Core principles of renal physiology and pathophysiology in critical illness

The glomerulus

The glomerulus is the filtering unit of the kidney ( Fig. 94.1 ). Located in the renal cortex, it is composed of a tuft of capillaries that filter plasma across a semipermeable barrier. The glomerular filtration barrier consists of three layers: the fenestrated endothelial cells of glomerular capillaries, the glomerular basement membrane, and specialized epithelial cells called podocytes. Mesangial cells surrounding the glomerular capillaries have contractile properties that alter the surface area available for filtration. After passing through the barrier, the filtrate collects in the Bowman space, encased by the Bowman capsule, before it passes into the renal tubule.

Proximal tubule

The proximal tubule is a hollow structure outlined by a single layer of epithelial cells that extends from the Bowman space to the loop of Henle (see Fig. 94.1 ). It is a key site for the reabsorption of sodium, water, bicarbonate, phosphate, potassium, calcium, and organic solutes (e.g., glucose, citrate, urea, and amino acids; Table 94.1 ). Transport occurs either paracellularly (across tight junctions) or transcellularly (across the apical and basolateral membrane of the epithelial cells). The resorptive function of the proximal tubule is enhanced by amplification of the luminal cell membrane into a “brush border” and by densely packed mitochondria on the basolateral cell surface, which supply energy for the active transport of solutes.

The loop of henle

The loop of Henle is divided into three segments: the thin descending limb, the thin ascending limb, and the thick ascending limb (see Fig. 94.1 ). Its primary function is to concentrate the urine by the countercurrent system. The countercurrent system is responsible for generating the osmotic gradient within the interstitium that increases from the renal cortex (~290 mOsm/kg) to the inner medulla (~1200 mOsm/kg). This is achieved by means of its U-shaped configuration and variable permeability to sodium and water. The thin descending limb is highly permeable to water but impermeable to sodium, whereas the thin and thick ascending limbs are impermeable to water but permeable to sodium, which is reabsorbed passively in the thin ascending limb and actively in the thick ascending limb. The thick ascending limb is also a primary site for magnesium reabsorption and urea secretion (see Table 94.1 ).

Macula densa

The macula densa lies at the apex of the nephron between the thick ascending limb and the distal convoluted tubule, adjacent to the parent glomerulus. The cells of the macula densa detect the composition of the tubular fluid and provide feedback to the afferent and efferent arterioles to control renal blood flow (RBF) and glomerular filtration rate (GFR) in a process called tubuloglomerular feedback (TGF).

Distal convoluted tubule

The distal convoluted tubule is a short nephron segment located between the thick ascending limb and the collecting duct (see Fig. 94.1 ). The early distal convoluted tubule participates in the reabsorption of sodium, potassium, calcium, and magnesium (see Table 94.1 ). It is impermeable to water, making it the final diluting segment of the kidney. The late distal convoluted tubule contains three cell types. Principal cells reabsorb sodium and water and secrete potassium under the control of antidiuretic hormone (ADH) and aldosterone, respectively. Alpha-intercalated cells secrete hydrogen ions, reabsorb bicarbonate, and either reabsorb or secrete potassium, depending on the plasma concentration. Beta-intercalated cells secrete bicarbonate and reabsorb hydrogen ions.

Collecting duct

The collecting duct connects the distal convoluted tubules of individual nephrons to calyces or directly to the renal pelvis (see Fig. 94.1 ). Like the late distal convoluted tubule, the collecting duct contains principal and alpha- and beta-intercalated cells. Collecting ducts are classified as cortical or medullary ducts; the proportion of intercalated cells (which are responsible for acid-base balance) decreases as the collecting duct enters the medulla. Urea is reabsorbed in the medullary collecting duct in response to ADH, which up-regulates urea transporters, increasing interstitial osmolality and enhancing the osmotic gradient of the countercurrent system.

Renal vasculature

Blood is delivered to the glomerular capillaries via the renal artery, interlobar artery, arcuate artery, interlobular artery, and afferent arteriole. Glomerular capillaries are composed of a single layer of endothelial cells, encased by the glomerular basement membrane and interdigitating podocyte processes. Capillaries drain into the efferent arteriole, which gives rise to the peritubular capillaries and vasa recta. The vasa recta are a series of vascular loops that supply oxygenated blood and nutrients to the cortex and medulla and return reabsorbed water and solutes to the circulation. The vasa recta converge to form the interlobular vein, arcuate vein, interlobar vein, and renal vein before emptying into the inferior vena cava.

The arrangement of vasa recta capillaries within the medulla is an important determinant of medullary oxygen delivery. The U-shaped configuration of these vessels ensures that the medullary osmotic gradient is maintained, such that solute entry and water loss in the descending branches is balanced by solute loss and water entry in the ascending branches (“countercurrent exchange”). Like solutes and water, oxygen can also diffuse directly from descending to ascending branches of the vasa recta, creating an environment of low oxygen tension in the medulla. This mode of oxygen shunting, coupled with low oxygen delivery and high metabolic activity, makes the medulla particularly prone to hypoxemia.

Glomerular filtration rate

The glomerulus initiates the formation of urine by producing a filtrate that enters the tubular lumen. The rate of filtrate production, the GFR, is determined by hydrostatic and oncotic pressure gradients between the glomerular capillary and Bowman space, in addition to the ultrafiltration coefficient, according to the equation:

where

• P _GC = the hydrostatic pressure in the glomerular capillary

• P _BS = the hydrostatic pressures in Bowman spaces

• π _GC = the oncotic pressure in the glomerular capillary

• π _BS = the oncotic pressure in Bowman spaces

• k _f = the ultrafiltration coefficient, which reflects the permeability of the glomerular filtration barrier

In healthy young adults, the normal GFR is approximately 120–130 mL/min/1.73m ² . The proportion of plasma filtered across the glomerulus (the GFR divided by the plasma flow rate) is referred to as the filtration fraction. Under normal conditions, it is roughly 0.2.

The previous equation provides important insight into the manner in which different renal pathologies can all reduce GFR. For example, urinary obstruction leads to congestion in the tubular lumen, which increases P _BS . Hypovolemic shock decreases RBF, which lowers P _GC . Direct damage to the filtration barrier, such as from immunologic injury, initially causes the filtration barrier to become leaky, which increases k _f , but with time, the filtration barrier becomes occluded secondary to thrombosis, which reduces k _f . RBF does not directly determine GFR, but contributes indirectly by influencing P _GC . Increases in P _GC , π _BS , or k _f all raise the filtration fraction.

Renal blood flow

To maintain a stable RBF across a range of systemic arterial pressures, the kidney employs two main autoregulatory mechanisms: the myogenic reflex and TGF. The myogenic reflex arises from the physical properties of smooth muscle: increased intravascular volume stretches arteriolar walls, which increases vascular smooth muscle contractile force to promote vasoconstriction. TGF responds to chemical stimuli. Increased renal perfusion pressure increases sodium delivery to the macula densa, which triggers the release of adenosine triphosphate (ATP) into the extracellular space and conversion of ATP to adenosine. ^, Adenosine causes vasoconstriction of the afferent arteriole and inhibits the release of renin from the juxtaglomerular apparatus. A reduction in renin reduces angiotensin II levels, inducing efferent arteriolar relaxation and reducing RBF and GFR. TGF is impaired by loop diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors, and in the setting of chronic kidney disease (CKD). Either the myogenic reflex or TGF may be overcome in the setting of critical illness with low renal perfusion pressure.

Autoregulatory mechanisms leverage the ability of the glomerular microcirculation to alter resistance in preglomerular and postglomerular vessels independently ( Table 94.2 ). If afferent arterioles preferentially constrict, RBF, P _GC , GFR, and filtration fraction fall. If efferent arterioles preferentially constrict, RBF decreases but P _GC , GFR, and filtration fraction will increase because vascular resistance increases distal to the glomerulus. This is a key concept: net constriction or dilatation of afferent arterioles changes RBF and GFR in the same direction, whereas net changes in efferent arteriolar tone change RBF and GFR in opposite directions.