Glomerular filtration

Glomerular filtration and hemodynamics

The glomerulus is composed of fenestrated capillaries. The afferent arteriole enters the glomerulus while the efferent arteriole leaves the glomerulus. Blood is filtered across the glomerulus and enters the Bowman’s space as an ultrafiltrate of plasma. Approximately 1 million nephrons are present in each kidney. The GFR or glomerular filtration rate for an individual will be an average of the GFR of all nephrons in that individual.

1. Factors affecting glomerular filtration: Starling forces affect filtration at the glomerulus. Filtration at each nephron can be given by the formula -

   Glomerular filtration = Kf X [(Pgc - Pbs) - (Pi gc - Pi bs)],

   Where Kf is the filtration coefficient; Pgc and Pbs are the hydrostatic pressures at the glomerular capillary and Bowman’s space respectively and Pi gc and Pi bs are the oncotic pressures in the glomerular capillary and Bowman’s space respectively.

   Pi gc changes from the afferent arteriolar end to the efferent arteriolar end. If filtration increases at the proximal end, it would lead to increased concentration of plasma proteins toward the distal end of the capillaries especially the peritubular capillaries. This will reduce filtration and favor absorption by altering the Starling forces. This mechanism assists in tubuloglomerular feedback that ensures that a constant fraction of the filtered load is reabsorbed by the PCT even though the filtered load may increase or decrease.

   Pi bs is effectively 0 as normally plasma proteins are not filtered across the glomerulus in an amount that affects oncotic pressure.

   Kf is comparatively greater for the glomerular capillaries allowing for glomerular filtration. It is dependent on the surface area available for filtration and the hydraulic conductivity. Reductions in glomerular surface area seen in glomerular diseases such as membranous nephropathy or following vasoconstrictors like NE will reduce Kf also. Hydraulic conductivity is reduced in glomerular diseases such as diabetic nephropathy.

   To sum up, factors increasing glomerular filtration are increased Kf, delta Pgc - Pbs, decreased oncotic pressure of glomerular capillary and increased glomerular plasma flow rate (Qa) which depends on renal blood flow. Of these, Pgc and Qa are the most important factors affecting GFR under physiological conditions.

   The glomerular filter is both a charge and size barrier. Movement of anionic molecules across the filter is relatively restricted. Movement of large molecules across the filter is also restricted. Glycocalyx layer on the endothelium of glomerular capillaries and heparan sulfate in the GBM are main contributors of negative charge of the glomerular filtration barrier. The net negative charge of the GBM is a crucial component of the glomerular capillary wall’s filtration barrier to plasma albumin, which is also negatively charged and should therefore be repelled by the GBM.

   The foot processes of podocytes form an intricate network joined together by slit diaphragms. The proteins podocin and nephrin are vital components of podocytes. Nephrin,a transmembrane domain protein with a large extracellular domain, is required for both normal slit diaphragm structure and function. Congenital defects in nephrin can cause nephrotic syndrome. Podocin, like nephrin, is an integral membrane protein. Podocin interacts directly with nephrin and is involved in its trafficking to the slit diaphragm. Defects in the podocin gene can result in congenital nephrosis or focal segmental glomerulosclerosis. The cytoskeletal protein actin is very important in podocyte structure and function. Mutations in the widely expressed actin-regulating proteins alpha-actinin-4 and INF2 lead to podocyte dysfunction, FSGS and progressive kidney disease.

   The GBM is formed by the fusion of basement membranes from both the endothelial and epithelial cells that form the glomerular corpuscle. Morphologically, the GBM contains a dense inner layer called the lamina densa, flanked by the thinner laminae rara interna and rara externa. Type IV collagen, laminin beta 2 and endothelial glycosaminoglycans are also present in the GBM. Mutations in collagen genes COL5A4, COL3A4 and COL4A4 are seen in Alport’s syndrome. Alterations in any of these components can lead to functional disturbances of the GBM and proteinuria.

   Glomerular capillary endothelium is covered by glycocalyx. Changes in the glycocalyx layer have been seen in diabetic nephropathy. VEGF produced locally by podocytes acts in a paracrine manner to help in repair and regeneration of glomerular endothelium.

   The glomerular mesangial processes contain bundles of actin and myosin-based microfilaments that extend to contact the GBM, in which they bind laminin alpha 5 via integrin alpha 3b1 and the basal cell adhesion molecule. These processes provide protection against glomerular pressure and may regulate glomerular capillary flow via contractile properties. The mesangial matrix produced by mesangial cells is composed of a diverse group of proteins, including collagen types III–VI , heparan sulfate proteoglycans and elastic fiber proteins including fibronectin, laminin, entactin and fibrillin-1. Accumulation of mesangial matrix and thickening of the GBM are features commonly observed in a number of glomerular diseases including diabetic nephropathy.

2. Laboratory Markers for GFR: Creatinine is a product of muscle breakdown. It is excreted by the kidneys and freely filtered at the glomerulus as well as secreted by the tubules to some extent. As it is normally produced in the body and it is convenient to determine it’s blood level, creatinine clearance is used as a marker of GFR. Only caveat is that creatinine clearance overestimates the GFR because creatinine is secreted to some extent by the tubules. Theoretically, inulin clearance is the best estimate of GFR, but as it is not normally present in the body and it is inconvenient to measure it, creatinine clearance supersedes it. Since creatinine is derived from muscle, its levels may vary between genders, ethnicities, state of nutrition etc as muscle mass and metabolism vary. So eGFR or estimated GFR is calculated which controls for the above variables. While increases in serum creatinine are quite specific for renal impairment, the test has low sensitivity, often requiring a 50% fall in GFR to cause an appreciable rise in serum creatinine. In an individual, the serum creatinine will approximately double for each halving of the GFR.

   Cystatin C, beta 2 microglobulin and beta trace protein have been recently proposed as better markers of GFR. Blood urea nitrogen concentration also rises when the GFR decreases and is used as a supplementary marker of decreased renal function and GFR.

3. Renal clearance: It is the volume of plasma that is completely cleared of a substance by the kidneys in a given period of time. It is given by following formula:

   C = Ux X V / Px, where C is the clearance, Ux is the concentration of a substance in the urine; Px is the concentration of the same substance in the plasma and V is the urine flow rate.

   Renal clearance of albumin and glucose is close to 0 as albumin is normally not filtered at the glomerulus while glucose is reabsorbed totally even if filtered. Electrolytes are also normally reabsorbed. Inulin clearance is equal to the GFR as once filtered, it is neither reabsorbed nor secreted. PAH or para-amino hippuric acid, and other organic acids have the highest clearances as they are both secreted by the renal tubular cells and filtered at the glomerulus.

   The clearance ratio is the ratio of clearance of a substance to the clearance of inulin. Clearance ratio = 1 means the clearance is equal to inulin clearance; ratio less than 1 means clearance is less than inulin while more than 1 means clearance is more than inulin clearance.

4. Factors affecting renal blood flow: The table lists the factors and mechanisms affecting renal blood flow.

The renal plasma flow can be estimated by PAH clearance. PAH is preferred as it is neither metabolized nor synthesized by the kidney, it does not alter renal plasma flow and almost all of it is removed by the kidney by filtration and secretion. More commonly, “effective” renal plasma flow (RPF) is calculated. Effective RPF underestimates true RPF by 10%. Renal blood flow (RBF) can then be calculated from the RPF as follows -

RBF = RPF / 1 - hematocrit

5. Filtration fraction: It is given by the formula:

   FF = GFR/RPF

   Where FF is the filtration fraction, GFR is the glomerular filtration rate and RPF is the renal plasma flow.

   Filtration fraction is the fraction of the renal plasma flow that is filtered across the glomerular capillaries. Normally it is 20%.