The tubular system consists of:
- Proximal tubule (PT):
- Proximal convoluted tubule
- Proximal straight tubule (PST)
- Loop of Henle:
- Thin descending limb
- Thin ascending limb
- Thick ascending limb
- Distal convoluted tubule
- Collecting ducts
Pathways of epithelial solute transport
- Paracellular: passive transport in between cells
- Transcellular: transport through cells; may be active or passive
- Located on the basolateral side of tubule cells
- 3 Na+ out of the cell
- 2 K+ into the cell
- Creates a Na+ concentration gradient and a voltage gradient:
- The tubule lumen becomes electronegative in the early proximal convoluted tubule (however, the electronegativity changes as substances are absorbed throughout the nephron).
- Active and passive transport mechanisms are dependent on these gradients.
Methods of water transport
- Water moves through the epithelial tight junctions (“leaky” subtype of tight junctions).
- Movement of water is dictated by osmolarity (osmosis).
- Water moves through the cell via specific channels known as aquaporins.
- Aquaporins are located in:
- Thin descending limb of the loop of Henle
- Collecting duct
- Solvent drag:
- Some solutes are “dragged” along as water moves.
- Solutes move via convective currents created by the movement of water.
- The reabsorption capacity for any given substance is limited.
- Once exceeded, additional substances are lost in the urine.
- Also referred to as the “renal threshold” for reabsorption
- For example, glucose:
- Has transport maximum (Tm) of 375 mg/min
- At this rate, the kidneys can reabsorb 100% of the filtered glucose up to a plasma glucose concentration of approximately 180 mg/dL.
- When plasma glucose exceeds 180 mg/dL:
- Kidneys are no longer capable of reabsorbing 100% of the filtered glucose.
- Excess glucose is lost in urine (“glucosuria”).
Peritubular capillary absorption
Peritubular capillary reabsorption differs from regular capillary reabsorption to maximize the reabsorption of substances back into the bloodstream.
- Regular capillaries filter along their 1st half and reabsorb along their 2nd half:
- Arterial half: higher capillary hydrostatic pressure and lower oncotic pressure → filtration
- Venous half: lower capillary hydrostatic pressure and higher oncotic pressure → reabsorption
- Peritubular capillaries reabsorb fluid across their entire length:
- Lower capillary hydrostatic pressure and higher capillary oncotic pressure across their entire length
- No area of filtration
Proximal Tubule: Reabsorption of Ions
Glomerular filtration is a very nonspecific process, resulting in the filtration of large quantities of important substances that the body needs to retain (e.g., Na+, HCO3–). The primary function of the PT is to reabsorb as much of these substances as possible. Subsequently, the other nephron segments fine-tune the urine composition.
Anatomy of the PT
- Divided into 2 parts: proximal convoluted tubule and PST
- Proximal convoluted tubule: primary location for PT reabsorption
- PST: important for PT secretion
- Brush border cells line the tubule lumen to increase the surface area for reabsorption.
- Na+/K+-ATPase is located on the basolateral side of the epithelial cells.
Sodium reabsorption in the PT
- Coupled with reabsorption of other substances via cotransporters:
- Amino acids
- Organic acids
- Powered by the Na+ gradient generated by the basolateral Na+/K+-ATPase:
- Low intracellular Na+ concentration
- High Na+ concentration in the tubule lumen and interstitial space on the basolateral side
- Na+ reabsorption drives the paracellular reabsorption of water:
- Na+ and water are reabsorbed at the same rate.
- Reabsorption of Na+ in the PT is isotonic to plasma.
- Efficiency: Approximately ⅔ of filtered water and Na+ are reabsorbed in the PT.
Chloride (Cl–) reabsorption in the PT
- Majority of the filtered Cl– is reabsorbed in the PT.
- Transport is primarily paracellular.
- Powered by the voltage gradient in the early PT generated by Na+/K+-ATPase:
- Cl– is repelled by the electronegative tubule lumen.
- Cl– is attracted to the electropositive basolateral interstitium.
Potassium, calcium (Ca2+), and magnesium (Mg2+) reabsorption in the PT
- Early PT: paracellular reabsorption via solvent drag
- Late PT: paracellular via voltage gradient
- Due to upstream reabsorption of Cl– in the early PT, the polarity in the late PT flips.
- In the late PT, the tubule lumen becomes more electropositive, and the basolateral interstitium becomes more electronegative.
- 80% of the filtered K+ is reabsorbed in the PT.
- 65% of the filtered Ca2+ is reabsorbed in the PT.
- 15% of the filtered Mg2+ is reabsorbed in the PT.
Bicarbonate reabsorption in the PT
Reabsorption of HCO3– requires a more complex mechanism:
- Sodium-hydrogen ion exchanger 3 (NHE3) reabsorbs Na+ and secretes H+.
- The secreted H+ combines with the filtered HCO3– to form carbonic acid (H2CO3) in the tubular lumen.
- H2CO3 is converted to H2O and CO2 by apical carbonic anhydrase-IV.
- CO2 diffuses freely across the apical membrane back into the cell.
- Intracellular carbonic anhydrase-II converts CO2 and H2O back into H2CO3.
- H2CO3 then dissociates into H+ and HCO3–:
- H+ is recycled through the process via secretion by NHE3.
- HCO3– is absorbed through the basolateral membrane via:
- Na+-HCO3– cotransporter
- HCO3–-Cl– exchanger
- Net effects of the entire process:
- Excretion of H+
- Absorption of HCO3–
- Efficiency: Under normal circumstances, 80% of the filtered HCO3– is reabsorbed in the PT.
Phosphate (PO43-) reabsorption in the PT
- PO43- reabsorption is regulated by the parathyroid hormone (PTH): PTH inhibits PO43- reabsorption.
- ↓ PTH → ↑ PO43- reabsorption:
- In the setting of ↓ PTH, Na+/PO43- cotransporters (transporting 3 Na+ and 1 PO43-) are inserted into the apical membrane
- PO43- moves across the cell and is transported across the basolateral membrane via an unknown transporter.
- ↑ PTH → ↓ PO43- reabsorption:
- PTH binds to a basolateral PTH receptor of the PT cell.
- Na+/PO43- cotransporters are downregulated.
Proximal Tubule: Reabsorption of Macromolecules
Glucose reabsorption in the PT
- Apical transporters: sodium-glucose linked transporter (SGLT)2 and SGLT1
- SGLT2 transporter:
- 1 Na+ and 1 glucose move into the cell.
- Responsible for the majority of glucose reabsorption in the PT
- SGLT1 transporter:
- 2 Na+ and 1 glucose move into the cell.
- Responsible for reabsorbing glucose that is not captured by SGLT2
- Lower capacity but higher affinity for glucose than SGLT2
- Both are powered by the concentration gradient of Na+ created by the basolateral Na+/K+-ATPase.
- SGLT2 transporter:
- Basolateral transporters: glucose transporter (GLUT)2 and GLUT1
- Glucose moves out of the cell and into the interstitium via the GLUT.
- GLUT2 is paired with SGLT2, and GLUT1 is paired with SGLT1.
- Efficiency: Under normal circumstances, 100% of glucose is reabsorbed within the 1st 25% of the PT.
Peptide reabsorption in the PT
- Early PT apical proteins:
- PepT1: H+/peptide cotransporter responsible for the majority of peptide reabsorption in the PT
- Peptidase: membrane-bound enzyme
- Located in the early segment of the PT
- Breaks down larger tripeptides within the tubule lumen
- The smaller broken-down peptides can then enter via PepT1.
- Late PT apical proteins:
- PepT2: H+/peptide cotransporter responsible for reabsorbing peptides not captured by PepT1
- Megalin and cubilin receptors:
- Bind and endocytose small proteins
- Endocytosed vacuoles bind to basolateral membrane and release contents.
- Peptides are digested into amino acids by proteases within the cell.
- Amino acids exit the cell via transporters on the basolateral membrane.
- 100% reabsorbed within the 1st 25% of the PT.
- Renal threshold for reabsorption can be exceeded → “overflow proteinuria”
Amino acid reabsorption
- Apical reabsorption:
- Anionic (acidic) or cationic (basic) amino acids: various ion exchangers
- Neutral amino acids: via Na+ or H+ cotransport
- Basolateral reabsorption:
- Aromatic amino acids: via facilitated diffusion
- Cationic (basic) and neutral amino acids: via Na+ cotransport
Proximal Tubule: Secretion
Secretion occurs primarily in the PST (i.e., late PT) and allows for the elimination of endogenous and exogenous substances such as toxins and drugs.
- Organic anions (OA–s) are moved from the basolateral side into cells by organic anion transporters (OATs).
- Transported into the tubule lumen by 2 proteins:
- Multidrug-resistant transporter (MRP2)
- OAT4 exchanger
- Examples of OA–s secreted in the PT: bile salts, urate, certain drugs (see table below)
- Organic cations (OC+s) are moved from the basolateral side into cells by organic cation transporters (OCTs).
- Transported into the tubule lumen by 2 proteins:
- Multidrug-resistant transporter (MDR1)
- Organic cation transporter novel (OCTN) exchanger
- Examples: creatinine, dopamine, certain drugs (see table below)
Organic ions secreted by the PT
Loop of Henle
The loop of Henle is a complex segment of the nephron with 2 main purposes: maintaining the corticomedullary gradient and reabsorbing moderate amounts of Na+ and water. These 2 processes are linked via the countercurrent multiplier system in the thin loops, and additional Na+ absorption occurs via active transport in the thick ascending limb.
Anatomy of the loop of Henle
- Descending thin limb
- Hairpin turn
- Ascending thin limb
- Thick ascending limb
- Osmolality of the renal interstitium ranges from approximately 300 mOsm/kg in the cortex to approximately 1200 mOsm/kg in the inner medulla.
- This gradient is necessary for dynamic control of water reabsorption later in the collecting duct.
- The gradient is established and maintained by the passive movement of fluid and solutes according to the countercurrent multiplier theory.
Countercurrent multiplier theory
The countercurrent multiplier theory explains how the movement of fluids and solutes creates a significant corticomedullary gradient. This process occurs primarily in the thin loops of Henle and via urea recycling.
Within the thin loops of Henle:
- Thin descending limb:
- Permeable only to water and not to solutes
- Increasing amounts of water exit the tubules as the tubule fluid descends through areas of the interstitium with increasingly high osmolality (known as “fluid displacement”).
- Tubule fluid becomes concentrated.
- Thin ascending limb:
- Permeable only to solutes (via passive transport) and not to water
- Increasing amounts of solutes exit the tubule as the tubule fluid ascends through areas of the interstitium with decreasing osmolality (known as a “single effect”).
- Tubule fluid becomes near isotonic again at the end of the thin ascending limb.
- Repeating “fluid displacement” followed by a “single effect” over and over again generates and maintains the corticomedullary gradient.
- In the PT: Approximately 50% of urea is reabsorbed via paracellular transport.
- In the loop of Henle:
- Approximately 50% of urea reenters the tubule (passive secretion).
- Approximately 30% is reabsorbed.
- In the collecting duct:
- Approximately 50% of urea is reabsorbed via the apical transporter UT-A1 and the basolateral transporter UT.
- Antidiuretic hormone (ADH) upregulates apical UT-A1 → ↑ urea reabsorption
- Reabsorbed urea in the interstitium contributes to the corticomedullary gradient.
- Ultimately, 60% of filtered urea is retained for this purpose and 40% is excreted.
Thick ascending limb
The Na-K-2Cl (NKCC2) cotransporter is the key transport protein in the thick ascending limb.
- NKCC2 transports the following into the cell from the tubule lumen:
- 1 Na+ (exits basolateral side via Na+/K+-ATPase)
- 1 K+ (can exit on the apical and/or basolateral side via the ROMK channel)
- 2 Cl– (exit basolateral side via Cl– channels, primarily the ClC-Kb channel)
- Generates an electrical gradient: net effect of NKCC2 is 2 Cl- and 1 Na+ on the basolateral side:
- K+ is recycled into the tubular fluid via ROMK channels (to facilitate further NKCC2 function).
- The basolateral side becomes more electronegative due to unmatched Cl–.
- Important for driving the paracellular transport of cations
- Contributes to the osmotic gradient between tubular fluid and interstitium:
- Water does not follow solutes (Na+, K+, Cl–) into the interstitium.
- Tubule fluid (i.e., urine) becomes hypotonic to plasma (“diluting segment”).
- Site of action for loop diuretics (furosemide, torsemide, bumetanide):
- Inhibit NKCC2 → more Na+, K+, and Cl– remain in the lumen
- Increased Na+ in tubule lumen obligates water to stay with it → both are excreted
Distal Convoluted Tubule
The distal convoluted tubule (DCT) is another “diluting segment” of the nephron, where the thiazide-sensitive NaCl cotransporter helps generate hypotonic tubule fluid due to the DCT not being permeable to water. The transport of K+, Mg+2, and Ca2+ also occurs in this segment.
- Reabsorbed via apical TRPV5 channels:
- TRPV5 is upregulated by the action of PTH.
- ↑ PTH → ↑ adenylyl cyclase and phospholipase C → ↑ phosphorylation of TRPV5 → ↑ open probability of TRPV5 channel → ↑ Ca2+ reabsorption
- Within the cell, Ca2+ is bound to the protein calbindin:
- Necessary due to the cytotoxic effects of high intracellular Ca2+
- Transports Ca2+ to the basolateral membrane
- Ca2+ is moved into the basolateral interstitium via 2 mechanisms:
- Ca2+ ATPase
- Ca2+-Na+ exchanger
- Reabsorbed via TRPM6 channels
- Does not require a cytosol transport protein (such as calbindin)
- Mechanism for movement into basolateral interstitium is unknown.
Occurs via 2 mechanisms:
- NaCl cotransporter:
- Na+ and Cl– are reabsorbed.
- Site of action of thiazide diuretics
- Epithelial sodium channels (ENaC):
- Na+ is reabsorbed by itself.
- Creates a voltage gradient because there is no matched transport of other charged ions (i.e., it is not exchanged for another cation, or cotransported with an anion)
- Also found in the collecting ducts
- Site of action of amiloride (K+-sparing diuretic)
- Early DCT: paired with Na+ via the NaCl cotransporter
- Late DCT (2 mechanisms):
- Driven by the electrical gradient generated by ENaC activity
- Cl– moves out of the electronegative lumen and toward the electropositive basolateral side.
- Accounts for the majority of Cl– transport in the late DCT
- Apical Cl– channel → basolateral Cl–-HCO3– exchanger
- Occurs only at intercalated cells (not abundant in the DCT; primarily located in the collecting ducts)
- K+ is not reabsorbed in the DCT, but it is secreted in the late DCT.
- Secretion occurs via ROMK channels of principal cells (primarily located in the collecting ducts, but also present in the late DCT):
- Driven by electronegative lumen from ENaC (same as in Cl– reabsorption)
- ROMK channels are upregulated by aldosterone.
- K+ secretion through ROMK will increase if ENaC activity increases.
Collecting ducts are the points where multiple nephrons come together during the final stages of urine formation. Intercalated cells and principal cells act to adjust the final composition and concentration of the urine, prior to elimination.
Intercalated cells are further divided into α and β subtypes, with each having a slightly different composition of transporters and other proteins.
- 1 H+ out of the cell, 1 K+ into the cell
- Involved in fine-tuning of K+ reabsorption
- 1 H+ out of the cell
- Involved in acid secretion
- Cl–/HCO3– exchanger (β-intercalated cells)
- Cl– channels
- H+-ATPase (β-intercalated cells):
- Paired with the apical Cl–/HCO3– exchanger
- Involved with acid homeostasis
- Cl–/HCO3– exchanger (α-intercalated cells):
- Paired with the apical Cl– channel
- Involved with Cl– reabsorption
Principal cells are responsible for the fine-tuning of Na+ and K+ in the urine, which is often in response to the hormone aldosterone. Principal cells are also the site of the apical aquaporin channel AQP2, which is a key component in adjusting urine concentration.
- ENaC channel: 1 Na+ moves into cell
- Na+ reabsorption is powered by the Na+ gradient generated by Na+/K+-ATPase.
- For each Na+ that moves into the cell, 1 Cl– is left behind in the tubular lumen.
- Creates an electrical gradient where the luminal side is more negative
- ↑ Expression/open probability with aldosterone
- ↑ Distal Na+ delivery results in ↑ ENaC channel activity
- ROMK channel: 1 K+ moves out of cell
- K+ secretion is powered by K+ chemical and electrical gradients generated by the Na+/K+-ATPase and ENaC channels.
- ROMK channels can open and close; there is an ↑ open probability with:
- ↓ Intracellular ATP (indicates ATP has just been used up by Na+/K+-ATPase to bring K+ into the cell)
- Aquaporin 2 (AQP2) channel: passive water channel
- Water in the renal medulla is hypertonic compared to urine due to the countercurrent multiplier system and diluting segments.
- Water will leave the collecting ducts following its osmotic gradient to allow efflux if aquaporin channels are present.
- ADH stimulates the production and insertion of aquaporins:
- ↑ ADH levels → ↑ aquaporins → ↑ water reabsorption → concentrated urine
- ↓ ADH levels → ↓ aquaporins → ↓ water reabsorption → dilute urine
- 3 Na+ move out of cell and 2 K+ move into the cell.
- Stimulated by aldosterone
The following table summarizes the reabsorption, secretion, and important regulatory molecules throughout the tubular system. Regulatory molecules are noted in parentheses, and “+” and “-” indicate stimulation and inhibition, respectively.
|Segments/molecules||Proximal tubule (proximal convoluted tubule and PST)||Loop of Henle||Distal tubule||Collecting duct||Excreted|
|Glucose||98% (proximal convoluted tubule); 2% (PST) reabsorbed||–||–||–||–|
|Amino acids and peptides||99% (proximal convoluted tubule); 1% (PST) reabsorbed||–||–||–||–|
|Phosphate||80% reabsorbed (-PTH)||–||10% reabsorbed||–||10%|
|Urea*||50% reabsorbed||30% reabsorbed; 50% secreted||–||50% reabsorbed||40%|
|Bicarbonate||80% reabsorbed||10% reabsorbed||6% reabsorbed||4% reabsorbed||–|
|Calcium||65% reabsorbed||25% reabsorbed||8% reabsorbed (+PTH)||1% reabsorbed||1%|
|Magnesium||15% reabsorbed||70% reabsorbed||10% reabsorbed||–||5%|
|Potassium (dietary intake)||80% reabsorbed||10% reabsorbed|
|Sodium||67% reabsorbed (+Ang-II)||25% reabsorbed (+Ang-II)||5% reabsorbed (+Ald, -ANP)||3% reabsorbed (+Ald, -ANP)||1%|
|Water||67% reabsorbed||15% reabsorbed||–||18% reabsorbed (+ADH, -ANP)||1%|
PTH: parathyroid hormone
PST: proximal straight tubule
ADH: antidiuretic hormone
ANP: atrial natriuretic peptide
- Renal cell carcinoma: the most common primary renal malignancy that originates from renal tubular cells (most commonly in the PT).
- SGLT2 inhibitors: a class of oral medications used in the management of type 2 diabetes mellitus. SGLT2 inhibitors block glucose reabsorption via the SGLT2 transporter in the PT, causing glucose to be excreted in the urine rather than being reabsorbed. The names of SGLT2 inhibitors end in -gliflozin (e.g., empagliflozin) and are considered 2nd-line options. An important side effect is the increased risk for genitourinary tract infections.
- Loop diuretics: a commonly used class of diuretics (including furosemide, bumetanide, and torsemide) that exert their effects by blocking the NKCC2 cotransporter in the thick ascending limb of the loop of Henle. Sodium ions remain in the tubule lumen and obligate water to remain with it, resulting in diuretic action. Hypokalemia is a common side effect due to the action of increased distal delivery of Na+ on the ROMK channels.
- ACEi: a commonly used class of antihypertensive drugs that inhibit the RAAS at the ACE level. The names of the drugs in this class end in -pril (e.g., lisinopril, enalapril) and are commonly used for the treatment of heart failure and proteinuria, in addition to hypertension. These drugs are clinically interchangeable with aldosterone receptor blockers.
- Aldosterone receptor blockers: a commonly used class of antihypertensive drugs that inhibit the RAAS at the aldosterone receptor level. The names of the drugs in this class end in -artan (e.g., losartan, candesartan) and are commonly used for the treatment of heart failure and proteinuria, in addition to hypertension. These drugs are clinically interchangeable with ACE inhibitors and are often used when ACE inhibitors are not tolerated owing to the relatively common side effect of coughing (which is not a feature of aldosterone receptor blockers).
- Diabetes insipidus (DI): a disease resulting from either the lack of ADH secretion (central DI) or the resistance to ADH (nephrogenic DI). The lack of ADH stimulation in the tubular cells results in decreased aquaporin channels in the collecting ducts, which, in turn, leads to decreased water reabsorption, inappropriately dilute urine, and polyuria. Treatment includes the administration of desmopressin (ddAVP), an ADH analog.
- V2 receptor blockers: also known as “vaptans,” this class of drugs inhibits the action of ADH at the receptor level. V2 receptor blockers are used in the treatment of SIADH, which causes hyponatremia from inappropriately high water reabsorption from the aquaporin channels in the collecting duct. Tolvaptan is the most commonly used oral drug in this class.
- Agarwal, S.K., Gupta, A. (2008). Aquaporins: The renal water channels. Indian Journal of Nephrology. 18(3), 95–100. https://doi.org/10.4103/0971-4065.43687
- Nielsen, S., et al. (2002). Aquaporins in the kidney: From molecules to medicine. Physiological Reviews. 82(1), 205–244. https://doi.org/10.1152/physrev.00024.2001
- DeSantis, A. (2020). Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus. UpToDate. Retrieved April 15, 2021, from https://www.uptodate.com/contents/sodium-glucose-co-transporter-2-inhibitors-for-the-treatment-of-hyperglycemia-in-type-2-diabetes-mellitus
- Eaton, D.C., Pooler, J.P. (Eds.). (2018). Basic transport mechanisms. In Vander’s Renal Physiology, 9e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2348§ionid=185663984
- Eaton, D.C., Pooler, J.P. (Eds.). (2018). Renal handling of organic solutes. In Vander’s Renal Physiology, 9e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2348§ionid=185664057
- Eaton, D.C., Pooler, J.P. (Eds.). (2018). Basic renal processes for sodium, chloride, and water. In Vander’s Renal Physiology, 9e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2348§ionid=185664120
- Eaton, D.C., Pooler, J.P. (Eds.). (2018). Regulation of sodium and water excretion. In Vander’s Renal Physiology, 9e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2348§ionid=185664222
- Eaton, D.C., Pooler, J.P. (Eds.). (2018). Regulation of potassium balance. In Vander’s Renal Physiology, 9e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2348§ionid=185664348
- Eaton, D.C., Pooler, J.P. (Eds.). (2018). Regulation of calcium, magnesium, and phosphate. In Vander’s Renal Physiology, 9e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2348§ionid=185664534