8th February 2024

Renal Physiology

Renal perfusion and glomerular filtration

Renal perfusion

Despite their size, the kidneys receive up to 25% of the resting cardiac output, equating to around 1200mls/minute.

The left and right renal arteries are branches of the abdominal aorta. They enter each kidney at the hilum before branching into segmental arteries and then into interlobar arteries that pass through the renal columns. Once they reach the base of the pyramids, they become known as arcuate arteries. These then divide into interlobular arteries, which pass through the renal lobules and supply each nephron with an afferent arteriole. 

From here, the blood supply enters a network of capillaries known as a glomerulus. Unlike other capillary bodies, the glomerulus is not followed by a venule but by a further arteriole known as the efferent arteriole. The efferent arteriole divides into a second capillary network known as the peritubular capillaries, which surround the proximal and distal tubules of the nephrons within the renal cortex. Tubules within medullary nephrons are supplied by long vasa recta capillaries, which also originate from the efferent arterioles.

The peritubular capillaries drain into the peritubular venules and the interlobular veins. Blood from the vasa recta drains directly into the interlobular veins. From here, blood enters the arcuate veins, followed by the interlobar veins, before exiting the kidney via the renal vein. 

Image Source: Pressbooks (2017). Urinary structures and function, Licensed under a creative commons licence. Available for free at: https://pressbooks.ccconline.org/bio106/chapter/urinary-structures-and-functions/  (Accessed: 9 January 2024).

Renal perfusion relies on total body volume, effective volume and cardiac output. Reducing any of these factors results in a reduced mean arterial pressure and, thus, reduced renal perfusion.

Glomerulus

Glomerular filtration is a passive process reliant on the hydrostatic pressure created by an ingoing wider afferent arteriole and an outgoing narrower efferent arteriole. The glomerular filtration rate is a measure of the kidney’s excretory function. Drugs such as NSAIDs and ACE inhibitors can reduce the GFR by reducing the hydrostatic pressure: 

• NSAIDS and tacrolimus cause constriction of the afferent arteriole, thus reducing the flow of blood into the glomerular bed.
• ACE inhibitors and ARBs cause dilation of the efferent arteriole, allowing blood to leave the glomerular bed more easily. 

Oncotic pressure counteracts the hydrostatic pressure. Other factors affecting the GFR include the permeability of the glomerulus. Factors that can reduce permeability include angiotensin II release (resulting in mesangial cell contraction) and inflammation of the glomerular basement membrane (GBM) thickening.

Serum creatinine is often a reliable measure for GFR as it is released from muscle cells at a constant rate and is freely filtered across the glomerular basement membrane with negligible further secretion or reabsorption as it passes through the nephron. When reviewing creatinine results, factors to consider are age and nutritional status – creatinine can be close to the normal range despite a drop in eGFR. Creatinine can also be unreliable in early renal disease.

Once the filtrate has passed through the glomerular basement membrane, it enters the renal tubule.

References

Kumar, P. and Clark, M., 2012. Kumar & Clark’s clinical medicine. 8th ed.

Fairweather, J., Findlay, M., & Isles, C. (2020). Clinical companion in nephrology. Springer International Publishing. 

Tortora, G. J., & Derrickson, B. (2017). Tortora’s principles of anatomy and physiology. John Wiley and Sons.

Proximal tubules

Overview

The proximal tubule is responsible for all glucose and amino acid reabsorption and 90% bicarbonate reabsorption via Na+/H+ antiporters. PTH, vitamin D and FGF-23 act on the proximal tubule to regulate phosphate reabsorption. Urea is also reabsorbed here and is done so in higher volumes during periods of dehydration. Half of the sodium filtered at the glomerulus is reabsorbed here via Na+/K+ ATPase channels. Water is also reabsorbed following the movement of the solutes. 

Image Source: Wikimedia Commons (2009). Proximal convoluted tubule., Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/f/f1/Proximal_convoluted_tubule.jpg (Accessed: 4 January 2024).

The renal tubule has both secretory and resorptive functions that require high levels of energy – this makes the renal tubules particularly susceptible to ischaemia during periods of poor perfusion. In prolonged poor blood flow periods, ongoing ischaemia can lead to cell death and cell shedding from the tubular basement membrane. Cell shedding can lead to the formation of casts, which may then obstruct the nephron. 

Tubular cells are also vulnerable to several substances. Medications, such as vancomycin, gentamicin, antivirals, and contrast mediums, are toxic to the tubular cells. Myoglobin (released during rhabdomyolysis), uric acid (released by cancer cells following chemotherapy), and Bence-Jones Proteins (produced in multiple myeloma) are also directly damaging. When injured, the tubular cells’ ability to secrete and reabsorb declines.

Alongside reabsorption, the proximal tubule is also responsible for secreting uric acid, creatinine and several drugs, including trimethoprim and diuretics.

References

Kumar, P. and Clark, M., 2012. Kumar & Clark’s clinical medicine. 8th ed.

Fairweather, J., Findlay, M., & Isles, C. (2020). Clinical companion in nephrology. Springer International Publishing. 

Tortora, G. J., & Derrickson, B. (2017). Tortora’s principles of anatomy and physiology. John Wiley and Sons.

Loop of Henle

Overview

Sodium is actively reabsorbed via Na+/K+/2Cl- cotransporters in the ascending limb. 90% of sodium is actively reabsorbed in between the proximal tubule and the ascending limb of the loop of Henle, creating a high osmolality within the renal medulla. Water then moves passively out of the descending limb of the loop of Henle to counteract this until an equilibrium is reached. The thick ascending limb is impermeable to water, creating a medullary concentration gradient and reducing the tubular osmolality when it reaches the distal convoluted tubule, allowing urine concentration. The counter-current mechanisms, i.e. the flow of tubular fluid through the nephron in one direction and the flow of blood through the vasa rectus in the opposite direction, along with the opposing flow of the tubular fluid in the descending and ascending limbs, also contribute to creating the osmotic gradient.  

Loop diuretics compete for the chloride binding sites on these cotransporters. As they are larger than chloride ions, they cannot be transported across the membrane, thus inhibiting the transporter. Reduced sodium reabsorption reduces the osmolality within the medulla, and therefore, less water moves passively out of the tubule, resulting in a greater urine volume.

Image Source: Wikimedia Commons (2011). Kidney nephron molar transport diagram, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/2/26/Kidney_nephron_molar_transport_diagram.svg  (Accessed: 4 January 2024).

References

Kumar, P. and Clark, M., 2012. Kumar & Clark’s clinical medicine. 8th ed.

Fairweather, J., Findlay, M., & Isles, C. (2020). Clinical companion in nephrology. Springer International Publishing. 

Tortora, G. J., & Derrickson, B. (2017). Tortora’s principles of anatomy and physiology. John Wiley and Sons.

Distal tubules and collecting ducts

Distal tubules

A small amount of sodium is reabsorbed in the distal convoluted tubule by Na+/Cl- cotransporters. The distal convoluted tubules are affected by aldosterone. It is also permeable towards calcium and allows calcium reabsorption in response to parathyroid hormone. 

Thiazide diuretics compete for chloride binding sites on these cotransporters.

Collecting ducts

Within the collecting duct, urine concentration is controlled by levels of antidiuretic hormone (ADH) within the blood. Osmoreceptors within the hypothalamus detect changes in osmotic pressure, i.e. blood volume. Raised pressures activate the osmoreceptors, activating neurosecretory cells within the hypothalamus to produce ADH. ADH is released from the posterior pituitary to the bloodstream. Conversely, low osmotic pressure inhibits osmoreceptors and, thus, ADH production and secretion. ADH travels within the blood to the kidney and then binds to receptors in the collecting duct, stimulating the insertion of aquaporin water channels into the luminal membrane. Water can then move out of the collecting duct, resulting in decreased urine concentration and increased water return to the blood. ADH also prevents water loss through sweating and causes arteriole constriction, increasing blood pressure.

In periods of fluid overload, atrial stretch releases atrial natriuretic peptide from the atria (ANP). This inhibits the adrenal release of aldosterone, reducing sodium reabsorption and pituitary release of ADH, preventing water reabsorption. The overall effect is an increased diuresis. 

Drugs can interfere with ADH activity in several ways. An example of this is alcohol, which inhibits the secretion of ADH, thus increasing urine volume. A further example is lithium, which can cause nephrogenic diabetes insipidus by inhibiting the collecting duct response to ADH, reducing aquaporin channels, and triggering increased urine output. 

Other functions of the collecting duct include a small amount of sodium reabsorption via aldosterone-activated sodium channels and hydrogen ion secretion.

References

Kumar, P. and Clark, M., 2012. Kumar & Clark’s clinical medicine. 8th ed.

Fairweather, J., Findlay, M., & Isles, C. (2020). Clinical companion in nephrology. Springer International Publishing. 

Tortora, G. J., & Derrickson, B. (2017). Tortora’s principles of anatomy and physiology. John Wiley and Sons.

Other functions

Erythropoiesis

Erythropoietin is secreted by the peri-tubular cells in response to hypoxia. This stimulates erythropoiesis within the bone marrow to produce red blood cells. Low levels of erythropoietin result in a reduced number of red blood cells produced with abnormal size and iron content. Uraemia also has a toxic effect on precursor cells within the bone marrow; therefore, waste excretion is essential to maintain bodily functions. 

Blood pressure

The kidneys play an integral role in blood pressure control. 

The juxtaglomerular apparatus within the distal convoluted tubule detects periods of reduced blood volume (whether due to dehydration or haemorrhage) and thus reduces blood pressure and renal perfusion. Renin is then released from the kidney, which converts angiotensinogen to angiotensin I. Angiotensin I travels within the bloodstream to the lungs and is, in turn, converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II results in vasoconstriction, increased thirst, and the release of aldosterone from the zona glomerulosa of the adrenal gland. This pathway can also initiated by hyponatraemia. 

Image Source: Wikimedia Commons (2019). Renal corpuscle-en, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/6/69/Renal_corpuscle-en.svg  (Accessed: 4 January 2024).

Aldosterone promotes sodium reabsorption by activating sodium channels within the distal convoluted tubule and collecting duct. Water then follows by osmosis, increasing blood volume and reducing urine output. Spironolactone causes diuresis by acting competitively against aldosterone to prevent the activation of these sodium channels.

Hyperkalaemia can also trigger the release of aldosterone from the adrenal gland, which attempts to normalise potassium levels by increasing potassium and hydrogen ion loss in the urine.  

ACE inhibitors such as ramipril interrupt this chain, preventing the conversion of angiotensin I and reducing blood pressure.

Image Source: Wikimedia Commons (2018). Renin angiotensin aldosterone system, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/3/36/Renin-angiotensin-aldosterone_system.svg  (Accessed: 4 January 2024).

Electrolyte balance and vitamin D metabolism

As we have seen already, the kidneys can influence the levels of some electrolytes within the body. Low calcium levels stimulate PTH release from the parathyroid glands. PTH acts on the kidneys to reduce calcium and magnesium loss in the urine and increase phosphate excretion. 

PTH also stimulates the activation of vitamin D in the kidneys thanks to the production of alpha-1-hydroxylase by the proximal tubular cells. This enzyme catalyses the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (calcitriol). Calcitriol then stimulates absorption of calcium, phosphate and magnesium from the gastrointestinal tract. In CKD, the production of alpha-1-hydroxylase drops. 

Acid-base balance

The kidneys have a significant role in acid-base balance.

References

Kumar, P. and Clark, M., 2012. Kumar & Clark’s clinical medicine. 8th ed.

Fairweather, J., Findlay, M., & Isles, C. (2020). Clinical companion in nephrology. Springer International Publishing. 

Tortora, G. J., & Derrickson, B. (2017). Tortora’s principles of anatomy and physiology. John Wiley and Sons.