a result of either renal artery branching or independent vessels branching off the aorta.
- The arteries branch into five interlobar arteries along the sides of the pyramids, which then divide into the arcuate arteries at the junction of the medulla and cortex
- The arcuate arteries then give rise to inter-lobular arteries
- The afferent arterioles feed into the glomeruli (Bowman's capsule) and drain into efferent arterioles (similar to portal blood vessels)
- In the cortex, which is the most highly vascularised part of the kidney, the efferent arterioles form a capillary network around the proximal tubules, known as the peritubular capillaries
- The juxtamedullary glomeruli give rise to the capillary networks known as the vasa recta, which eventually drain into the renal vein by forming tributaries
- The vasa recta, peritubular capillaries and the loops of Henle are involved in the countercurrent exchange mechanism responsible for urinary concentration
Urine flows from the pelvis of the kidney through the ureters to the bladder and then out via the urethra. The ureters are about 25–30 cm long.
The ureters receive both a sympathetic and parasympathetic supply via the spinal segments of the L1 and L2 nerve roots.
- The sympathetic supply is from the renal and intermesenteric plexus (upper ureter), the superior hypogastric plexus (middle ureter) and the inferior hypogastric (lower ureter)
- The parasympathetic vagal supply is via the coeliac plexus and the pelvic splanchnic nerves
The blood supply to the ureter comes from the renal, abdominal aorta, testicular or ovarian, common iliac, internal iliac, vesical and uterine arteries. The venous drainage is paired with the arterial supply, and the lymphatic drainage is to the lumbar, common and internal iliac and vesical nodes.
The bladder and urethra
The bladder is a chamber for holding urine. It consists of a body in which urine collects, and a funnel-shaped bladder neck, which passes inferiorly into the urogenital triangle (the anterior perineum) and connects with the urethra. The external sphincter surrounds the junction of the bladder neck and the urethra. In the posterior wall of the bladder immediately above the bladder neck is the trigone, which has a smooth mucosa as opposed to the general rugae lining the rest of the bladder. The upper angles of the trigone mark the entry of the ureters and the lower the exit of the urethra.
The bladder has variable stretching ability as it consists of connective tissue and smooth muscle known as detrusor. Its unique structure enables it hold up to 500–1000 mL of urine comfortably.
Males have a longer urethra than females with valves between the bladder and the exit of the urethra. Abnormalities of the intravesical region are among the commonest causes of congenital renal disease in males.
- The bladder lies posterior to the pubic symphysis, anterior to the rectum in males and the vagina in females
- The superior surface is covered by the peritoneum
- In males the prostate surrounds the upper part of the urethra
The bladder and urethra are supplied by S2–4 parasympathetic nerve fibres, which stimulate bladder emptying, vasodilation and penile erection. The sympathetic supply to the bladder arises from T10/11–L3 nerve root segments and their drive reduces bladder tone by inhibiting the parasympathetic effect. The bladder neck and proximal urethra are more richly innervated by sympathetic fibres, which act to facilitate their closure. This explains why α-blockers can induce incontinence or relieve the outflow obstruction in benign prostate hypertrophy. The bladder rests on the pelvic diaphragm, which is innervated by somatic motor neurones S2–4 that assist in voluntary contraction (Table 1.1).
The act of urinating (micturition) occurs through a complex coordinated stimulation of parasympathetic and inhibition of sympathetic tone. The act of voiding and its control is also dependent on the somatic nerve supply to the pelvic diaphragm and on the central nervous system.
The blood supply of the bladder and urethra comes from branches of the internal iliac arteries; the veins drain into the iliac internal veins. The lymphatic drainage is to the external, internal and sacral lymph nodes.
Histology of the urinary tract
A sagittal section of the renal tract reveals the parenchyma of the kidney; the outer dark brown cortex and the inner pale medulla and renal pelvis. The parenchyma is made up of interstitial tissue and nephrons, which consist of the glomeruli and their draining tubules (Figure 1.5). Each kidney contains over a million nephrons, although this number decreases with increasing age. This is known as a reduction in nephron mass, and explains why renal function decreases with age.
The majority of the glomeruli are located in the cortex, with about 15% in the juxtamedullary region, the deepest region of the cortex. The medulla consists of dark, striated regions called the pyramids, which have apices known as papillae. The papillae project into the renal pelvis, which continues as the ureter (Figure 1.3).
These are made up of tufts of vasculature (capillaries) contained within the cupped end of the renal tubule, known as glomerular capsules (or Bowman's capsule). The glomerular basement membrane (GBM) acts as the skeleton of the glomerular tuft and is lined by epithelial cells with projections forming filtration slits (podocytes) and interspersing phagocytic mesangial cells.
The renal tubules are the small epithelial tubes making up the nephron that connect the glomerular capsules with the renal papillae. The capsule gives rise to the proximal convolted tubule (PCT), the descending and ascending limbs of the loop of Henle, the distal convoluted tubule (DCT), which has an early convoluted segment, a short connecting segment and a late segment. Finally, the DCT becomes the collecting duct as it passes through the outer and inner medulla and opens at the tip of the renal papilla, draining filtrate into the renal pelvis.
Embryology of the urinary tract
During early development in males and females, both the urinary and genital ducts open out into the cloaca, the distal portion of the hindgut. The distal aspect of the excretory duct continues to be shared in males while in females the primitive part undergoes regression. The fetal urine passes into the allantoic or amniotic fluid sac from where it is reabsorbed. Interestingly, the kidney does not take on its excretory function until after birth even though it is fully developed by the 12th week. The kidney derives from the sequential development of the embryonic mesodermal kidney structures: pronephros, mesonephros and metanephros (Figure 1.6).
The kidneys develop from the metanephros, whereas the bladder and ureters develop from the urogenital sinus. In males, the prostate develops from an outgrowth of the urethral epithelium.
The human body consists of 60% fluid in adult males, 50% in adult females and 75% in newborns. The body is divided into extracellular and intracellular fluid compartments. A 70 kg man would therefore have a total fluid content of approximately 42 L, with 28 L located in the intracellular and 14 L in the extracellular compartment. The extracellular fluid has 11 L as interstitial fluid and 3 L as plasma.
The constituents of the fluid are important for maintaining an optimum and steady physiological environment for cellular function. The main ions dissolved in the fluid (i.e. electrolytes) are sodium (Na+), potassium (K+), calcium (Ca2+), magnesium (Mg2+), chloride (Cl−), hydrogen phosphate (HPO42−) and hydrogen carbonate (HCO3−, also commonly known as bicarbonate). Sodium is the most abundant extracellular electrolyte while potassium is the main intracellular electrolyte.
Plasma osmolality is a measure of the body fluid/electrolyte balance and is normally between 275–295 mOsm/kg, i.e. milliosmoles of solute (electrolytes) per kilogram of solvent (water).
The kidneys have a central function in maintaining body fluid homeostasis. Their specific functions include:
- Excretion of metabolic waste products and foreign chemicals from the body
- Regulation of water, body electrolytes and fluid osmolality
- Regulation of acid-base balance
- Endocrine functions via specialised cells involved in the secretion, metabolism and excretion of hormones
- Blood pressure regulation
The purpose of urine formation is to excrete metabolic waste products and foreign chemicals. Urine formation starts by ultrafiltration of plasma (blood without red blood cells (RBCs)). This occurs in the glomerular capsules. Blood enters via the afferent arterioles and is then filtered through the basement membrane of the glomerular tufts in the glomerular capsule. Filtration is also influenced by the podocytes and mesangium.
Filtration is largely determined by the size of the molecules and the space between the podocyte foot processes known as slit diaphragms, which are around 30–40 nm in diameter. These are partially occluded by zipper-like structures so the actual spaces are even smaller. For example albumin has a molecular weight of 67 kDa and so does not pass through in normal physiological situations. Podocytes also affect filtration through their negative surface charge repelling negatively-charged molecules, discouraging their passage through the slits.
Mesangial cells fill the intercapillary spaces and regulate blood flow within the glomerular capillaries. Contraction of mesangia decreases GBM surface area, and therefore decreases the rate at which fluid is filtered by the glomeruli; the glomerular filtration rate (GFR).
Glomerular filtration rate
GFR can be estimated by comparing the amount of a specific chemical in plasma and urine that has a steady blood concentration, passes through the filtration slits unhindered, and is not reabsorbed or secreted by tubular cells. The rate is therefore the amount of the chemical in urine that came from a known amount in the blood, over time.
- CY is the renal clearance of substance ‘y’ (i.e. GFR)
- UY is the urine concentration
- V is the urine flow rate
- PY is the plasma concentration of substance ‘y’
Factors affecting GFR
The major determinants of GFR are the:
- Renal blood flow and renal perfusion pressure
- Hydrostatic pressure difference between the tubule and the capillaries
- Surface area available for ultrafiltration
Renal blood flow
The blood supply to the kidneys is between 20% and 25% of cardiac output, i.e. approximately 1200 mL/min. Of this, renal plasma flow is about 660 mL/min, and 120 mL/min is filtered out of the blood and into the nephron. Ultimately, about 1.2 mL of this fluid is excreted as urine (1% of filtered load).
Renal blood flow is determined by the difference in pressure between the renal artery and the renal vein and is dependent on total renal vascular resistance. The renal vascular resistance is determined by the sum of the resistance in the arteries, arterioles, capillaries and veins.
The vascular resistance of these vessels is determined by the sympathetic nervous system, hormones including adrenaline, noradrenaline, endothelin, renin, angiotensin II, prostaglandins and local internal renal mechanisms. Sometimes external variables such as high glucose levels or high protein intake lead to increased renal blood flow.
For any given substance, this is dependent on the GFR and is increased by tubular secretion but reduced by tubular reabsorption of the substance.
Nitrogenous products such as urea, creatinine and urate are among the main metabolic products removed in urine. Urea is a breakdown product of amino acids, consisting of ammonia combined with carbon dioxide to make it less toxic. Urea excretion is partly dependent on dietary protein intake and liver function. Creatinine is a breakdown product of creatine phosphate, hence its concentration varies according to an individual's muscle bulk.
If a substance is freely filtered by the glomerulus and not reabsorbed or secreted, then its renal clearance will be equal to its GFR or the volume of plasma filtered per unit time. Very few substances meet these criteria. However, to obtain an accurate assessment of renal function substances such as inulin, iohexol and 51Cr ethylenediaminetetraacetic acid (51Cr EDTA) or 99mTc diethylene triamine pentaacetic acid (99mTc DTPA) are used. Creatinine levels are routinely used to assess renal function but limitations include its variable tubular secretion in the proximal tubules. Urea is also used but has limitations.
Regulation of body fluid, osmolality and electrolyte concentration
Body fluid, osmolality and electrolyte concentration are regulated by the kidney through tubular reabsorption and secretion of sodium (Na), potassium (K), calcium (Ca), phosphate (PO4), magnesium (Mg), chloride (Cl) and bicarbonate (HCO3) (Figures 1.7 and 1.8a–e). The kidneys also regulate water balance and subsequently osmolality by controlling ion and water excretion in the tubules. The normal range for plasma osmolality is 275–299 mOsm/kg. This is maintained by a variety of feedback mechanisms.
The water balance influences plasma volume and has a direct effect on the blood pressure. The mechanism by which the kidney concentrates and dilutes the urine is largely dependent on the tubules.
Tubular reabsorption and secretion
The tubule arises from the glomerular capsule initially as the PCT, which is divided into segments S1 and S2. The PCT is lined with cuboidal cells with multiple microvilli and is responsible for reabsorption of two thirds of the filtered salt, water, and organic solutes such as amino acids and glucose.
Sodium and water reabsorption are driven by osmosis whereas organic solute absorption is active and depends on co-transport channels involving ATPase. The S2 segment is followed by S3, the straight proximal tubule (PST).
Loop of Henle
The loop of Henle is the U-shaped part of the tubule, consisting of a descending and ascending limb. Its main function is to enable concentration of the urine. The descending loop is impermeable to salt but not water while the ascending loop is impermeable to water. This feature and the dense capillaries surrounding this part of the tubule enable the countercurrent exchange mechanism (also known as the countercurrent multiplication system):
- Fluid leaving the ascending loop is hypo-osmolar: 100 mOsm/kg compared with that entering it (1000–1200 mOsm/kg)
- The osmolality of the fluid at the bend of the loop is several times higher than that of the fluid entering it
- The tissue interstitium in the cortex around the limbs of the loop has a much lower osmolality (100 mOsm/kg) than the osmolality of the tissue around the bend of the loop (1200 mOsm/kg) in the medulla
The third factor provides the optimal milieu for the collecting ducts, which pass from the cortex to the medulla, extracting as much water as possible, under the influence of anti-diuretic hormone (ADH). Finally, they drain into the renal pelvises.
DCT and collecting duct
The ascending loop of Henle and collecting duct are connected by the DCT. The cells lining the DCT are dense in mitochondria and the ion exchange occurring in this segment of the tubule is largely hormone-driven by parathyroid hormone (Ca reabsorbed, PO4 excreted), aldosterone (Na reabsorbed, K excreted) and atrial natriuretic peptide (Na excretion).
By the end of the DCT, the filtrate has only 3% of its water content compared to the capsular filtrate. Osmosis is responsible for the resorption of 97.9% of the glomerular filtrate water entering the convoluted tubules and collecting ducts.
Similar to the kidney's role in regulating osmolality, extracellular fluid and electrolyte balance, it is also responsible – in conjunction with the lungs – for maintaining homeostasis of the plasma pH. The kidneys are mainly responsible for long-term adjustments; they achieve this through hydrogen ion excretion to bring about a steady state. Chapter 8 deals with the mechanism for acid transport in different parts of nephron, and clinical and biochemical features of acid–base derangement as well as the defence mechanisms to prevent abrupt changes in pH.
Secretion, metabolism and excretion of hormones
Renin is a 406 amino acid enzyme that is central to blood pressure control (Figure 1.9). It is synthesised and stored in the juxtaglomerular apparatus (JGA) of the kidneys (Figure 1.10). The JGA is formed by part of the ascending loop of Henle, where it turns to become the DCT and passes close to its own Bowman's capsule, coming in to contact with the afferent and efferent arterioles. The DCT cells in this area are known as the macula densa and the afferent arteriole wall cells as granular cells. Renin is released by the granular cells when:
- A fall in ECF volume is detected by peripheral baroreceptors, causing increased sympathetic activity to granular cells
- The macula densa cells sense a decrease in [Na] within the DCT and secrete prostaglandin, stimulating granular cell release of renin
- A fall in ECF decreases pressure in the afferent arterioles, detected by granular cells.
The effects of renin on blood pressure are by its actions on angiotensinogen, an α2 globulin produced by the liver:
- Renin converts angiotensinogen to angiotensin I (a decapeptide), which is then converted by angiotensin–converting enzyme (ACE) to angiotensin II (an octapeptide)
- Angiotensin II acts to maintain vascular pressure by causing vasoconstriction, and by stimulating aldosterone production from the zona glomerulosa of the adrenals
- Angiotensin II at higher concentrations causes vasoconstriction of the afferent arteriole, leading to a reduction in GFR. At lower concentrations, it causes vasoconstriction of the efferent arteriole, helping to maintain GFR by elevating intra-glomerular pressure.
The kidney produces 80% of the body's erythropoietin, the liver synthesises the rest. Hypoxia stimulates its prostaglandin-mediated production by mesangial and tubular cells, which leads to increased erythropoiesis in the bone marrow. Release of erythropoietin is also enhanced by catecholamines acting via β-receptors.
Vitamin D is a steroid hormone synthesised in the skin, and then hydroxylated in the liver (25-hydroxycholecalciferol) and in the kidney (1, 25 dihydroxycholecalciferol). It is essential for bone and teeth mineralisation and acts by enhancing absorption of calcium and phosphate from the gut (Figure 1.11). It is counter-regulated by the parathyroid gland hence problems with its production can lead to parathyroid disease (see Chapter 4).
Prostaglandins and other arachidonate metabolites
Arachidonates are complex lipids that are synthesised by most of the cells in the body. Those peculiar to the kidney include the prostaglandins (PGs) PGE2, PGI2, PGF2a, PGD2 and thromboxane A2. They are produced by cortical and medullary interstitial cells and also by the epithelial cells of the collecting ducts. PGs have a vasodilatory role and can also contribute to diuresis and naturesis.
Endothelins are a family of peptides that act on the renal vasculature to induce potent vasoconstriction. Endothelins 1–3 are produced by the mesangial cells, and the afferent and efferent arterioles. They have both autocrine and paracrine effects, and induce contraction and vasoconstriction. This may lead to alteration in renal blood flow and GFR particularly in pathological conditions such as contrast nephropathy and congestive heart failure. Their exact homeostatic function in normal physiology is less clear.
Purines produced by the kidneys include adenosine and adenosine triphosphate (ATP). They are locally produced and appear to act both on tubules, affecting water and sodium reabsorption, and on the arterioles, causing vasoconstriction. Their precise physiological role is still being explored.
Most gluconeogenesis (synthesis of glucose) is carried out by the liver. However, the renal cortex has gluconeogenic enzymes and, in situations such as prolonged fasting, can contribute up to 50% of the body's production. It produces glucose from lactate, glycerol and glutamine as opposed to glycogen, the predominant source for glucose production by the liver. Glucose production by the kidney is partly regulated by insulin and catecholamines.