Glomerular filtration

Glomerular filtration and hemodynamics

The glomerulus is made of fenestrated capillaries. The afferent arteriole brings blood into the glomerulus, and the efferent arteriole carries blood away. Fluid is filtered across the glomerular capillary wall into Bowman’s space, forming an ultrafiltrate of plasma.

Each kidney contains approximately 1 million nephrons. An individual’s GFR (glomerular filtration rate) is the average filtration rate across all nephrons.

1. Factors affecting glomerular filtration: Starling forces determine filtration at the glomerulus. Filtration at each nephron can be described by:

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

   Where:

   • Kf is the filtration coefficient
   • Pgc and Pbs are the hydrostatic pressures in the glomerular capillary and Bowman’s space, respectively
   • Pi gc and Pi bs are the oncotic pressures in the glomerular capillary and Bowman’s space, respectively

   Pi gc changes along the length of the glomerular capillary, from the afferent end to the efferent end. If filtration increases at the proximal end, plasma proteins become more concentrated toward the distal end of the capillary (and especially in the peritubular capillaries). This raises oncotic pressure downstream, which reduces further filtration and favors absorption by shifting the Starling forces. This mechanism contributes to tubuloglomerular feedback, helping ensure that a constant fraction of the filtered load is reabsorbed by the PCT even when the filtered load increases or decreases.

   Pi bs is effectively 0 because plasma proteins are not normally filtered in amounts large enough to create a meaningful oncotic pressure in Bowman’s space.

   Kf is relatively high in glomerular capillaries, which supports filtration. Kf depends on:

   • Surface area available for filtration
   • Hydraulic conductivity

   Reductions in glomerular surface area (for example, in membranous nephropathy or after vasoconstrictors like NE) reduce Kf. Hydraulic conductivity is reduced in glomerular diseases such as diabetic nephropathy.

   In summary, factors that increase glomerular filtration include:

   • Increased Kf
   • Increased delta Pgc - Pbs
   • Decreased oncotic pressure in the glomerular capillary
   • Increased glomerular plasma flow rate (Qa), which depends on renal blood flow

   Of these, Pgc and Qa are the most important determinants of GFR under physiological conditions.

   The glomerular filter acts as both a charge barrier and a size barrier:

   • Anionic molecules cross less readily.
   • Large molecules cross less readily.

   The glycocalyx layer on the glomerular capillary endothelium and heparan sulfate in the GBM are major contributors to the negative charge of the filtration barrier. The net negative charge of the GBM is an important part of the barrier to plasma albumin, which is also negatively charged and is therefore repelled.

   Podocyte foot processes form an interlocking network connected by slit diaphragms. Two key podocyte proteins are podocin and nephrin.

   • Nephrin is a transmembrane protein with a large extracellular domain. It is required for normal slit diaphragm structure and function. Congenital defects in nephrin can cause nephrotic syndrome.
   • Podocin is an integral membrane protein that interacts directly with nephrin and helps traffic it to the slit diaphragm. Defects in the podocin gene can cause congenital nephrosis or focal segmental glomerulosclerosis.

   The cytoskeletal protein actin is essential for podocyte structure and function. Mutations in actin-regulating proteins alpha-actinin-4 and INF2 can lead to podocyte dysfunction, FSGS, and progressive kidney disease.

   The GBM (glomerular basement membrane) forms by fusion of the basement membranes from the endothelial and epithelial cells of the glomerular corpuscle. Morphologically, the GBM includes:

   • A dense inner layer (lamina densa)
   • Two thinner layers (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 disrupt GBM function and lead to proteinuria.

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

   Glomerular mesangial processes contain bundles of actin- and myosin-based microfilaments that extend to contact the GBM, where they bind laminin alpha 5 via integrin alpha 3b1 and the basal cell adhesion molecule. These processes help protect against glomerular pressure and may regulate glomerular capillary flow through contractile properties.

   The mesangial matrix produced by mesangial cells contains a diverse set of proteins, including collagen types III-VI, heparan sulfate proteoglycans, and elastic fiber proteins such as fibronectin, laminin, entactin, and fibrillin-1. Accumulation of mesangial matrix and thickening of the GBM are commonly observed in several glomerular diseases, including diabetic nephropathy.

2. Laboratory Markers for GFR: Creatinine is a product of muscle breakdown. It is excreted by the kidneys and is freely filtered at the glomerulus, with some additional tubular secretion. Because creatinine is produced endogenously and its blood level is convenient to measure, creatinine clearance is commonly used as a marker of GFR.

   A key caveat is that creatinine clearance overestimates true GFR because creatinine is secreted by the tubules to some extent. Inulin clearance is theoretically the best estimate of GFR because inulin is filtered but neither reabsorbed nor secreted. However, inulin is not normally present in the body and is inconvenient to measure, so creatinine clearance is used more often.

   Because creatinine production depends on muscle mass and metabolism, serum creatinine varies with factors such as gender, ethnicity, and nutritional state. For this reason, eGFR (estimated GFR) is calculated to account for these variables.

   Increases in serum creatinine are quite specific for renal impairment, but the test has low sensitivity. Often, a ~50% fall in GFR is required before serum creatinine rises appreciably. In an individual, serum creatinine approximately doubles for each halving of the GFR.

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

3. Renal clearance: Renal clearance is the volume of plasma that is completely cleared of a substance by the kidneys per unit time. It is given by:

   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:

   • Albumin is normally not filtered at the glomerulus.
   • Glucose is normally completely reabsorbed even if it is filtered.

   Electrolytes are also normally reabsorbed.

   Inulin clearance equals GFR because, once filtered, inulin is neither reabsorbed nor secreted. PAH (para-amino hippuric acid) and other organic acids have the highest clearances because they are both filtered at the glomerulus and secreted by renal tubular cells.

   The clearance ratio is the ratio of the clearance of a substance to the clearance of inulin.

   • Clearance ratio = 1 means clearance equals inulin clearance.
   • Ratio < 1 means clearance is less than inulin clearance.
   • Ratio > 1 means clearance is greater 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 because it is not metabolized or synthesized by the kidney, it does not alter renal plasma flow, and almost all of it is removed by the kidney through 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 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%.