Glomerular Filtration

Urine formation begins with glomerular filtration, the bulk flow of fluid from the glomerular capillaries into Bowman’s capsule. The glomerular filtrate (ie, the fluid within Bowman’s capsule) is very much like blood plasma. However, it contains very little total protein. The large plasma proteins like albumin and globulins are virtually excluded from moving through the filtration barrier. Smaller proteins, such as many of the peptide hormones, are present in the filtrate, but their mass in total is miniscule compared with the mass of large plasma proteins in the blood. The filtrate contains most inorganic ions and low-molecular-weight organic solutes in virtually the same concentrations as in the plasma. Substances that are present in the filtrate at the same concentration as found in the plasma are said to be freely filtered. (Note that freely filtered does not mean all filtered. The amount filtered is in exact proportion to the fraction of plasma volume that is filtered.) Many low-molecular-weight components of blood are freely filtered. Among the most common substances included in the freely filtered category are the ions sodium, potassium, chloride, and bicarbonate; the neutral organics glucose and urea; amino acids; and peptides like insulin and antidiuretic hormone (ADH).
The volume of filtrate formed per unit time is known as the GFR. In a normal
young adult male, the GFR is an incredible 180 L/day (125 mL/min)! Contrast this value with the net filtration of fluid across all the other capillaries in the body: approximately 4 L/day. The implications of this huge GFR are extremely important. When we recall that the average total volume of plasma in humans is approximately 3 L, it follows that the entire plasma volume is filtered by the kidneys some 60 times a day. The opportunity to filter such huge volumes of plasma enables the kidneys to excrete large quantities of waste products and to regulate the constituents of the internal environment very precisely. One of the general consequences of aging and of many renal pathologies is a reduction in the GFR.

BASIC RENAL PROCESSES

Filtration is the process by which water and solutes in the blood leave the vascular system through the filtration barrier and enter Bowman’s space (a space that is topologically outside the body). Secretion is the process of moving substances into the tubular lumen from the cytosol of epithelial cells that form the walls of the nephron. Secreted substances may originate by synthesis within the epithelial cells or, more often, by crossing the epithelial layer from the surrounding renal interstitium. Reabsorption is the process of moving substances from the lumen across the epithelial layer into the surrounding interstitium. In most cases, reabsorbed substances then move from the interstitium into surrounding blood vessels, so that the term reabsorption implies a 2-step process of removal from the lumen followed by movement into the blood. Excretion means exit of the substance from the body (ie, the substance is present in the final urine produced by the kidneys). Synthesis means that a substance is constructed from molecular precursors, and catabolism means the substance is broken down into smaller component molecules.

The 3 basic renal processes. Only the directions of reabsorption and secretion, not specific sites or order of occurrence, are shown. Depending on the specific substance, reabsorption and secretion can occur at various sites along the tubule.

The renal handling of any substance consists of some combination of the justmentioned processes. If we can answer the following questions, we can know what the kidney does with a given substance. Is it filtered? Is it secreted? Is it reabsorbed? Is it synthesized? Is it catabolized?

Renal Innervation

The kidneys receive a rich supply of sympathetic neurons. These are distributed to the afferent and efferent arterioles, the JG apparatus, and many portions of the tubule. There is no significant parasympathetic innervation. The sensory endings of many afferent neurons are distributed throughout the kidneys as well, which feedback to the neural centers that regulate sympathetic outflow.

The Juxtaglomerular Apparatus

Reference was made earlier to the macula densa, a portion of the late thick ascending limb at the point where, in all nephrons, this segment comes between the afferent and efferent arterioles at the vascular pole of the renal corpuscle from which the tubule arose. This entire area is known as the juxtaglomerular (JG) apparatus. (Do not confuse the term juxtaglomerular apparatus with juxtamedullary nephron.) Each JG apparatus is made up of 3 cell types: (1) granular cells, also called juxtaglomerular cells, which are differentiated smooth muscle cells in the walls of the afferent arterioles; (2) extraglomerular mesangial cells; and (3) macula densa cells, which are specialized thick ascending limb epithelial cells.
The granular cells (so called because they contain secretory vesicles that appear granular in light micrographs) are the cells that secrete the hormone renin. Renin is a crucial substance for the control of renal function and systemic blood pressure. The extraglomerular mesangial cells are morphologically similar to and continuous with the glomerular mesangial cells but lie outside Bowman’s capsule. The macula densa cells are detectors of the luminal content of the nephron at the very end of the thick ascending limb and contribute to the control of glomerular filtration rate (GFR) and to the control of renin secretion.

Nephron Heterogeneity

As stated earlier, there are more than 2 million nephrons in the 2 human kidneys. These nephrons manifest significant differences in anatomic, biochemical, and functional characteristics beyond those described in the previous section. For simplicity, however, we generally ignore these complexities, many of which currently are not fully understood.

Categories of Nephrons

There are important regional differences in the various tubular segments of the nephron. All the renal corpuscles are in the cortex (accounting for its granular appearance) as well as the convoluted portions of the proximal tubule, cortical portions of Henle’s loops, distal convoluted tubules, connecting tubules, and cortical collecting ducts. The medulla contains the medullary portions of Henle’s loops and the medullary collecting ducts.

The renal microcirculation. The kidney is divided into a cortex and a medulla. The cortex contains an arterial network, glomeruli, a dense peritubular capillary plexus, and a venous drainage system. In the cortex, arcuate arteries, which run parallel to the surface, give rise to cortical radial (interlobular) arteries radiating toward the surface. Afferent arterioles originate from the cortical radial arteries at an angle that varies with cortical location. Blood is supplied to the peritubular capillaries of the cortex from the efferent flow out of superficial glomeruli. Blood is supplied to the medulla from the efferent flow out of juxtamedullary glomeruli. Efferent arterioles of juxtamedullary glomeruli give rise to bundles of descending vasa recta in the outer stripe of the outer medulla. In the inner stripe of the outer medulla, descending vasa recta and ascending vasa recta returning from the inner medulla run side by side in the vascular bundles, allowing exchange of solutes and water. The descending vasa recta from the bundle periphery supply the interbundle capillary plexus of the inner stripe, whereas those in the center supply blood to the capillaries of the inner medulla. Contractile pericytes in the walls of the descending vasa recta regulate flow. DVR, descending vasa recta.AVR, ascending vasa recta. (Used with permission from Pallone TL, Zhang Z, Rhinehart K.Am J Physiol Renal Physiol 2003;284:F253–F266.)

Nephrons are categorized according to the locations of their renal corpuscles in the cortex: (1) In superficial cortical nephrons, renal corpuscles are located within 1 mm of the capsular surface of the kidneys; (2) in midcortical nephrons, renal corpuscles are located, as their name implies, in the midcortex, deep relative to the superficial cortical nephrons but above (3) the juxtamedullary nephrons, which, as mentioned previously, have renal corpuscles located just above the junction between cortex and medulla. One major distinction among these 3 categories of nephrons is the length of Henle’s loop. All superficial cortical nephrons have short loops, which make their hairpin turn above the junction of outer and inner medulla. All juxtamedullary nephrons have long loops, which extend into the inner medulla, often to the tip of a papilla. Midcortical nephrons may be either short looped or long looped. The additional length of Henle’s loop in long-looped nephrons is due to a longer descending thin limb and the presence of an ascending thin limb. Finally, the beginning of the thick ascending limb marks the border between the outer and inner medulla; in other words, the thick ascending limbs are found only in the cortex and outer medulla.

BLOOD SUPPLY TO THE NEPHRONS

The kidneys receive an enormous amount of blood relative to their mass. Blood enters each kidney via a renal artery, which then divides into progressively smaller branches: interlobar, arcuate, and finally interlobular arteries (usually called cortical radial arteries because they radiate outward toward the kidney surface). As each of the interlobular arteries projects toward the outer kidney surface, a series of parallel arterioles branch off at right angles, each of which leads to a glomerulus. These are called afferent arterioles. Note that these arteries and glomeruli are found only in the cortex, never in the medulla.
Normally about 20% of the plasma (and none of the erythrocytes) entering the glomerulus is filtered from the glomerulus into Bowman’s capsule, leaving the remaining 80% to flow on to the next vascular segment. In most organs, capillaries recombine to form the beginnings of the venous system, but the glomerular capillaries instead recombine to form another set of arterioles called the efferent
arterioles. Thus, blood enters each glomerulus through a single afferent arteriole and leaves via a single efferent arteriole at the vascular pole of Bowman’s capsule. The afferent and efferent arterioles both penetrate Bowman’s capsule on the same side, with the thick ascending limb of the nephron that originated from that capsule passing between and in contact with each arteriole. The efferent arterioles soon subdivide into a second set of capillaries. These are usually the peritubular capillaries, which are profusely distributed throughout the cortex. The peritubular capillaries then rejoin to form the veins by which blood ultimately leaves the kidney.
The medulla receives much less blood than does the cortex, and in a quite different manner. There are no glomeruli in the medulla. In contrast to most efferent arterioles in the cortex, those from juxtamedullary glomeruli do not branch into peritubular capillaries, but rather descend downward into the outer medulla, where they divide many times to form bundles of parallel vessels that penetrate deep into the medulla. These are called descending vasa recta (Latin recta for “straight” and vasa for “vessels”). Although it is still uncertain, a small fraction of the descending vasa recta may branch off from the cortical radial arteries before the glomeruli, not after. The vasa recta on the outside of the vascular bundles “peel off” and give rise to interbundle plexi of capillaries that surround Henle’s loops and the collecting ducts in the outer medulla. Only the center-most vasa recta supply capillaries in the inner medulla; thus, limited blood flows into the papilla. The capillaries from the inner medulla re-form into ascending vasa recta that run in close association with the descending vasa recta within the vascular bundles. The structural and functional properties of the vasa recta are rather complex. The beginnings of the descending vasa recta are like arterioles, with pericytes containing smooth muscle in their walls, but become more capillary like as they descend. The ascending vasa recta have a fenestrated endothelium like that found in the glomerular capillaries. Therefore, the vasa recta, in addition to being conduits for blood, also participate in exchanging water and solutes between plasma and interstitium. The whole arrangement of descending and ascending blood flowing in parallel has major significance for the formation of both concentrated and diluted urine because plasma and medullary interstitial constituents exchange between descending and ascending vessels.