Formation of Glomerular Filtrate

As stated in Chapter 1, the glomerular filtrate is nearly protein-free2 and contains most inorganic ions and low-molecular-weight organic solutes in virtually the same concentrations as in the plasma.
In order to form a glomerular filtrate, filtered fluid must pass through the glomerular filtration barrier. The filtration barrier separates the blood from the urinary space that topologically connects to the outside world via the renal tubules, ureters, bladder, and urethra. The route that filtered substances takes from the blood through the filtration barrier of a renal corpuscle into Bowman’s space is a 3-step process: through fenestrae in the glomerular-capillary endothelial layer, through the basement membrane, and finally through slit diaphragms between podocyte foot processes. The fraction of endothelial surface area occupied by fenestrae is about 10%. Both the slit diaphragm and basement membrane are composed of an array of proteins, and while the basement membrane may contribute to selectivity of the filtration barrier, integrity of the slit diaphragms is essential to prevent excessive leak of plasma protein (albumin). Some protein-wasting diseases are associated with abnormal slit diaphragm structure. Selectivity of the barrier to filtered solute is based on both molecular size and electrical charge. Let us look first at size.
The filtration barrier of the renal corpuscle provides no hindrance to the movement of molecules with molecular weights less than 7000 Da (ie, solutes this small are all freely filtered). This includes all small ions, glucose, urea, amino acids, and many hormones. The filtration barrier almost totally excludes plasma albumin (molecular weight of approximately 66,000 Da). (We are, for simplicity, using molecular weight as our reference for size; in reality, it is molecular radius and shape that is critical.) The hindrance to plasma albumin is not 100%, however, and so the glomerular filtrate does contain extremely small quantities of albumin, on the order of 10 mg/L or less. This is only about 0.02% of the concentration of albumin in plasma and is the reason for the use of the phrase “nearly protein-free” earlier. (Note: Some small substances are partly or mostly bound to large plasma proteins and are thus not free to be filtered, even though, when not bound to plasma proteins, they can easily move through the filtration barrier. This includes hydrophobic hormones of the steroid and thyroid categories and about 40% of the calcium in the blood.)
For molecules with a molecular weight ranging from 7000 and 70,000 Da, the amount filtered becomes progressively smaller as the molecule becomes larger. Thus, many normally occurring plasma peptides and small proteins are filtered to a significant degree. Moreover, when certain small proteins not normally present in the plasma appear because of disease (eg, hemoglobin released from damaged erythrocytes or myoglobin released from damaged muscles), considerable filtration of these may occur.
Electrical charge is the second variable determining filterability of macromolecules. For any given size, negatively charged macromolecules are filtered to a lesser extent, and positively charged macromolecules to a greater extent, than neutral molecules. This is because the surfaces of all the components of the filtration barrier (the cell coats of the endothelium, the basement membrane, and the cell coats of the podocytes) contain fixed polyanions, which repel negatively charged macromolecules during filtration. Because almost all plasma proteins bear net negative charges, this electrical repulsion plays a very important restrictive role , enhancing that of purely size hindrance. (For example, when neutral dextrans, the same size as plasma albumin, are administered to experimental animals, they are found to be 5–10% filterable rather than albumin’s 0.02%.) In other words, if albumin were not charged or the filtration barrier were not charged, even albumin would be filtered to a considerable degree. Certain diseases that cause glomerular capillaries to become “leaky” to protein do so by eliminating negative charges in the membranes.
It must be emphasized that the negative charges in the filtration membranes act as a hindrance only to macromolecules, not to mineral ions or low-molecularweight organic solutes. Thus, chloride and bicarbonate ions, despite their negative charge, are freely filtered.