The nephron is the basic functional unit of a kidney. It consists of three parts: the renal corpuscle, the filtering component, the renal tubule, which is responsible for absorption and ion secretion, and the collecting duct, which is responsible for the final reabsorption of water and for storing urine. The renal tubule has 3 components: the proximal convoluted tubule (PCT), the Loop of Henle and the distal convoluted tubule (DCT). This article will focus on ion absorption within the proximal convoluted tubule.
The proximal convoluted tubule (PCT) has a high capacity for reabsorption, hence it has specialised features to aid with this. It is lined with simple cuboidal epithelial cells which have a brush border to increase surface area on the apical side. The epithelial cells have large amounts of mitochondria present to support the processes involved in transporting ions and substances.
Moreover, they also have a large number of channels on both the apical and basolateral membrane which provides a large surface area for transport of ions and other substances to occur.
The proximal tubule can be divided into pars convolute and pars recta. The pars convolute resides in the renal cortex and it can further be divided into 2 segments; S1 (segment 1) and the proximal part of S2. The pars recta is a straight segment present in the outer medulla. It makes up the distal part of S2 and S3.
A large amount of reabsorption occurs in the proximal convoluted tubule. Reabsorption is when water and solutes within the PCT are transported into the bloodstream. In the PCT this process occurs via bulk transport. The solutes and water move from the PCT to the interstitium and then into peritubular capillaries. The reabsorption in the proximal tubule is isosmotic.
The proximal tubules reabsorb about 65% of water, sodium, potassium and chloride, 100% of glucose, 100% amino acids, and 85-90% of bicarbonate. This reabsorption occurs due to the presence of channels on the basolateral (facing the interstitium) and apical membranes (facing the tubular lumen).
There are two routes through which reabsorption can take place: paracellular and transcellular. The transcellular route transports solutes through a cell. The paracellular route transports solutes between cells, through the intercellular space.
The driving force for the reabsorption in the PCT is sodium, due to the presence of many sodium-linked symporters e.g. sodium glucose linked transporters (SGLTs) on the apical membrane. Sodium is usually co-transported with other solutes e.g. amino acids and glucose, or in later segments of the tubule with chloride ions. Thus sodium moving down its concentration allows other solutes to move against their own concentration gradient.
To create an electrochemical gradient for sodium, Na+-K+-ATPases on the basolateral surface pump out 3 Na+ ions, in exchange for bringing 2 K+ ions into the cell. This transporter uses primary active transport. This movement of Na+ creates an electrochemical gradient favouring the movement of Na+ into the cell from the tubule lumen.
The S1 segment of the PCT is not permeable to urea and chloride ions, hence their concentration increases in S1 which creates a concentration gradient which can be utilised in the S2 and S3 segments. Additional sodium is transported via an antiporter mechanism that reabsorbs sodium whilst secreting other ions, especially H+.
Co-transport refers to the movement of multiple solutes through the same channel. There are two types of co-transporters:
- Symporters – transporters that move two (or more) molecules in the same direction e.g. SGLTs
- Antiporters – transporters that move two (or more) molecules in opposite directions e.g. Na+/H+ antiporter
The sodium concentration gradient allows other molecules, such as glucose, to be transported across the apical membrane against their concentration gradient. For example, SGLT transporters move glucose together with two sodium ions across the apical membrane. Glucose then crosses the basolateral membrane via facilitated diffusion.
Na+/Amino acid symporters are present on the apical side of cells in the S1 segment of the PCT which reabsorbs all the amino acids in the PCT.
Na+/H+ antiporter is found on the apical surface of PCT cells. It is an antiporter and therefore transports ions across the cell membrane in opposite directions. In this case, the Na+ ions move into the tubular cells, while the H+ is expelled into the lumen. The primary function of this transporter is to maintain the pH.
Movement of Water
In the PCT, large volumes of solute are transported into the bloodstream. This means that as we move along the tubule, solute concentration in the tubule decreases while the solute concentration in the interstitium increases.
The difference in concentration gradient results in the water moving into the interstitium via osmosis. Water mainly takes the paracellular route to move out of the renal tubule but it can also take the transcellular route.
Secretion is when substances are removed from the blood and transported into the PCT. This is very useful as only 20% of the blood is filtered in the glomerulus every minute, so this provides an alternative route for substances to enter the tubular lumen. The PCT secretes:
- Organic acids and bases – e.g. bile salts, oxalate and catecholamines (waste products of metabolism)
- Hydrogen ions (H+) – important in maintaining acid/base balance in the body. H+ secretion allows reabsorption of bicarbonate via the use of the enzyme carbonic anhydrase (Fig 2). The net result is for every one molecule of H+ secreted, one molecule of bicarbonate and Na+ is reabsorbed into the blood stream. As the H+ is consumed in the reaction in the tubular lumen, there is no net excretion of H+. In this way, about 85% of filtered bicarbonate is reabsorbed in the PCT (the rest is reabsorbed by the intercalated cells at the DCT/CD later on)..
- Drugs/toxins – Secretion of organic cations such as dopamine or morphine occurs via the H+/OC+ exchanger on the apical side of the tubule cell, which is driven by the Na+/H+ antiporter.
Clinical Relevance – Renal Cell Carcinoma
Renal cell carcinoma (RCC) is the most common primary renal malignancy originating from the PCT. RCC has been linked to mutations in chromosome 3 which can be either hereditary or de novo. It most commonly affects men between the ages of 50-70 and has been linked with smoking and obesity.
Some of the symptoms it presents with are clinically with:
- Abdominal pain – particularly in the flanks
- Weight loss
- Night sweats
RCC can invade into the renal vein and then into the inferior vena cava. From here, it can metastasize hematogenously to lung and bones. RCC can also have paraneoplastic effects. These include Cushing-like symptoms and hypercalcaemia and are caused by release of adreno-corticotropic hormone (ACTH) or parathyroid hormone-related protein (PTHrP).
Clinical Relevance – Acute Tubular Necrosis
Acute tubular necrosis (ATN) can be caused by ischaemia which is usually caused by reduced renal blood flow (e.g. due to hypotension or sepsis). It can also be caused by nephrotoxic agents such as aminoglycosides and myoglobin. The ischaemia and toxins results in the death of tubular cells, particularly cells of the PCT.
Typically, ‘muddy brown’ casts of epithelial cells can be seen on urinalysis in ATN. Acute tubular necrosis itself cannot be treated and the main form of management is treating the underlying cause. ATN can cause complications, particularly acute kidney injury (AKI).
|Ion channel||Location||Type of transporter||Pathology|
|3Na-2K-ATPase||Basolateral||Antiporter-like activity but it is not an antiporter *|
|Sodium-dependent glucose transporter||Apical
|Symporter||When glucose concentration exceeds the transport maximum, the extra glucose spills into the urine. Since glucose has an osmotic potential water follows the filtrate resulting in both glycosuria and polyuria.
|Na+/Amino acid transporter||Apical||Symporter|
Clinical Relevance – SGLT2 inhibitors
Known as ‘-gliflozins’ e.g. canaglifozin or dapagliflozin, these are relatively new drugs. They can either be used to treat type 2 diabetes mellitus or as diuretics. Recent studies have also shown their benefit in non-diabetic cardiovascular disease and preventing progression of CKD as well.
They work by inhibiting SGLT2 transporters in the PCT. This prevents sodium and glucose reuptake, which has two main effects. Firstly, glucose cannot be reabsorbed and is thus excreted, reducing blood-glucose levels. Secondly, since less sodium (and glucose) can be reabsorbed, this means the filtrate is more concentrated. As a result, less water is reabsorbed and thus more water is excreted.
Side effects include frequent UTIs and fungal infections (due to the glucose-rich urine) and reported ‘euglycaemic diabetic ketoacidosis’.