Kidney disease

Glomerulus

The glomerulus is formed from a specialized capillary network. Each capillary develops into approximately 40 glomerular loops around 200 μm in size and consisting of a variety of different cell types supported on a specialized basement membrane ( Fig. 49.3 , top ). Some endothelial and epithelial cells act in concert with the specialized glomerular basement membrane (GBM) to form the glomerular filtration barrier, in addition to mesangial cells.

The capillary endothelial cells are about 40 nm thick and are in contact with each other. However, in contrast to the continuous endothelial linings seen elsewhere in the body, circular fenestrations (pores) with diameters of approximately 60 nm collectively constitute 20 to 50% of the glomerular endothelial surface. The endothelium permits virtually free access of plasma and small solutes to the basement membrane. However, although the fenestrations are far larger than the diameter of albumin (3.5 nm), it is thought that permselectivity to such larger molecules begins at the level of the endothelium because of the endothelial surface lining—a glycocalyx coating of negatively charged glycoproteins, glycosaminoglycans, proteoglycans, and absorbed plasma proteins, including orosomucoid and albumin. Estimates of the thickness of this layer vary depending on the visualization and preparation techniques used, but it may be between 200 and 400 nm thick.

The basement membrane (see Fig. 49.3 , bottom ) of the glomerular capillaries is much thicker (approximately 300 nm) than that of other vascular beds and consists of three distinct electron-dense layers: the lamina rara interna, the lamina densa, and the lamina rara externa. The lamina densa consists of a close feltwork of fine, mainly type IV, collagen fibrils (each 3 to 5 nm thick) embedded in a gel-like matrix of laminin, nidogen/entactin, glycoproteins, and proteoglycans such as agrin and perlecan. The lamina densa forms the main size discriminant barrier to protein passage into the tubular lumen. The other two layers of the basement membrane are rich in negatively charged polyanionic glycoproteins, such as heparan sulfate; these may form a charge discriminant barrier to the passage of proteins, although the importance of the GBM in charge discrimination is still uncertain.

The epithelial cells of the glomerulus line the outside of the glomerular capillaries, thus facing Bowman’s capsule and the primary urine (see Fig. 49.3 , top ). These cells are called podocytes and have an unusual octopus-like structure in that they have a large number of cytoplasmic extensions or foot processes that are embedded in the basement membrane. Foot processes are anchored to the GBM via integrin molecules and dystroglycans and are divided into primary and secondary. The secondary processes between adjacent cells interdigitate to form filtration slits, which are 25 to 60 nm wide. The podocytes are covered by a complex diaphragm (“slit diaphragm”), some of the molecular components of which (e.g., nephrin) appear crucial for the maintenance of larger proteins within the circulation. The resulting structure is relatively impermeable to most proteins above 60 kDa, but passage of proteins is modulated by their charge and shape. Podocytes are also covered by a glycocalyx of sulfated molecules, including glycosaminoglycans and glycoconjugates (e.g., podocalyxin). The surface anionic charge helps to maintain the foot process structure and the distance between the parietal and visceral epithelial cells constituting Bowman’s space.

The final cellular components of the glomerulus are the mesangial cells, which are found in the central part (“stalk”) of the glomerulus between and within the capillary loops suspended in a matrix that they synthesize. They are in direct contact with glomerular endothelial cells and the inner layer of the GBM (lamina rara interna) and also with the extraglomerular mesangium and the JGA (see Fig. 49.3 , top ). Mesangial cells have the characteristics of smooth muscle cells (pericytes), in that they are rich in microfilaments and respond to and produce a variety of stimuli (e.g., angiotensin II [AII] and arginine vasopressin [antidiuretic hormone, ADH]). Mesangial matrix is rich in collagens and proteoglycans but is different in composition from the matrix of the GBM. Its composition and volume are tightly regulated in health but can be markedly altered during certain diseases (e.g., diabetic nephropathy, immunoglobulin (Ig)A nephropathy). Mesangial cells have both structural and housekeeping functions. They have anchoring filaments to GBM opposite the podocytes and their contractile properties enable them to alter intraglomerular capillary flow and glomerular ultrafiltration surface area, and thereby single nephron glomerular filtration rate (GFR). The cells appear to respond to capillary stretch by generating soluble factors such as vascular endothelial growth factor and transforming growth factor-β (TGF-β), and by activating intracellular signaling pathways. Mesangial cells also have specific and nonspecific mechanisms for removing macromolecules that reach the mesangial and subendothelial space, preventing their accumulation. These mechanisms include phagocytosis and degradation by the cells and trafficking along the mesangial stalk to the juxtaglomerular region, followed by elimination via the renal lymphatics, or by regurgitation into the glomerular capillary.

Proximal tubule

Bowman’s capsule forms the beginning of the tightly coiled, proximal convoluted tubule ( pars convoluta ), which on its progress toward the renal medulla becomes straightened and is then called the pars recta. The proximal tubule is about 15 mm long. The epithelial cells lining the convoluted section are cuboidal/columnar cells with a luminal brush border consisting of millions of microvilli, which expand the surface area for absorption of tubular fluid. The proximal tubule is the most metabolically active part of the nephron ( Table 49.1 ).

Loop of henle

The pars recta drains into the descending thin loop of Henle, which after passing through a hairpin loop becomes first the thin ascending limb and then the thick ascending limb. The cells of the thin ascending limb are very similar to those in the descending (with little brush border, flattened and interdigitated), but important differences are evident in their permeability to water and in their capability for active transport. The thick ascending limb is lined with cuboidal/columnar cells similar in size to those in the proximal tubule, but they do not possess a brush border. At the end of the thick ascending limb, near where it reenters the cortex and closely associated with the glomerulus and the efferent arteriole, a cluster of cells known as the macula densa is present ( Fig. 49.4 , see later). The main role of the loop of Henle is to assist in generating concentrated urine, hypertonic with respect to plasma: it also has several other functions (see Table 49.1 ).

Distal convoluted tubule

The distal convoluted tubule begins at a variable distance beyond the macula densa and extends to the first fusion with other tubules to form the collecting ducts. The cells of the distal convoluted tubule are cuboidal and contain numerous mitochondria. Na, K-ATPase activity is higher than in any other segment of the nephron, being located in the basolateral membrane and providing the main driving force for ion transport. Reabsorption of sodium and chloride, with passive reabsorption of water, is the main function of the distal convoluted tubule (see later).

Collecting duct

The collecting ducts are formed from approximately six distal tubules. These are successively joined by other tubules to form ducts of Bellini, which ultimately drain into a renal calyx. Two main cell types are found in the collecting duct: principal (light) cells and intercalated (dark) cells. Intercalated cells have a dark granular cytoplasm with high carbonic anhydrase activity but no Na, K-ATPase activity.

Definitions

Urine is defined as a fluid excreted by the kidneys, passed through the ureters, stored in the bladder, and discharged through the urethra. In health, it is sterile and clear and has an amber color, a slightly acid pH (approximately 5.0 to 6.0) and a characteristic odor. In addition to dissolved compounds it contains a number of cellular fragments and complete cells, derived from normal turnover of tubular cells, casts, and crystals (formed elements). Urinary casts are cylindrical proteinaceous structures formed in the distal convoluted tubule and collecting ducts, which dislodge and pass into the urine, where they can be detected by microscopy.

Urination, also termed micturition, is the discharge of urine. In normal adults adequate homeostasis is maintained with a urine output of 400 to 2000 mL/day. Alterations in urinary output are described as anuria (<100 mL/day), oliguria (<400 mL/day), or polyuria (>3 L/day or 50 mL/kg body weight/day). The most common disorder of micturition is altered frequency, which may be associated with increased urinary volume or with partial urinary tract obstruction (e.g., in prostatic hypertrophy).

Formation of urine—an overview

The first step in urine formation is filtration of plasma water at the glomeruli. A net filtration pressure of about 17 mm Hg in the capillary bed of the tuft drives the filtrate through the glomerular membrane. The filtrate is called an ultrafiltrate because its composition is essentially the same as that of plasma, but with a notable reduction in molecules of molecular weight exceeding 15 kDa. Each nephron produces about 100 μL of ultrafiltrate per day. Overall, approximately 170 to 200 L of ultrafiltrate passes through the glomeruli daily. In the passage of ultrafiltrate through the tubules, reabsorption of solutes and water in various regions of the tubules reduces the total urine volume.

Transport of solutes and water occurs both across and between the epithelial cells that line the renal tubules. Transport is both active (energy requiring) and passive, but many of the so-called passive transport processes are dependent upon or secondary to active transport processes, particularly those involving sodium transport. All known transport processes involve receptor or mediator molecules, the activity of many of which is regulated by phosphorylation facilitated by protein kinase C or A. Their renal distribution has been shown to correlate with known regional functional activities, but the same transporters, or isoforms of them, can be found in other tissues, particularly the digestive tract. For instance, at least five independent proximal tubular transport processes may be noted for amino acids, including those for (1) basic amino acids plus cystine, (2) glutamic and aspartic acid, (3) neutral amino acids, (4) imino amino acids, and (5) glycine. Inherited disorders of tubular transporters, discussed later in this chapter, may occur, as well as a well-known generalized disorder affecting all of the transport processes, causing Fanconi syndrome (see later) and resulting in decreased reabsorption of electrolytes and nutrients (e.g., glucose, amino acids).

Direct coupling of adenosine triphosphate (ATP) hydrolysis is an example of an active transport process. The most important enzymatic transporter in the nephron is Na, K-ATPase, which is located on the basolateral membranes of the tubuloepithelial cells. Na, K-ATPase accounts for much of renal oxygen consumption and drives more than 99% of renal sodium reabsorption ( Fig. 49.5 ). Other examples of primary active transport mechanisms include a Ca-ATPase, an H-ATPase, and an H, K-ATPase. These enzymes establish ionic gradients, polarizing cell membranes and thus driving secondary transport processes.

Many renal epithelial cell membranes also contain proteins that act as ion channels. For example, there is one for sodium that is closed by amiloride and modulated by hormones such as atrial natriuretic peptide (ANP). Ion channels enable much faster rates of transport than ATPases but are relatively fewer in number e.g., approximately 100 sodium and chloride channels versus 10 ⁷ Na, K-ATPase molecules per cell.

Different regions of the tubule have been shown to specialize in certain functions. The proximal tubule facilitates the reabsorption of 60 to 80% of the glomerular filtrate volume—including 70% of the filtered load of sodium and chloride, and most of the potassium, glucose, bicarbonate, calcium, phosphate, sulfate, and other ions—and secreting 90% of the hydrogen ion excreted by the kidney (see Table 49.1 ). Uric acid is reabsorbed in the proximal tubule by a passive sodium-dependent mechanism, but there is also an active secretory mechanism. Creatinine is secreted but only to a small extent, approximately 2.5 μmol/min.

Glucose is virtually completely reabsorbed, predominantly in the proximal tubule by a transport process that is saturated at a blood glucose concentration of about 180 mg/dL (10 mmol/L). On the apical membrane of the proximal tubule cells sodium/glucose cotransporters (SGLTs) are responsible for the transport of glucose, in conjunction with sodium, into the cells. The two main transporters involved are SGLT2, a low-affinity–high-capacity transporter expressed on the apical membranes of the convoluted proximal tubule cells (S1 and S2), and SGLT1, a high-affinity–low-capacity transporter found on the apical membranes of the straight proximal tubule (S3) cells. Approximately 90% of glucose is reabsorbed by SGLT2 with SGLT1 scavenging the remainder in the later (S3) portions of the proximal tubule. Glucose is returned to the circulation following transport out of the proximal tubule cells through the actions of basolateral sugar transporters GLUT2, located in the S1 segment of the tubule, and GLUT1, located in the S3 segment of the tubule ( Fig. 49.6 ).

Certain nonbiological compounds such as phenolsulfonphthalein and p -aminohippurate are secreted by the proximal tubule and have been used for the evaluation of renal tubular secretory capacity. When blood concentrations of creatinine increase above normal, creatinine is secreted in this region of the nephron. In the loop of Henle, chloride and more sodium without water are reabsorbed, generating dilute urine. Water reabsorption in the more distal tubules and collecting ducts is then regulated by vasopressin. In the distal tubule, secretion is the prominent activity; organic ions, potassium ions, and hydrogen ions are transported from the blood in the efferent arteriole into the tubular fluid.

Tubular epithelial cells synthesize a vast range of growth factors and cytokines in response to a variety of stimuli that can have both autocrine and paracrine effects. All cells secrete a range of cell adhesion molecules that are essential for cellular attachment to the tubular basement membrane.

Electrolyte homeostasis

A complex interplay has been noted between the tubular transport systems regulating individual electrolytes. For simplicity, we have considered each electrolyte individually and have restricted our discussion to the systems of major physiologic, pharmacologic, and pathologic significance.

Sodium.

Sodium reabsorption is required for the reabsorption of water and many solutes. The proximal tubule is highly permeable to sodium, and the net flux of reabsorption from the tubular lumen is achieved against a high backflux, particularly from paracellular ^b

b Paracellular transport is that occurring between tubular epithelial cells and occurs by passive diffusion or by solvent drag.

movement. Approximately 60% of filtered sodium is reabsorbed in the proximal tubule in an energy-dependent manner, driven by basolateral Na, K-ATPase pumps (see Fig. 49.5 ). Approximately 80% of sodium entering proximal tubular cells does so in exchange for hydrogen ion secretion, facilitated by apical Na-H exchangers. This process in turn permits bicarbonate reabsorption via carbonic anhydrases that are present in both the brush border and the intracellular compartment. A variety of apical sodium cotransporters also allow for reabsorption of other organic and inorganic solutes (e.g., chloride, calcium, phosphates, bicarbonate, sulfates, glucose, urea, amino acids). Sodium transport activity is regulated by many factors, including protein kinase–dependent phosphorylation, which can increase both activity and channel numbers.

A further 30% of filtered sodium is reabsorbed in the thick ascending limb of the loop of Henle, where it is achieved by an apical, bumetanide-sensitive, 130 kDa, electroneutral, Na-K-2Cl cotransporter (NKCC2), itself driven by a favorable inward gradient generated by the basolateral Na, K-ATPase pump ( Fig. 49.7 ). NKCC2 is a kidney-specific member of a class of such channels found throughout secretory epithelia. Activation of these cotransporters appears, in part, to be a result of cell shrinkage. The distal tubule reabsorbs 5 to 8% of sodium via the apical thiazide-sensitive Na-Cl cotransporter (NCCT). Final sodium balance is achieved in the collecting duct via selective amiloride-sensitive, apical sodium channels (ENaCs) in exchange for potassium. ENaCs are controlled in part by the effects of aldosterone on the mineralocorticoid receptor ( Fig. 49.8 ).

Water homeostasis

Approximately 180 L glomerular filtrate is formed each day. The unique physiology of the kidney enables approximately 99% of this to be reabsorbed in the production of urine with variable osmolality (between 50 and 1400 mOsmol/kg H ₂ O at extremes of water intake). Plasma membranes of all human cells are water permeable but to variable degrees. In the kidney, different segments of the nephron show differing permeability to water, enabling the body to both retain water and produce urine of variable concentration. Water reabsorption occurs both isosmotically, in association with electrolyte reabsorption in the proximal tubule, and differentially, in the loop of Henle, distal tubule, and collecting duct in response to the action of vasopressin. Absorption of water depends on the driving force for water reabsorption (predominantly active sodium transport) and the osmotic equilibration of water across the tubular epithelium. The generation of concentrated urine depends upon medullary hyperosmolality: this in turn requires low water permeability in some kidney segments (ascending limb of the loop of Henle), whereas in other kidney segments (e.g., proximal tubule) there is a requirement for high water permeability. Differing permeability and facilitation of hormonal control appears to be partly achieved by differential expression along the nephron of a family of proteins known as the aquaporins (AQPs), which act as water channels.

At least 11 different mammalian AQPs have been identified, of which 7 (AQP1, -2, -3, -4, -6, -7, -8) are expressed in the kidney. ^, Many of these have extrarenal expression sites as well (e.g., AQP1 may be important in fluid removal across the peritoneal membrane). Two asparagine-proline-alanine sequences in the molecule are thought to interact in the membrane to form a pathway for water translocation. AQP1, which is found in the proximal tubule and the descending thin limb of the loop of Henle, constitutes almost 3% of total membrane protein in the kidney. It appears to be constitutively expressed and is present in both the apical and basolateral plasma membranes, representing entry and exit ports for water transport across the cell, respectively. Approximately 70% of water reabsorption occurs at this site, predominantly via a transcellular (e.g., AQP1) rather than a paracellular route. Water reabsorption in the proximal tubule passively follows sodium reabsorption, so that fluid entering the loop of Henle is still almost isosmotic with plasma.

Urinary concentration is partly achieved by countercurrent multiplication in the loop of Henle, where approximately 5% of water reabsorption occurs ( Fig. 49.9 ). The descending thin limb is very permeable to water, but the ascending limb and the collecting duct are not (the collecting ducts are also poorly permeable to urea). Fluid entering the loop of Henle is isotonic to plasma but is hypotonic on leaving it. The ascending limb has active sodium reabsorption driven by Na, K-ATPase with electroneutralizing transport of chloride, a combined process that can be inhibited by the so-called loop diuretics (e.g., furosemide, see later). In this section of the nephron, sodium reabsorption is not accompanied by water, creating a hypertonic medullary interstitium and facilitating water reabsorption from the anatomically adjacent descending limb. The descending limb cells are permeable to sodium chloride, which is cycled from the descending limb back to the ascending limb. Countercurrent multiplication is responsible for generating approximately half of the maximal medullary concentration gradient (1200 mOsmol/kg H ₂ O), the remainder being generated by urea recycling (see later).

A further 10% of water reabsorption occurs in the distal tubule, with the remainder (>20 L/day) reabsorbed in the collecting ducts. Entry of water into the collecting duct cells occurs via apical AQP2 channels, with exit probably occurring via basolateral AQP3 (cortical and outer medullary collecting ducts) and AQP4 (inner medullary collecting ducts). AQP2 appears to be the primary target for vasopressin regulation of water reabsorption. Vasopressin (Mr 1080) is a cyclic nonapeptide synthesized in the posterior hypothalamus and stored in the posterior pituitary. It is mainly released into the circulation in response to rising plasma osmolality, detected by osmoreceptors in the anterior hypothalamus, but other important stimuli include pain, acidosis, vomiting, hypoxia, hypotension and hypovolaemia. AQP2 is stored in subapical vesicles in the collecting duct cells. Following vasopressin stimulation, these vesicles are cycled through, and inserted into, the plasma membrane by a cytoskeletal, dynein-mediated transport process. Stimulation occurs following binding of vasopressin to a V ₂ receptor in the basolateral plasma membrane of the principal cells of the collecting duct, which promotes a cyclic adenosine monophosphate (cAMP)/protein kinase A cascade, resulting in phosphorylation and activation of AQP2. Vasopressin regulates the acute cellular water-retaining response (AQP2 trafficking) and its longer-term regulation via a conditioning effect on AQP2 gene transcription. The AQP2 gene has a cAMP response element that is involved in the long-term upregulation of AQP2 expression by vasopressin. It is likely that there are also vasopressin-independent regulatory pathways of AQP2 expression (e.g., oxytocin). Membrane insertion of AQP2 allows water to pass into the collecting duct cells under the influence of medullary hyperosmolality. Maintenance of medullary hyperosmolality depends upon efficient fluid removal, which is the function of the ascending vasa recta , a specialized medullary vasculature, and the close anatomic relations of all medullary constituents (see Fig. 49.2 ). AQP2 expression is decreased in a variety of polyuric conditions (e.g., diabetes insipidus, lithium treatment, hypokalemia, hypercalcemia, urinary obstruction) and is increased in some water-retaining states (e.g., heart failure, cirrhosis, and pregnancy). ^, A variety of V ₂ receptor antagonists have been designed that block the actions of vasopressin. In contrast to diuretics, these agents promote the excretion of electrolyte-free water and have exciting therapeutic potential in water-retaining states.

Vasopressin also increases the permeability of collecting duct cells to urea, which is the major osmotically active component of luminal fluid in the distal tubule. Fluid of high urea concentration therefore enters the deepest layers of the medullary interstitium, passing down its concentration gradient, contributing to medullary hyperosmolality.

Erythropoietin

EPO is a large glycoprotein hormone (Mr 34 kDa) containing 165 amino acids responsible for stimulating erythroid progenitor cells within the bone marrow to produce red blood cells. It is secreted chiefly by renal peritubular capillary endothelial cells in the adult and by the liver in the fetus. Physiologically, reduced oxygen delivery to the kidneys initiates a process coordinated by hypoxia inducible factor-2 resulting in release of EPO, thereby stimulating erythropoiesis. Conversely, with a surplus of oxygen in blood traversing the kidneys, as in some forms of polycythemia, the release of EPO into blood is diminished. The use of recombinant human erythropoietin (rhEPO, epoetin) in the management of anemia of kidney disease is discussed later.

Prostaglandins and thromboxanes

Prostaglandins and thromboxanes are synthesized from arachidonic acid by the cyclooxygenase (COX) enzyme system. The COX system is present in many parts of the kidney and has an important role in regulating the physiologic action of other hormones on renal vascular tone, mesangial contractility, and tubular processing of salt and water. Prostaglandins have a critical role in renal hemodynamics, control of tubular function, and renin release. The major renal vasodilatory prostaglandin is PGE ₂ , which is synthesized predominantly in the medulla. The major vasoconstrictor prostaglandin is thromboxane A ₂ , which is produced primarily within the renal cortex. PGE ₂ increases renal blood flow rate, inhibits sodium reabsorption in the distal nephron and collecting duct, and stimulates renin release. These actions promote natriuresis and diuresis. In patients with chronic kidney disease (CKD), renal PGE ₂ production is increased, representing a compensatory response to loss of nephron mass. Vasodilatory prostaglandins are synthesized following stimulation with renal sympathetic adrenergic and AII-dependent mechanisms to offset or modulate vasoconstriction. In the tubule, prostaglandins act as autocoids, exerting their effects locally, near the site of synthesis.

In pathophysiologic circumstances, including various forms of acute kidney injury (AKI), thromboxane A ₂ and various prostaglandins may have a significant role in inflammation and alteration of vascular tone. The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on renal prostaglandin metabolism are considered later. The lipoxygenase pathway, which leads to formation of leukotrienes, is also present within the kidneys, although the major source of leukotrienes in inflammatory disease of the kidneys is infiltrating white cells and macrophages.

1,25(OH ₂ )D ₃

The kidneys are primarily responsible for producing 1,25(OH ₂ )D ₃ from 25-hydroxycholecalciferol as a result of the action of the enzyme 25-hydroxycholecalciferol 1α-hydroxylase found in proximal tubular epithelial cells. Regulation of this system is considered in Chapter 54 . The management of renal mineral-bone disorders is considered later.

Regulation of glomerular filtration rate

The factors involved in regulation of GFR are listed in Table 49.3 . Autoregulation of renal blood flow and GFR is widely thought to be explained by the myogenic theory. This theory is based on the principle that an increase in wall tension of the afferent arterioles, brought about by an increase in perfusion pressure, causes automatic contraction of arteriolar smooth muscle, thus increasing resistance and keeping the flow constant despite the increase in perfusion pressure.

The tubuloglomerular feedback mechanism, involving the macula densa and release of the vasodilator adenosine, must also be considered. Although not fully understood, this mechanism appears to regulate GFR, with changes in renal blood flow as a secondary consequence. For individual nephrons, evidence indicates that each single nephron GFR is influenced by the composition of the tubular fluid in the distal tubule, which in turn is influenced by the filtration rate. The macula densa is thought to sense the distal tubular sodium chloride content, its osmolality, or the rate at which sodium chloride is transported. The macula densa then signals the JGA via an uncertain mechanism to cause the release of adenosine and possibly AII and prostaglandins, which in turn affects vascular resistance. ^e

e Vascular resistance is the resistance to flow that must be overcome to push blood through the circulatory system.

The result of the combination of myogenic mechanisms and tubuloglomerular feedback is that the net filtration pressure or P _GCap is kept reasonably constant over a wide range of systemic arterial pressures. It should be noted that renal blood flow and GFR change across this range of systemic pressures but to a significantly smaller extent than would be predicted if these autoregulatory mechanisms were not in place.

Other factors influencing renal blood flow are indicated in Table 49.4 . The afferent and efferent arterioles are richly supplied with renal sympathetic nerves. Epinephrine acts via α-adrenergic receptors, leading to constriction of both arterioles and causing a decrease in renal blood flow.

Nitric oxide (NO) has been identified as an important vasodilator produced by vascular endothelial cells. NO is synthesized from L-arginine and oxygen by nitric oxide synthase (NOS), of which three isoenzymes are differentially located and regulated. Within the kidney are eNOS (endothelial) and iNOS (inducible) isoenzymes. Activation of NOS has been shown to occur as a result of shear stress (e.g., increased arteriolar tone). A variety of physiologic vasoconstrictors are present, including acetylcholine, bradykinin, endothelin, and serotonin; a rise in intracellular ionized calcium is required for the vasoconstrictors. NO synthesis is now known to play an important role in the regulation of human vascular tone and has a crucial role in control of blood pressure and kidney function.

Age and the kidney

Kidney function varies throughout life. In utero, urine is produced by the developing fetus from about the ninth week of gestation. Nephrogenesis is complete by approximately 35 weeks gestation, although kidney function remains immature during the first 2 years of life. The kidney of the term infant receives approximately 6% of the cardiac output, compared with 25% in adults. Renal vascular resistance is relatively high and the low renal blood flow is particularly directed to the medulla and inner cortex. The gradual increase in renal blood flow that occurs with increasing age is directed mainly to the outer cortex and is mediated by local neurohormonal mechanisms. The GFR at birth is approximately 30 mL/min/1.73 m ² . It increases rapidly during the first weeks of life to reach approximately 70 mL/min/1.73 m ² by age 16 days. Normal adult values are achieved by age 14 years. Tubular functions, including salt and water conservation, are also immature at birth. Birth is associated with rapid changes in kidney function, with a switch to salt and water conservation mediated by catecholamines, the renin-angiotensin system, vasopressin, glucocorticoids, and thyroid hormone. The immaturity of the neonatal kidney contributes to the relatively common problems of water and electrolyte disturbances in infants. These disturbances are more likely to occur in premature infants, particularly those born before 35 weeks gestation.

Aging is associated with a range of microscopic, macroscopic, and molecular changes in the kidney, which begin in early middle-age, including decreasing kidney weight, decreasing number of glomeruli, with the cortical glomeruli being particularly affected, GBM thickening, increased prevalence of renal cysts, parenchymal calcifications, and cortical scars. There is also glomerular sclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis; collectively this tetrad of abnormalities is termed nephrosclerosis. At a molecular level, these changes are accompanied by cellular senescence, telomere shortening, and apoptosis.

Structural change is accompanied by functional changes, which in many respects are the reverse of those seen in early life. On average, GFR declines with age by approximately 1 mL/min/1.73 m ² /yr over the age of 40 years. Renal blood flow, particularly to the cortical area, also decreases with age at a rate of approximately 10%/year from the fourth to fifth decade onward, while the filtration fraction (i.e., GFR/renal plasma flow) and renal vascular resistance increase. Tubular function, such as the ability to concentrate urine, retain sodium, and excrete water and salt load, is decreased, and nocturnal polyuria is common. These changes in part account for the increased risk of dehydration and AKI observed in older individuals. The prevalence of albuminuria rises over the age of approximately 40 years. ^,

It is a moot point whether these changes are the result of a normal aging process (i.e., involutional) or whether they are caused by the interplay of pathology and age. Cumulative exposure to common causes of CKD such as (1) atherosclerosis, (2) hypertension, (3) heart failure, (4) diabetes, (5) obstructive nephropathy, (6) infection, (7) immune insult, (8) nephrotoxins such as lead, and (9) dietary protein ^, increases with age and it is difficult to separate these effects from those of “healthy” aging. In the absence of these and other identifiable causes of kidney disease, many individuals have stable GFR as they age.

Loss of kidney function with aging appears to be heterogeneous and is not inevitable. ^, Kidney function may be well preserved in healthy older people, and assumptions with respect to GFR based solely on age could be erroneous. Furthermore, attention to the common causes of CKD could preserve function in older people. Kidney disease is more common among older people. Studies from England, France, and Iceland have demonstrated a near exponential rise in CKD with age. Data from the United States show the prevalence of GFR between 30 and 60 mL/min/1.73 m ² to be 4.3% of the total noninstitutionalized population overall, but this rises to 25% among those over 70 years. The prevalence may be even higher among institutionalized older people (e.g., 82% of a residential home population were identified as having a GFR <60 mL/min/1.73 m ² ). The incidence of AKI also increases with age.

Tubular reabsorption

The final urinary concentration of proteins depends on the filtered load, but also on the efficiency of the proximal tubular reabsorptive process, in addition to any contribution of tubular secretion. Proteins are reabsorbed by receptor-mediated, low-affinity, high-capacity processes. Megalin (600 kDa) and cubilin (460 kDa) are endocytic, multiligand receptors that are important in protein reabsorption. Megalin belongs to the low-density lipoprotein (LDL) receptor family whereas cubilin is identical to the intestinal intrinsic factor-vitamin B12 receptor. In the kidney, both are localized in clathrin-coated pits in the apical brush border of renal proximal tubular cells and bind filtered proteins in a calcium-dependent process. This apparatus is found throughout the proximal tubule although there are notably fewer clathrin-coated pits and vesicles in the S3 segment. Megalin appears capable of both binding and internalizing its ligands whereas the cubilin-ligand complex requires megalin to be internalized. Some proteins such as albumin will bind to either receptor, whereas others are specific (e.g., transferrin binds to cubilin only, retinol-binding protein [RBP] and α1-microglobulin to megalin only).

Once proteins have been internalized, they are transported by the endocytic vesicle and fuse with lysosomes. Proteolysis occurs, and the resultant amino acids are released into the tubulointerstitial space across the basolateral surface of the tubular epithelial cell. The membrane vesicles are then recycled to the brush border to complete the reabsorption cycle. Some small peptide fragments of proteins may be released back into the urinary space. An alternative reabsorptive pathway involves interaction with MHC-related Fc receptor (FcRN), leading to dissociation of albumin from megalin/cubilin and subsequent transcytosis of albumin i.e., transport of intact reabsorbed albumin across the tubular epithelial cell and back into the circulation. The quantitative significance of this mechanism remains unclear. In health, the reabsorptive mechanism removes the majority of the filtered protein, thus retaining most of the essential amino acid constituents for reuse. Capture of filtered transport proteins is also important in conserving vitamin status (e.g., vitamin A associated with RBP).

The tubular reabsorptive process is saturable. Any increase in the filtered load (caused by glomerular damage, increased glomerular vascular permeability [e.g., inflammatory response], or increased circulating concentration of low molecular weight proteins) or decrease in reabsorptive capacity (caused by tubular damage) can result in increased urinary protein loss ( proteinuria ).

Tubular secretion of proteins also contributes to urinary total protein concentration. In particular, in health, uromodulin (also known as Tamm Horsfall glycoprotein, THG) accounts for ~50% of urinary total protein. Uromodulin (200 kDa), a highly glycosylated acidic protein, is secreted into the tubular fluid only by the thick ascending limb and the early distal convoluted tubule and is thought to play a role in inhibiting kidney stone formation. ^, It is a major constituent of renal tubular casts along with albumin and traces of other proteins. Investigation for proteinuria is mandatory in any patient with suspected kidney disease and was considered in Chapter 34 .

Consequences of proteinuria

Experimental data indicate that proteinuria is not just a marker of, but contributes directly to, progression of kidney disease. ^, The accumulation of proteins in abnormal amounts in the tubular lumen may trigger release of profibrogenic and proinflammatory molecules (see later), which in turn contribute to tubulointerstitial structural damage and expansion, and progression of kidney disease. Increasing evidence suggests that megalin may not just be a scavenger receptor for albumin, but that it may have signaling functions that regulate cell survival. Evidence gathered from in vitro studies suggests that glomerular filtration of abnormal amounts or types of protein induces mesangial cell injury, leading to glomerulosclerosis, and that these same proteins can have adverse effects on proximal tubular cell function. Excessive quantities of albumin in the tubular lumen may downregulate proximal tubular megalin expression, increasing cell sensitivity to apoptosis.

Numerous studies have demonstrated that proteinuria is a potent risk marker for progression of renal disease in both nondiabetic and diabetic kidney disease. Furthermore, reducing proteinuria slows the rate of progression of proteinuric kidney disease. This effect has been observed in clinical trials in patients treated with ACE inhibitors, angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists, given alone or in combination. ^{, ,} Reduction of proteinuria has been proposed as a therapeutic target, ^, although this view is not universally held.

General management of chronic kidney disease

Complications of CKD that develop before the need for RRT are numerous and include cardiovascular disease, metabolic acidosis, bone disease, and anemia. There is a broad, and often causal, relationship between the burden of illness and the level of GFR. Rate of progression of CKD, irrespective of underlying cause, is dependent on both nonmodifiable factors, such as age, gender, race, and level of kidney function at diagnosis, and modifiable characteristics, including proteinuria, blood pressure control, and smoking. Progression and specific treatment options for diabetic and hypertensive nephropathy are discussed separately later. The current discussion focuses on optimal treatment for nondiabetic CKD. Lowering blood pressure and reducing proteinuria have been shown to ameliorate the progression of CKD. The Modification of Diet in Renal Disease (MDRD) study compared the rates of decline in GFR in 840 patients with various causes of CKD versus a “usual” or “low” blood pressure goal. Patients with type 1 diabetes were excluded. Outcome data suggest that a low blood pressure goal had some beneficial effect in those patients with higher levels of proteinuria. ^, The study supported the concept that proteinuria is an independent risk factor for progression of kidney disease. For patients with proteinuria greater than 1 g/day the suggested target for mean blood pressure was 92 mm Hg (125/75 mm Hg). The target blood pressure recommended by the eighth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) is less than 140/90 mm Hg for patients with diabetes or kidney disease and the general population aged less than 60 years. There is concern that lower blood pressures may be associated with worse outcomes in some patients. Hence target ranges in addition to thresholds are sometimes recommended. In the United Kingdom a target systolic blood pressure of less than 140 mm Hg (range 120 to 139 mm Hg) and diastolic blood pressure less than 90 mm Hg is recommended for most patients with CKD. A lower target systolic blood pressure of less than 130 mm Hg (target range 120 to 129 mm Hg) and diastolic target of less than 80 mm Hg is recommended in patients with an ACR greater than 70 mg/mmol (approximately equivalent to >1 g/day proteinuria) and/or diabetes.

Data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988 to 1994) reveal, that among hypertensive individuals with an increased serum creatinine concentration, 75% were on antihypertensive treatment, and only 11% had their blood pressure reduced to lower than 130/85 mm Hg.

ACE inhibitors are more effective than other antihypertensive drugs in slowing the rate of progression of proteinuric CKD, although they do induce a mild decrease in GFR (<10 mL/min/1.73 m ² ). It should also be noted that the evidence base for ACE inhibitor use in the setting of CKD may not be generalizable to older (>70 years) nonproteinuric adults, who form the majority of patients with CKD. The development of hypotension, AKI, or hyperkalemia (plasma potassium concentration >5.5 mmol/L) should prompt discontinuation of the drug until other causes have been excluded. Short-term studies show that ARBs have effects on blood pressure and proteinuria that are similar to those of ACE inhibitors.

Low-nitrogen (protein) diets have been advocated from the early years of treatment of severe chronic uremia. The very-low-protein diets tested in the MDRD study were of marginal benefit in these well-supervised patients with very low renal function, but are not well adhered to in practice, may lead to negative nitrogen balance, and are not recommended. Protein intake is restricted spontaneously to approximately 0.6 to 0.8 g/kg/day by uremic patients not receiving dietary advice. To prevent malnutrition, patients receive professional dietary advice, with diets containing an increased proportion of protein and a total calorie content of up to 35 kcal/kg/day. The NHANES III has confirmed an association with reduced GFR and malnutrition in noninstitutionalized individuals studied in a cross-sectional survey of more than 5000 participants stratified according to GFR.

Although intuitively one might expect correction of renal acidosis to be beneficial, unanticipated secondary effects may impact on patient survival (e.g., increased vascular calcification following alkalinization or increased risk of heart failure). ^, A relatively small trial suggested that bicarbonate supplementation can slow the rate of progression of CKD and further reports generally support this suggestion. ^, However, a pragmatic study (BiCARB) among older patients with CKD did not observe benefit from oral sodium bicarbonate supplementation in terms of improving physical function or reducing kidney function decline.

Cardiovascular complications of chronic kidney disease

The spectrum of cardiovascular pathology predominant among patients with CKD (hypertensive cardiomyopathy, arrhythmias, heart failure, valvular disease, and peripheral vascular disease) differs from that predominant in the general population (atheromatous coronary artery disease). The incidence of cardiovascular disease is 7- to 10-fold greater in patients with CKD than in non-CKD age- and gender-matched controls. By the time patients develop the need for RRT, there is an approximately 17 times greater risk of cardiovascular death or nonfatal myocardial infarction among age- and sex-matched individuals without kidney disease. ^, Among patients treated by dialysis, the prevalence of coronary artery disease is approximately 40% and the prevalence of left ventricular hypertrophy (LVH) is approximately 75%. ^, Cardiovascular mortality, defined as death caused by arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction, atherosclerotic heart disease, and pulmonary edema, has been estimated to be approximately 9% per year in dialysis patients, accounting for 50% of deaths of all patients with ESRD. Even after stratification by age, gender, race, and the presence or absence of diabetes, cardiovascular mortality in dialysis patients is 10 to 20 times higher than in the general population ( Fig. 49.14 ). ^, Patients with ESRD should be considered in the highest risk group for subsequent cardiovascular events.

Risk factors for cardiovascular disease in CKD consist of a mixture of the traditional and CKD-specific factors. Traditional risk factors such as diabetes, hypertension, and dyslipidemia are more likely in CKD patients. In addition, there are a number of CKD-related risk factors ( Box 49.1 ).