Renal physiology: Function and anatomy

Renal anatomy

Each kidney is 10–12 cm in length (depending on patient size), weighs approximately 150 g and is located retroperitoneally either side of the spinal column. They are covered in a layer of fascia and fat, and each has an adrenal gland lying at their upper pole. The right kidney lies slightly lower than the left as it is pushed downwards by the liver. The kidneys move gently with respiration and excursion of the diaphragm. Renal blood supply arises directly from the descending aorta through the renal artery, which leaves the aorta inferior to the origin of the superior mesenteric artery at the level of L1–2. The right renal artery passes posteriorly to the inferior vena cava, and the right renal vein to reach the renal hilum. The left renal artery is shorter than the right because the descending aorta lies to the left of the vena cava. Correspondingly the left renal vein is longer than the right renal vein. The renal arteries are 4–6 cm in length and around 0.5–0.6 cm in diameter. Each renal artery branches to an anterior and posterior branch and splits further to supply the kidney. Around 30% of the population have one or more accessory renal arteries, and there may be early branching in 10% of the population; this is important for successful anastomosis in renal transplantation. The branches ultimately divide into arterioles and form the capillary network of the glomerulus. These capillaries reform into arterioles and branch off smaller arteries which bring oxygenated blood to the functioning unit of the kidney, the nephron. The blood then passes through the nephron and into the renal vein, back to the inferior vena cava and returns to the right side of the heart ( Fig. 11.1 ).

The kidneys receive 20%–25% of cardiac output, which is a very large proportion compared with their relatively small size; this reflects their importance and function as filtering units of the circulation.

The kidney is separated into an outer cortex and inner medulla, surrounded by a capsule of fibrous tissue overlying the cortex. This outer cortex contains the majority of nephrons. The nephron is the functional unit of the kidney and comprises the glomerulus and Bowman's capsule; proximal convoluted tubule; descending then ascending loop of Henle, which in turn becomes the thick ascending limb; distal convoluted tubule; and finally the collecting duct, which progresses down into the renal papilla.

Glomerular anatomy, filtration and tubular feedback

A typical adult kidney contains between 800,000 and 1,000,000 nephrons. Within the nephron renal blood flow divides down to the afferent arterioles that become the capillary network of the glomerulus ( Fig. 11.2 ). After this, instead of forming a venous system they become the efferent arterioles. The efferent arterioles divide to become a second set of capillaries, the vasa recta. These serve to supply oxygenated blood to the renal medulla, descending with the loop of Henle, and also to maintain the solute gradients of the medulla necessary for the countercurrent multiplier and concentration of urine. This configuration results in the bulk of the blood supply directed towards the cortex but leaves delivery of oxygen to the tubules in the medullary region, with limited reserve if there is decreased perfusion, even in health. Small alterations in this renal perfusion can lead to tubular ischaemia.

Blood enters each glomerulus via an afferent arteriole and on into a network of capillaries that form the bulk of the glomerulus. These capillaries are lined by fenestrated endothelial cells with pores 50–100 nm in diameter. Glomerular filtration of blood into the tubule occurs as a result of the high hydrostatic pressure within the glomerular capillaries, which is maintained by tonic differential vasoconstriction of the afferent and efferent arterioles, compared with the relatively low pressure in Bowman's space. The endothelial pores allow free filtration of fluid, solutes and small proteins less than 70 kDa in size but prevent the passage of blood cells and larger proteins. The glomerular basement membrane (GBM) is the next barrier to filtration. The GBM is synthesised predominantly of type IV collagen (which contains the autoantigen responsible for antiglomerular basement membrane disease) and contains ultrastructural pores approximately 3.5 nm in diameter that prevent the passage of most proteins. The final barrier to filtration is specialised epithelial cells called podocytes, which are attached to the GBM and face into Bowman's space. The podocytes synthesise a negatively charged glycocalyx, which forms an integral component of the glomerular filtration barrier and limits the filtration of proteins with a negative charge. Albumin, the most abundant plasma protein, is able to traverse the endothelial pores and GBM because of its flexibility and epilipsoid shape, but the negative charge of this glycocalyx prevents significant filtration of albumin in health. The ultrafiltrate in Bowman's space contains fluid of the same composition and osmolality as plasma but lacking the majority of dissolved proteins. Two healthy kidneys generate a glomerular filtration rate (GFR) of 125 ml min ^–1 , equivalent to the production of 180 L of urine per day.

Tubuloglomerular feedback is the mechanism by which the kidney autoregulates blood flow and filtration pressure to maintain an optimal GFR. The key components of this process are the macula densa and granular cells within the juxtaglomerular apparatus. Within each nephron the distal collecting tubule folds back upon itself to bring a portion, the macula densa, to lie adjacent to the glomerulus and to the afferent and efferent arterioles. The macula densa detects the tubular sodium and chloride concentrations in the thick ascending limb and distal convoluted tubule. High sodium or chloride concentrations are interpreted as signifying an increased GFR, which leads to increased activity of the apical Na-K-2Cl cotransporter, causing increased intracellular Na ⁺ , cell swelling and release of adenosine triphosphate (ATP). This ultimately results in afferent arteriolar vasoconstriction, reducing glomerular blood flow; contraction of glomerular mesangial cells, reducing the area for filtration; and inhibition of renin release by granular cells, which collectively decrease GFR. In the setting of a decreased GFR, less Na ⁺ or Cl ^– is detected by the macula densa, and the opposite occurs.

The myogenic mechanism of renal autoregulation is more straightforward. When the perfusion pressure of the kidney increases, the afferent arterioles detect this increased pressure through stretch receptors: The smooth muscle of the arteriole contracts, increasing resistance to flow to the glomerulus. When pressure drops, the afferent arteriole relaxes to allow increased flow so that overall blood flow is relatively constant.

Renin–angiotensin–aldosterone system and vasopressin

The renin–angiotensin–aldosterone system (RAAS) is activated either by low tubular flow rates at the macula densa or low systemic blood pressure detected by baroreceptors in the carotid sinus ( Fig. 11.3 ). Causes include hypotension secondary to heart failure, hypovolaemia or vasodilatory states such as sepsis. Specifically, low pressure in the afferent arterioles, reduced Na ⁺ and Cl ^– in tubular fluid at the juxtaglomerular apparatus or renal sympathetic activation (β ₁ -mediated) stimulates release of the proteolytic enzyme renin from the juxtaglomerular cells. This cleaves the plasma protein angiotensinogen into the decapeptide angiotensin I. Angiotensin-converting enzyme (ACE) then cleaves two amino acids from angiotensin I to produce an octapeptide, angiotensin II, which acts to increase arterial blood pressure and renal perfusion. Within the kidney there is vasoconstriction of both the afferent and efferent arterioles (more pronounced on the efferent arteriole), resulting in increased vascular resistance and preservation of GFR. Angiotensin II also causes constriction of systemic arterial resistance vessels and venoconstriction. It triggers the release of aldosterone from the zona glomerulosa of the adrenal cortex, which promotes Na ⁺ reabsorption in exchange for K ⁺ and water in the distal tubule to expand intravascular volume. Angiotensin-converting enzyme is the target of ACE inhibitors (e.g. ramipril, lisinopril, perindopril) used in the control of hypertension and heart failure. Inhibition of ACE leads to lower arteriolar resistance and dilation of both arteries and veins, thus deceasing preload and afterload on the heart. Increased urinary Na ⁺ and water excretion decreases blood volume. Angiotensin-converting enzyme inhibitors (ACEIs) also inhibit cardiac and vascular remodelling.

Angiotensin II receptor blockers (ARBs, e.g. losartan, candesartan) have similar pharmacological effects; these drugs are used for the same indications in patients intolerant of ACEIs.

Proximal convoluted tubule

The PCT is the segment of the nephron where the majority of water and solute reabsorption occurs. The surface area over which this reabsorption occurs is significantly increased by the presence of densely packed microvilli forming a brush border on the luminal surface of the proximal tubule. The cytoplasm of the proximal tubule epithelial cells (PTEC) is densely packed with mitochondria to supply the ATP needed for the Na/K–adenosine triphosphatase (ATPase) pump, situated basolaterally. This pump drives active transport of Na ⁺ ions across the basolateral surface of the PTEC, thereby creating the necessary concentration gradient to drive Na ⁺ (and water) reabsorption from the early urine into the PTEC. This process enables the proximal tubule to reabsorb approximately two thirds of the Na ⁺ and water in the early ultrafiltrate ( Fig. 11.4 ).

Reabsorption of glucose, amino acids and phosphate from the filtrate occurs via cell membrane cotransporters, which rely on the same Na ⁺ gradient and are therefore similarly ATP dependent. The threshold for glucose reabsorption by the proximal tubule is 9–10 mmol L ^–1 , or 160–180 mg dl ^–1 . Above this concentration the capacity of the PCT to reabsorb glucose is exceeded, and glucose will appear in the urine. This threshold is lower in pregnant women – typically around 7 mmol L ^–1 or 125 mg dl ^–1 , hence the finding of non-diabetic glycosuria in pregnant women.

Approximately 65% of the filtered K ⁺ is resorbed by solvent drag and simple diffusion in the proximal tubule. Bicarbonate reabsorption occurs in exchange for hydrogen ions. A failure of proximal tubule bicarbonate reabsorption leads to proximal (type 2) renal tubular acidosis.

A small quantity of creatinine is secreted into the filtrate in the PCT.

Carbonic anhydrase inhibitors such as acetazolamide have their site of action in the PCT.

Loop of Henle

The loop of Henle is responsible for reabsorption of 25% of filtered solutes and 20% of filtered water. Most of the processes responsible for concentration of urine and its final composition occur in the loop of Henle. The structure of the loop of Henle is specifically designed to generate and maintain a concentration gradient between the tubular fluid and the surrounding medulla to promote water reabsorption by means of the countercurrent multiplier. It comprises three main sections.

Thin descending limb of the loop of Henle

The first part is the thin descending limb, which has a low permeability to solutes whilst being permeable to water because of the presence of aquaporin I channels. On passage through the thin descending limb the osmolarity of the filtrate increases as water is removed. The filtrate typically has an osmolarity of 300 mOsm L ^–1 when it enters from the PCT, but as it descends the osmolarity increases as the water diffuses from the tubule into the higher osmolarity of the interstitial fluid of the medullary space ( Fig. 11.5 ). As the tubule descends deeper into the medulla, the medullary space osmolarity gradually increases from 600 mOsm L ^–1 in the outer medulla to a maximum of 1200 mOsm L ^–1 in the inner medulla. This causes movement of water but not solutes (because the epithelial cells are relatively impermeable) from the lumen of the thin descending limb into the surrounding interstitial fluid of the medulla. The tip of the loop represents the highest concentrating ability of the nephron. The loop then reflects upwards and becomes the thin ascending limb of the loop of Henle.

Thin ascending limb of the loop of Henle

In contrast to the thin descending limb, the thin ascending limb of the loop of Henle is relatively impermeable to water, whereas permeability for solutes is increased, and solutes are reabsorbed principally via the Na-K-2Cl symporter and the Na-H antiporter. As a consequence of solute reabsorption, the osmolarity of the tubular fluid falls from 1200 mOsm L ^–1 to 100–150 mOsm L ^–1 .

Thick ascending limb of the loop of Henle

Unlike the thin descending and ascending limbs of the loop of Henle, where movement of water and solutes is through passive diffusion down concentration gradients, the thick ascending limb of the loop of Henle utilises ATP-dependent active transport to drive reabsorption of water and solutes. The main stimulus for active transport is the Na/K ATPase transporter situated in the basolateral membrane of the tubular epithelial cells. The Na/K ATPase generates ion gradients within the tubular epithelial cells as a consequence of movement of 3 Na ⁺ ions out of the cell into the peritubular fluid and movement of 2 K ⁺ ions into the cell. This provides the necessary intracellular driver for Na ⁺ , K ⁺ and Cl ^– reabsorption by secondary active transport via the luminal Na-K-2Cl symporter and Na ⁺ reabsorption via the luminal Na-H antiporter, as a means of maintaining electrochemical neutrality. The generated electrical and concentration gradients also drive magnesium and calcium reabsorption through specific membrane-bound transporters.

Loop diuretics inhibit the luminal Na-K-2Cl cotransporter in the thick ascending limb, thereby preventing reabsorption of Na ⁺ , K ⁺ and Cl ^– , promoting natriuresis, kaliuresis and diuresis.

The cortical thick ascending limb transitions into the distal convoluted tubule.

Distal convoluted tubule

The distal convoluted tubule (DCT) is largely impermeable to water and is principally responsible for the regulation of K ⁺ , Na ⁺ , HCO ₃ ^– and Ca ²⁺ excretion (see Fig. 11.4 ). At the junction of the thick ascending limb of the loop of Henle and the DCT lies the macula densa, a group of specialised epithelial cells whose function is to monitor the osmolality of tubular filtrate, principally sensing the tubular concentration of Na ⁺ and Cl ^– and providing tubuloglomerular feedback.

As the filtrate passes along the DCT there is regulated reabsorption of HCO ₃ ^– and secretion of H ⁺ , the extent to which this occurs being dependent on body pH. Na ⁺ reabsorption is regulated by aldosterone, which increases Na ⁺ reabsorption in exchange for K ⁺ (See Figs 11.4 and 11.6 ). Ca ²⁺ reabsorption in the DCT is regulated by parathyroid hormone, secreted in response to decreased serum Ca ²⁺ concentrations detected by the calcium-sensing receptors on the surface of parathyroid cells.

The DCT contains the thiazide-sensitive Na-Cl cotransporter.

Pharmacology of drugs acting on the kidney