The first step in renal processing involves the filtration of plasma in the glomerulus. Glomerular filtration is a process of bulk flow: water and low molecular weight substances move from the lumen of the capillary, across the filtration membrane, and into Bowman’s space.
What is filtered? Any low-molecular weight substance that is freely dissolved in plasma is filtered. This includes various polar organic molecules such as glucose or amino acids, ions, peptides, drugs, and waste products of organic metabolism such as creatinine and urea. Because filtration involves bulk flow, the concentration of a substance in Bowman’s space will be the same as its concentration in the plasma.
What is not filtered? Cells, of course, are too large to be filtered. Importantly, proteins are not filtered, but are retained in the plasma. Also, small molecular weight substances that are bound to proteins will not be filtered. It is the structure of the filtration membrane that prevents proteins from being filtered.
There are three layers that make up the filtration membrane: two epithelia and the basement membrane that lies between them. Figure 1 is a three-dimensional illustration of part of a capillary loop in the glomerulus and depicts the layers making up the filtration membrane.
Figure 2 depicts a cross-section of the filtration membrane, as might be seen in a high-powered transmission EM. A substance that is filtered passes first through a fenestra in the capillary endothelium (red). Next, it passes across the glomerular basement membrane (tan), which consists of a network of collagen fibrils and other structural proteins that create small pores that exclude many proteins on the basis of their size. Additionally, negatively charged proteoglycans in the basement membrane may prevent protein filtration on the basis of charge. Finally, the substance passes through the filtration slits, that are found between the interdigitating foot processes (blue and green).
A structure called the slit diaphragm (pink), made of various proteins that are synthesized by the podocytes, extends across the filtration slits. The slit diaphragm is one of the most important barriers to the filtration of protein. Proteins from adjacent foot processes interact to form a mesh-like barrier that appears to exclude proteins based on their size.
When the filtration membrane is not functioning properly, it ceases to be an effective barrier. What then occurs is proteinuria, an abnormal accumulation of protein in the urine. A very small amount of protein gets filtered normally, but this is almost completely reabsorbed in the proximal tubule by endocytosis. If protein is detected in the urine, it usually means that there is a breakdown in the filtration barrier.
There are a number of ways that the filtration membrane can be damaged. We know that the slit diaphragm is an important component of the filtration membrane because rare, inherited forms of congenital proteinuria occur when genetic mutations disrupt key structural proteins of the slit diaphragm.
Acquired disorders may also disrupt the structure of the podocyte foot processes and filtration slits and cause proteinuria. The foot processes retract and the podocytes make broad flat contacts with the basement membrane, a condition known as podocyte effacement. The major disorders that disrupt the filtration barrier are diabetes mellitus, hypertension, and glomerulonephritis. In diabetes mellitus, hyperglycemia and/or reduced insulin signaling trigger a set of changes in the filtration membrane that cause a loss of selectivity and result in proteinuria. Hypertension is damaging because the high pressure in the glomerular capillaries damages the filtration membrane. In glomerulonephritis, there is inflammatory damage to the filtration membrane due to immunological attack.
When proteinuria is severe (greater than 3.5g/day), it is called nephrotic syndrome. Nephrotic syndrome consists of a set of symptoms, and may occur as a consequence of any of the various diseases that affect the filtration membrane. Excessive proteinuria causes a low level of protein in the plasma. This combined with sodium retention leads to edema. Other symptoms of nephrotic syndrome are hyperlipidemia and hypertension.
The degree of proteinuria is a good predictor for the progression of chronic renal disease. This is due to the fact that high levels of protein in the filtrate have a pathogenic effect on the renal tubules. Increased endocytosis of protein by renal tubular cells ultimately stimulates inflammation and fibrosis, and leads to the loss of nephrons.
Because of this pathogenic effect of filtered protein, treatments that decrease proteinuria will have a renoprotective effect. Good control of blood pressure is important. Several major studies have shown that drugs that block the renin-angiotensin-aldosterone system (RAAS) (ACE inhibitors, angiotensin II receptor blockers and the direct renin inhibitor, aliskiren) are particularly effective at reducing proteinuria. These drugs appear to be helpful even beyond their effect on blood pressure, and this is because of the specific effects of angiotensin II within the kidney. One effect is that the efferent arteriole vasoconstricts more in response to angiotensin II, and so blocking the RAAS prevents excessive pressure in the glomerular capillaries. Another is that angiotensin II causes changes in the renal corpuscle that affect the permeability and selectivity of the filtration membrane.