Acute Kidney Injury

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PART 13: Disorders of the Kidney and Urinary Tract


 

332e  

Cellular and Molecular Biology of the Kidney

Alfred L. George, Jr., Eric G. Neilson


The kidney is one of the most highly differentiated organs in the body. At the conclusion of embryologic development, nearly 30 different cell types form a multitude of filtering capillaries and segmented nephrons enveloped by a dynamic interstitium. This cellular diversity modulates a variety of complex physiologic processes. Endocrine functions, the regulation of blood pressure and intraglomerular hemodynamics, solute and water transport, acid-base balance, and removal of drug metabolites are all accomplished by intricate mechanisms of renal response. This breadth of physiology hinges on the clever ingenuity of nephron architecture that evolved as complex organisms came out of water to live on land.

EMBRYOLOGIC DEVELOPMENT

Kidneys develop from intermediate mesoderm under the timed or sequential control of a growing number of genes, described in Fig. 332e-1. The transcription of these genes is guided by morphogenic cues that invite two ureteric buds to each penetrate bilateral metanephric blastema, where they induce primary mesenchymal cells to form early nephrons. The two ureteric buds emerge from posterior nephric ducts and mature into separate collecting systems that eventually form a renal pelvis and ureter. Induced mesenchyme undergoes mesenchymal epithelial transitions to form comma-shaped bodies at the proximal end of each ureteric bud leading to the formation of S-shaped nephrons that cleft and enjoin with penetrating endothelial cells derived from sprouting angioblasts. Under the influence of vascular endothelial growth factor A (VEGF-A), these penetrating cells form capillaries with surrounding mesangial cells that differentiate into a glomerular filter for plasma water and solute. The ureteric buds branch, and each branch produce a new set of nephrons. The number of branching events ultimately determines the total number of nephrons in each kidney. There are approximately 900,000 glomeruli in each kidney in normal birth weight adults and as few as 225,000 in low-birth-weight adults, with the latter producing numerous comorbid risks.

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FIGURE 332e-1   Genes controlling renal nephrogenesis. A growing number of genes have been identified at various stages of glomerulotubular development in the mammalian kidney. The genes listed have been tested in various genetically modified mice, and their location corresponds to the classical stages of kidney development postulated by Saxen in 1987.

Glomeruli evolve as complex capillary filters with fenestrated endothelia under the guiding influence of VEGF-A and angiopoietin-1 secreted by adjacently developing podocytes. Epithelial podocytes facing the urinary space envelop the exterior basement membrane supporting these emerging endothelial capillaries. Podocytes are partially polarized and periodically fall off into the urinary space by epithelial-mesenchymal transition, and to a lesser extent apoptosis, only to be replenished by migrating parietal epithelia from Bowman capsule. Impaired replenishment results in heavy proteinuria. Podocytes attach to the basement membrane by special foot processes and share a slit-pore membrane with their neighbor. The slit-pore membrane forms a filter for plasma water and solute by the synthetic interaction of nephrin, annexin-4, CD2AP, FAT, ZO-1, P-cadherin, podocin, TRPC6, PLCE1, and Neph 1-3 proteins. Mutations in many of these proteins also result in heavy proteinuria. The glomerular capillaries are embedded in a mesangial matrix shrouded by parietal and proximal tubular epithelia forming Bowman capsule. Mesangial cells have an embryonic lineage consistent with arteriolar or juxtaglomerular cells and contain contractile actin-myosin fibers. These mesangial cells make contact with glomerular capillary loops, and their local matrix holds them in condensed arrangement.

Between nephrons lies the renal interstitium. This region forms a functional space surrounding glomeruli and their downstream tubules, which are home to resident and trafficking cells such as fibroblasts, dendritic cells, occasional lymphocytes, and lipid-laden macrophages. The cortical and medullary capillaries, which siphon off solute and water following tubular reclamation of glomerular filtrate, are also part of the interstitial fabric as well as a web of connective tissue that supports the kidney’s emblematic architecture of folding tubules. The relational precision of these structures determines the unique physiology of the kidney.

Each nephron is partitioned during embryologic development into a proximal tubule, descending and ascending limbs of the loop of Henle, distal tubule, and the collecting duct. These classic tubular segments build from subsegments lined by highly unique epithelia serving regional physiology. All nephrons have the same structural components, but there are two types whose structures depend on their location within the kidney. The majority of nephrons are cortical, with glomeruli located in the mid-to-outer cortex. Fewer nephrons are juxtamedullary, with glomeruli at the boundary of the cortex and outer medulla. Cortical nephrons have short loops of Henle, whereas juxtamedullary nephrons have long loops of Henle. There are critical differences in blood supply as well. The peritubular capillaries surrounding cortical nephrons are shared among adjacent nephrons. By contrast, juxtamedullary nephrons depend on individual capillaries called vasa recta. Cortical nephrons perform most of the glomerular filtration because there are more of them and because their afferent arterioles are larger than their respective efferent arterioles. The juxtamedullary nephrons, with longer loops of Henle, create an osmotic gradient for concentrating urine. How developmental instructions specify the differentiation of all these unique epithelia among various tubular segments is still unknown.

DETERMINANTS AND REGULATION OF GLOMERULAR FILTRATION

Renal blood flow normally drains approximately 20% of the cardiac output, or 1000 mL/min. Blood reaches each nephron through the afferent arteriole leading into a glomerular capillary where large amounts of fluid and solutes are filtered to form the tubular fluid. The distal ends of the glomerular capillaries coalesce to form an efferent arteriole leading to the first segment of a second capillary network (cortical peritubular capillaries or medullary vasa recta) surrounding the tubules (Fig. 332e-2A). Thus, nephrons have two capillary beds arranged in a series separated by the efferent arteriole that regulates the hydrostatic pressure in both capillary beds. The distal capillaries empty into small venous branches that coalesce into larger veins to eventually form the renal vein.

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FIGURE 332e-2   Renal microcirculation and the renin-angiotensin system. A. Diagram illustrating relationships of the nephron with glomerular and peritubular capillaries. B. Expanded view of the glomerulus with its juxtaglomerular apparatus including the macula densa and adjacent afferent arteriole. C. Proteolytic processing steps in the generation of angiotensins.

The hydrostatic pressure gradient across the glomerular capillary wall is the primary driving force for glomerular filtration. Oncotic pressure within the capillary lumen, determined by the concentration of unfiltered plasma proteins, partially offsets the hydrostatic pressure gradient and opposes filtration. As the oncotic pressure rises along the length of the glomerular capillary, the driving force for filtration falls to zero on reaching the efferent arteriole. Approximately 20% of the renal plasma flow is filtered into Bowman space, and the ratio of glomerular filtration rate (GFR) to renal plasma flow determines the filtration fraction. Several factors, mostly hemodynamic, contribute to the regulation of filtration under physiologic conditions.

Although glomerular filtration is affected by renal artery pressure, this relationship is not linear across the range of physiologic blood pressures due to autoregulation of GFR. Autoregulation of glomerular filtration is the result of three major factors that modulate either afferent or efferent arteriolar tone: these include an autonomous vasoreactive (myogenic) reflex in the afferent arteriole, tubuloglomerular feedback, and angiotensin II-mediated vasoconstriction of the efferent arteriole. The myogenic reflex is a first line of defense against fluctuations in renal blood flow. Acute changes in renal perfusion pressure evoke reflex constriction or dilatation of the afferent arteriole in response to increased or decreased pressure, respectively. This phenomenon helps protect the glomerular capillary from sudden changes in systolic pressure.

Tubuloglomerular feedback (TGF) changes the rate of filtration and tubular flow by reflex vasoconstriction or dilatation of the afferent arteriole. TGF is mediated by specialized cells in the thick ascending limb of the loop of Henle called the macula densa that act as sensors of solute concentration and tubular flow rate. With high tubular flow rates, a proxy for an inappropriately high filtration rate, there is increased solute delivery to the macula densa (Fig. 332e-2B) that evokes vasoconstriction of the afferent arteriole causing GFR to return toward normal. One component of the soluble signal from the macula densa is adenosine triphosphate (ATP) released by the cells during increased NaCl reabsorption. ATP is metabolized in the extracellular space to generate adenosine, a potent vasoconstrictor of the afferent arteriole. During conditions associated with a fall in filtration rate, reduced solute delivery to the macula densa attenuates TGF, allowing afferent arteriolar dilatation and restoring glomerular filtration to normal levels. Angiotensin II and reactive oxygen species enhance, while nitric oxide (NO) blunts, TGF.

The third component underlying autoregulation of GFR involves angiotensin II. During states of reduced renal blood flow, renin is released from granular cells within the wall of the afferent arteriole near the macula densa in a region called the juxtaglomerular apparatus (Fig. 332e-2B). Renin, a proteolytic enzyme, catalyzes the conversion of angiotensinogen to angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme (ACE) (Fig. 332e-2C). Angiotensin II evokes vasoconstriction of the efferent arteriole, and the resulting increased glomerular hydrostatic pressure elevates filtration to normal levels.

MECHANISMS OF RENAL TUBULAR TRANSPORT

The renal tubules are composed of highly differentiated epithelia that vary dramatically in morphology and function along the nephron (Fig. 332e-3). The cells lining the various tubular segments form monolayers connected to one another by a specialized region of the adjacent lateral membranes called the tight junction. Tight junctions form an occlusive barrier that separates the lumen of the tubule from the interstitial spaces surrounding the tubule and also apportions the cell membrane into discrete domains: the apical membrane facing the tubular lumen and the basolateral membrane facing the interstitium. This regionalization allows cells to allocate membrane proteins and lipids asymmetrically. Owing to this feature, renal epithelial cells are said to be polarized. The asymmetric assignment of membrane proteins, especially proteins mediating transport processes, provides the machinery for directional movement of fluid and solutes by the nephron.

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FIGURE 332e-3   Transport activities of the major nephron segments. Representative cells from five major tubular segments are illustrated with the lumen side (apical membrane) facing left and interstitial side (basolateral membrane) facing right. A. Proximal tubular cells. B. Typical cell in the thick ascending limb of the loop of Henle. C. Distal convoluted tubular cell. D. Overview of entire nephron. E. Cortical collecting duct cells. F. Typical cell in the inner medullary collecting duct. The major membrane transporters, channels, and pumps are drawn with arrows indicating the direction of solute or water movement. For some events, the stoichiometry of transport is indicated by numerals preceding the solute. Targets for major diuretic agents are labeled. The actions of hormones are illustrated by arrows with plus signs for stimulatory effects and lines with perpendicular ends for inhibitory events. Dotted lines indicate free diffusion across cell membranes. The dashed line indicates water impermeability of cell membranes in the thick ascending limb and distal convoluted tubule.

EPITHELIAL SOLUTE TRANSPORT

There are two types of epithelial transport. Movement of fluid and solutes sequentially across the apical and basolateral cell membranes (or vice versa) mediated by transporters, channels, or pumps is called cellular transport. By contrast, movement of fluid and solutes through the narrow passageway between adjacent cells is called paracellular transport. Paracellular transport occurs through tight junctions, indicating that they are not completely “tight.” Indeed, some epithelial cell layers allow rather robust paracellular transport to occur (leaky epithelia), whereas other epithelia have more effective tight junctions (tight epithelia). In addition, because the ability of ions to flow through the paracellular pathway determines the electrical resistance across the epithelial monolayer, leaky and tight epithelia are also referred to as low- or high-resistance epithelia, respectively. The proximal tubule contains leaky epithelia, whereas distal nephron segments, such as the collecting duct, contain tight epithelia. Leaky epithelia are most well suited for bulk fluid reabsorption, whereas tight epithelia allow for more refined control and regulation of transport.

MEMBRANE TRANSPORT

Cell membranes are composed of hydrophobic lipids that repel water and aqueous solutes. The movement of solutes and water across cell membranes is made possible by discrete classes of integral membrane proteins, including channels, pumps, and transporters. These different mechanisms mediate specific types of transport activities, including active transport (pumps), passive transport (channels), facilitated diffusion (transporters), and secondary active transport (cotransporters). Active transport requires metabolic energy generated by the hydrolysis of ATP. Active transport pumps are ion-translocating ATPases, including the ubiquitous Na+/K+-ATPase, the H+-ATPases, and Ca2+-ATPases. Active transport creates asymmetric ion concentrations across a cell membrane and can move ions against a chemical gradient. The potential energy stored in a concentration gradient of an ion such as Na+ can be used to drive transport through other mechanisms (secondary active transport). Pumps are often electrogenic, meaning they can create an asymmetric distribution of electrostatic charges across the membrane and establish a voltage or membrane potential. The movement of solutes through a membrane protein by simple diffusion is called passive transport. This activity is mediated by channels created by selectively permeable membrane proteins, and it allows solute or water to move across a membrane driven by favorable concentration gradients or electrochemical potential. Facilitated diffusion is a specialized type of passive transport mediated by simple transporters called carriers or uniporters. For example, hexose transporters such as GLUT2 mediate glucose transport by tubular cells. These transporters are driven by the concentration gradient for glucose that is highest in extracellular fluids and lowest in the cytoplasm due to rapid metabolism. Many other transporters operate by translocating two or more ions/solutes in concert either in the same direction (symporters or cotransporters) or in opposite directions (antiporters or exchangers) across the cell membrane. The movement of two or more ions/solutes may produce no net change in the balance of electrostatic charges across the membrane (electroneutral), or a transport event may alter the balance of charges (electrogenic). Several inherited disorders of renal tubular solute and water transport occur as a consequence of mutations in genes encoding a variety of channels, transporter proteins, and their regulators (Table 332e-1).

TABLE 332e-1

INHERITED DISORDERS AFFECTING RENAL TUBULAR ION AND SOLUTE TRANSPORT

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SEGMENTAL NEPHRON FUNCTIONS

Each anatomic segment of the nephron has unique characteristics and specialized functions enabling selective transport of solutes and water (Fig. 332e-3). Through sequential events of reabsorption and secretion along the nephron, tubular fluid is progressively conditioned into urine. Knowledge of the major tubular mechanisms responsible for solute and water transport is critical for understanding hormonal regulation of kidney function and the pharmacologic manipulation of renal excretion.

PROXIMAL TUBULE

The proximal tubule is responsible for reabsorbing ~60% of filtered NaCl and water, as well as ~90% of filtered bicarbonate and most critical nutrients such as glucose and amino acids. The proximal tubule uses both cellular and paracellular transport mechanisms. The apical membrane of proximal tubular cells has an expanded surface area available for reabsorptive work created by a dense array of microvilli called the brush border, and leaky tight junctions enable high-capacity fluid reabsorption.

Solute and water pass through these tight junctions to enter the lateral intercellular space where absorption by the peritubular capillaries occurs. Bulk fluid reabsorption by the proximal tubule is driven by high oncotic pressure and low hydrostatic pressure within the peritubular capillaries. Cellular transport of most solutes by the proximal tubule is coupled to the Na+ concentration gradient established by the activity of a basolateral Na+/K+-ATPase (Fig. 332e-3A). This active transport mechanism maintains a steep Na+ gradient by keeping intracellular Na+ concentrations low. Solute reabsorption is coupled to the Na+ gradient by Na+-dependent transporters such as Na+-glucose and Na+-phosphate cotransporters. In addition to the paracellular route, water reabsorption also occurs through the cellular pathway enabled by constitutively active water channels (aquaporin-1) present on both apical and basolateral membranes.

Proximal tubular cells reclaim bicarbonate by a mechanism dependent on carbonic anhydrases. Filtered bicarbonate is first titrated by protons delivered to the lumen by Na+/H+ exchange. The resulting carbonic acid (H2CO3) is metabolized by brush border carbonic anhydrase to water and carbon dioxide. Dissolved carbon dioxide then diffuses into the cell, where it is enzymatically hydrated by cytoplasmic carbonic anhydrase to re-form carbonic acid. Finally, intracellular carbonic acid dissociates into free protons and bicarbonate anions, and bicarbonate exits the cell through a basolateral Na+/HCO3 cotransporter. This process is saturable, resulting in urinary bicarbonate excretion when plasma levels exceed the physiologically normal range (24-26 meq/L). Carbonic anhydrase inhibitors such as acetazolamide, a class of weak diuretic agents, block proximal tubule reabsorption of bicarbonate and are useful for alkalinizing the urine.

The proximal tubule contributes to acid secretion by two mechanisms involving the titration of the urinary buffers ammonia (NH3) and phosphate. Renal NH3 is produced by glutamine metabolism in the proximal tubule. Subsequent diffusion of NH3 out of the proximal tubular cell enables trapping of H+ secreted by sodium-proton exchange in the lumen as ammonium ion (NH4+). Cellular K+ levels inversely modulate proximal tubular ammoniagenesis, and in the setting of high serum K+ from hypoaldosteronism, reduced ammoniagenesis facilitates the appearance of type IV renal tubular acidosis. Filtered hydrogen phosphate ion (HPO42) is also titrated in the proximal tubule by secreted H+ to form H2PO4, and this reaction constitutes a major component of the urinary buffer referred to as titratable acid. Most filtered phosphate ion is reabsorbed by the proximal tubule through a sodium-coupled cotransport process that is regulated by parathyroid hormone.

Chloride is poorly reabsorbed throughout the first segment of the proximal tubule, and a rise in Cl concentration counterbalances the removal of bicarbonate anion from tubular fluid. In later proximal tubular segments, cellular Cl reabsorption is initiated by apical exchange of cellular formate for higher luminal concentrations of Cl. Once in the lumen, formate anions are titrated by H+ (provided by Na+/H+ exchange) to generate neutral formic acid, which can diffuse passively across the apical membrane back into the cell where it dissociates a proton and is recycled. Basolateral Cl exit is mediated by a K+/Cl cotransporter.

Reabsorption of glucose is nearly complete by the end of the proximal tubule. Cellular transport of glucose is mediated by apical Na+-glucose cotransport coupled with basolateral, facilitated diffusion by a glucose transporter. This process is also saturable, leading to glycosuria when plasma levels exceed 180-200 mg/dL, as seen in untreated diabetes mellitus.

The proximal tubule possesses specific transporters capable of secreting a variety of organic acids (carboxylate anions) and bases (mostly primary amine cations). Organic anions transported by these systems include urate, dicarboxylic acid anions (succinate), ketoacid anions, and several protein-bound drugs not filtered at the glomerulus (penicillins, cephalosporins, and salicylates). Probenecid inhibits renal organic anion secretion and can be clinically useful for raising plasma concentrations of certain drugs like penicillin and oseltamivir. Organic cations secreted by the proximal tubule include various biogenic amine neurotransmitters (dopamine, acetylcholine, epinephrine, norepinephrine, and histamine) and creatinine. The ATP-dependent transporter P-glycoprotein is highly expressed in brush border membranes and secretes several medically important drugs, including cyclosporine, digoxin, tacrolimus, and various cancer chemotherapeutic agents. Certain drugs like cimetidine and trimethoprim compete with endogenous compounds for transport by the organic cation pathways. Although these drugs elevate serum creatinine levels, there is no change in the actual GFR.

The proximal tubule, through distinct classes of Na+-dependent and Na+-independent transport systems, reabsorbs amino acids efficiently. These transporters are specific for different groups of amino acids. For example, cystine, lysine, arginine, and ornithine are transported by a system comprising two proteins encoded by the SLC3A1 and SLC7A9 genes. Mutations in either SLC3A1 or SLC7A9 impair reabsorption of these amino acids and cause the disease cystinuria. Peptide hormones, such as insulin and growth hormone, β2-microglobulin, albumin, and other small proteins, are taken up by the proximal tubule through a process of absorptive endocytosis and are degraded in acidified endocytic lysosomes. Acidification of these vesicles depends on a vacuolar H+-ATPase and Cl channel. Impaired acidification of endocytic vesicles because of mutations in a Cl channel gene (CLCN5) causes low-molecular-weight proteinuria in Dent disease.

LOOP OF HENLE

The loop of Henle consists of three major segments: descending thin limb, ascending thin limb, and ascending thick limb. These divisions are based on cellular morphology and anatomic location, but also correlate with specialization of function. Approximately 15–25% of filtered NaCl is reabsorbed in the loop of Henle, mainly by the thick ascending limb. The loop of Henle has an important role in urinary concentration by contributing to the generation of a hypertonic medullary interstitium in a process called countercurrent multiplication. The loop of Henle is the site of action for the most potent class of diuretic agents (loop diuretics) and also contributes to reabsorption of calcium and magnesium ions.

The descending thin limb is highly water permeable owing to dense expression of constitutively active aquaporin-1 water channels. By contrast, water permeability is negligible in the ascending limb. In the thick ascending limb, there is a high level of secondary active salt transport enabled by the Na+/K+/2Cl cotransporter on the apical membrane in series with basolateral Cl channels and Na+/K+-ATPase (Fig. 332e-3B). The Na+/K+/2Cl cotransporter is the primary target for loop diuretics. Tubular fluid K+ is the limiting substrate for this cotransporter (tubular concentration of K+ is similar to plasma, about 4 meq/L), but transporter activity is maintained by K+ recycling through an apical potassium channel. The cotransporter also enables reabsorption of NH4+ in lieu of K+, and this leads to accumulation of both NH4+ and NH3 in the medullary interstitium. An inherited disorder of the thick ascending limb, Bartter syndrome, also results in a salt-wasting renal disease associated with hypokalemia and metabolic alkalosis; loss-of-function mutations in one of five distinct genes encoding components of the Na+/K+/2Cl cotransporter (NKCC2), apical K+ channel (KCNJ1), basolateral Cl channel (CLCNKB, BSND), or calcium-sensing receptor (CASR) can cause Bartter syndrome.

Potassium recycling also contributes to a positive electrostatic charge in the lumen relative to the interstitium that promotes divalent cation (Mg2+ and Ca2+) reabsorption through a paracellular pathway. A Ca2+-sensing, G-protein-coupled receptor (CaSR) on basolateral membranes regulates NaCl reabsorption in the thick ascending limb through dual signaling mechanisms using either cyclic AMP or eicosanoids. This receptor enables a steep relationship between plasma Ca2+ levels and renal Ca2+ excretion. Loss-of-function mutations in CaSR cause familial hypercalcemic hypocalciuria because of a blunted response of the thick ascending limb to extracellular Ca2+. Mutations in CLDN16 encoding paracellin-1, a transmembrane protein located within the tight junction complex, leads to familial hypomagnesemia with hypercalciuria and nephrocalcinosis, suggesting that the ion conductance of the paracellular pathway in the thick limb is regulated.

The loop of Henle contributes to urine-concentrating ability by establishing a hypertonic medullary interstitium that promotes water reabsorption by the downstream inner medullary collecting duct. Countercurrent multiplication produces a hypertonic medullary interstitium using two countercurrent systems: the loop of Henle (opposing descending and ascending limbs) and the vasa recta (medullary peritubular capillaries enveloping the loop). The countercurrent flow in these two systems helps maintain the hypertonic environment of the inner medulla, but NaCl reabsorption by the thick ascending limb is the primary initiating event. Reabsorption of NaCl without water dilutes the tubular fluid and adds new osmoles to medullary interstitial fluid. Because the descending thin limb is highly water permeable, osmotic equilibrium occurs between the descending limb tubular fluid and the interstitial space, leading to progressive solute trapping in the inner medulla. Maximum medullary interstitial osmolality also requires partial recycling of urea from the collecting duct.

DISTAL CONVOLUTED TUBULE

The distal convoluted tubule reabsorbs ~5% of the filtered NaCl. This segment is composed of a tight epithelium with little water permeability. The major NaCl-transporting pathway uses an apical membrane, electroneutral thiazide-sensitive Na+/Cl cotransporter in tandem with basolateral Na+/K+-ATPase and Cl channels (Fig. 332e-3C). Apical Ca2+-selective channels (TRPV5) and basolateral Na+/Ca2+ exchange mediate calcium reabsorption in the distal convoluted tubule. Ca2+ reabsorption is inversely related to Na+ reabsorption and is stimulated by parathyroid hormone. Blocking apical Na+/Cl cotransport will reduce intracellular Na+, favoring increased basolateral Na+/Ca2+ exchange and passive apical Ca2+ entry. Loss-of-function mutations of SLC12A3 encoding the apical Na+/Cl cotransporter cause Gitelman syndrome, a salt-wasting disorder associated with hypokalemic alkalosis and hypocalciuria. Mutations in genes encoding WNK kinases, WNK-1 and WNK-4, cause pseudohypoaldosteronism type II or Gordon syndrome characterized by familial hypertension with hyperkalemia. WNK kinases influence the activity of several tubular ion transporters. Mutations in this disorder lead to overactivity of the apical Na+/Cl cotransporter in the distal convoluted tubule as the primary stimulus for increased salt reabsorption, extracellular volume expansion, and hypertension. Hyperkalemia may be caused by diminished activity of apical K+ channels in the collecting duct, a primary route for K+ secretion. Mutations in TRPM6 encoding Mg2+ permeable ion channels also cause familial hypomagnesemia with hypocalcemia. A molecular complex of TRPM6 and TRPM7 proteins is critical for Mg2+ reabsorption in the distal convoluted tubule.

COLLECTING DUCT

The collecting duct modulates the final composition of urine. The two major divisions, the cortical collecting duct and inner medullary collecting duct, contribute to reabsorbing ~4-5% of filtered Na+ and are important for hormonal regulation of salt and water balance. The cortical collecting duct contains high-resistance epithelia with two cell types. Principal cells are the main water, Na+-reabsorbing, and K+-secreting cells, and the site of action of aldosterone, K+-sparing diuretics, and mineralocorticoid receptor antagonists such as spironolactone. The other cells are type A and B intercalated cells. Type A intercalated cells mediate acid secretion and bicarbonate reabsorption also under the influence of aldosterone. Type B intercalated cells mediate bicarbonate secretion and acid reabsorption.

Virtually all transport is mediated through the cellular pathway for both principal cells and intercalated cells. In principal cells, passive apical Na+ entry occurs through the amiloride-sensitive, epithelial Na+ channel (ENaC) with basolateral exit via the Na+/K+-ATPase (Fig. 332e-3E). This Na+ reabsorptive process is tightly regulated by aldosterone and is physiologically activated by a variety of proteolytic enzymes that cleave extracellular domains of ENaC; plasmin in the tubular fluid of nephrotic patients, for example, activates ENaC, leading to sodium retention. Aldosterone enters the cell across the basolateral membrane, binds to a cytoplasmic mineralocorticoid receptor, and then translocates into the nucleus, where it modulates gene transcription, resulting in increased Na+ reabsorption and K+ secretion. Activating mutations in ENaC increase Na+ reclamation and produce hypokalemia, hypertension, and metabolic alkalosis (Liddle’s syndrome). The potassium-sparing diuretics amiloride and triamterene block ENaC, causing reduced Na+ reabsorption.

Principal cells secrete K+ through an apical membrane potassium channel. Several forces govern the secretion of K+. Most importantly, the high intracellular K+ concentration generated by Na+/K+-ATPase creates a favorable concentration gradient for K+ secretion into tubular fluid. With reabsorption of Na+ without an accompanying anion, the tubular lumen becomes negative relative to the cell interior, creating a favorable electrical gradient for secretion of potassium. When Na+ reabsorption is blocked, the electrical component of the driving force for K+ secretion is blunted, and this explains lack of excess urinary K+ loss during treatment with potassium-sparing diuretics or mineralocorticoid receptor antagonists. K+ secretion is also promoted by aldosterone actions that increase regional Na+ transport favoring more electronegativity and by increasing the number and activity of potassium channels. Fast tubular fluid flow rates that occur during volume expansion or diuretics acting “upstream” of the cortical collecting duct also increase K+ secretion, as does the presence of relatively nonreabsorbable anions (including bicarbonate and semisynthetic penicillins) that contribute to the lumen-negative potential. Off-target effects of certain antibiotics, such as trimethoprim and pentamidine, block ENaCs and predispose to hyperkalemia, especially when renal K+ handling is impaired for other reasons. Principal cells, as described below, also participate in water reabsorption by increased water permeability in response to vasopressin.

Intercalated cells do not participate in Na+ reabsorption but, instead, mediate acid-base secretion. These cells perform two types of transport: active H+ transport mediated by H+-ATPase (proton pump), and Cl/HCO3 exchange. Intercalated cells arrange the two transport mechanisms on opposite membranes to enable either acid or base secretion. Type A intercalated cells have an apical proton pump that mediates acid secretion and a basolateral Cl/HCO3 anion exchanger for bicarbonate reabsorption (Fig. 332e-3E); aldosterone increases the number of H+-ATPase pumps, sometimes contributing to the development of metabolic alkalosis. Secreted H+ is buffered by NH3 that has diffused into the collecting duct lumen from the surrounding interstitium. By contrast, type B intercalated cells have the anion exchanger on the apical membrane to mediate bicarbonate secretion while the proton pump resides on the basolateral membrane to enable acid reabsorption. Under conditions of acidemia, the kidney preferentially uses type A intercalated cells to secrete the excess H+ and generate more HCO3. The opposite is true in states of bicarbonate excess with alkalemia where the type B intercalated cells predominate. An extracellular protein called hensin mediates this adaptation.

Inner medullary collecting duct cells share many similarities with principal cells of the cortical collecting duct. They have apical Na+ and K+ channels that mediate Na+ reabsorption and K+ secretion, respectively (Fig. 332e-3F). Inner medullary collecting duct cells also have vasopressin-regulated water channels (aquaporin-2 on the apical membrane, aquaporin-3 and -4 on the basolateral membrane). The antidiuretic hormone vasopressin binds to the V2 receptor on the basolateral membrane and triggers an intracellular signaling cascade through G-protein-mediated activation of adenylyl cyclase, resulting in an increase in the cellular levels of cyclic AMP. This signaling cascade stimulates the insertion of water channels into the apical membrane of the inner medullary collecting duct cells to promote increased water permeability. This increase in permeability enables water reabsorption and production of concentrated urine. In the absence of vasopressin, inner medullary collecting duct cells are water impermeable, and urine remains dilute.

Sodium reabsorption by inner medullary collecting duct cells is also inhibited by the natriuretic peptides called atrial natriuretic peptide or renal natriuretic peptide (urodilatin); the same gene encodes both peptides but uses different posttranslational processing of a common preprohormone to generate different proteins. Atrial natriuretic peptides are secreted by atrial myocytes in response to volume expansion, whereas urodilatin is secreted by renal tubular epithelia. Natriuretic peptides interact with either apical (urodilatin) or basolateral (atrial natriuretic peptides) receptors on inner medullary collecting duct cells to stimulate guanylyl cyclase and increase levels of cytoplasmic cGMP. This effect in turn reduces the activity of the apical Na+ channel in these cells and attenuates net Na+ reabsorption, producing natriuresis.

The inner medullary collecting duct transports urea out of the lumen, returning urea to the interstitium, where it contributes to the hypertonicity of the medullary interstitium. Urea is recycled by diffusing from the interstitium into the descending and ascending limbs of the loop of Henle.

HORMONAL REGULATION OF SODIUM AND WATER BALANCE

The balance of solute and water in the body is determined by the amounts ingested, distributed to various fluid compartments, and excreted by skin, bowel, and kidneys. Tonicity, the osmolar state determining the volume behavior of cells in a solution, is regulated by water balance (Fig. 332e-4A), and extracellular blood volume is regulated by Na+ balance (Fig. 332e-4B). The kidney is a critical modulator of both physiologic processes.

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FIGURE 332e-4   Determinants of sodium and water balance. A. Plasma Na+ concentration is a surrogate marker for plasma tonicity, the volume behavior of cells in a solution. Tonicity is determined by the number of effective osmoles in the body divided by the total body H2O (TB H2O), which translates simply into the total body Na (TB Na+) and anions outside the cell separated from the total body K (TB K+) inside the cell by the cell membrane. Net water balance is determined by the integrated functions of thirst, osmoreception, Na reabsorption, vasopressin release, and the strength of the medullary gradient in the kidney, keeping tonicity within a narrow range of osmolality around 280 mosmol/L. When water metabolism is disturbed and total body water increases, hyponatremia, hypotonicity, and water intoxication occur; when total body water decreases, hypernatremia, hypertonicity, and dehydration occur. B. Extracellular blood volume and pressure are an integrated function of total body Na+ (TB Na+), total body H2O (TB H2O), vascular tone, heart rate, and stroke volume that modulates volume and pressure in the vascular tree of the body. This extracellular blood volume is determined by net Na balance under the control of taste, baroreception, habit, Na+ reabsorption, macula densa/tubuloglomerular feedback, and natriuretic peptides. When Na+ metabolism is disturbed and total body Na+ increases, edema occurs; when total body Na+ is decreased, volume depletion occurs. ADH, antidiuretic hormone; AQP2, aquaporin-2.

WATER BALANCE

Tonicity depends on the variable concentration of effective osmoles inside and outside the cell causing water to move in either direction across its membrane. Classic effective osmoles, like Na+, K+, and their anions, are solutes trapped on either side of a cell membrane, where they collectively partition and obligate water to move and find equilibrium in proportion to retained solute; Na+/K+-ATPase keeps most K+ inside cells and most Na+ outside. Normal tonicity (~280 mosmol/L) is rigorously defended by osmoregulatory mechanisms that control water balance to protect tissues from inadvertent dehydration (cell shrinkage) or water intoxication (cell swelling), both of which are deleterious to cell function (Fig. 332e-4A).

The mechanisms that control osmoregulation are distinct from those governing extracellular volume, although there is some shared physiology in both processes. While cellular concentrations of K+ have a determinant role in any level of tonicity, the routine surrogate marker for assessing clinical tonicity is the concentration of serum Na+. Any reduction in total body water, which raises the Na+ concentration, triggers a brisk sense of thirst and conservation of water by decreasing renal water excretion mediated by release of vasopressin from the posterior pituitary. Conversely, a decrease in plasma Na+ concentration triggers an increase in renal water excretion by suppressing the secretion of vasopressin. Whereas all cells expressing mechanosensitive TRPV1, 2, or 4 channels, among potentially other sensors, respond to changes in tonicity by altering their volume and Ca2+ concentration, only TRPV+ neuronal cells connected to the organum vasculosum of the lamina terminalis are osmoreceptive. Only these cells, because of their neural connectivity and adjacency to a minimal blood-brain barrier, modulate the downstream release of vasopressin by the posterior lobe of the pituitary gland. Secretion is stimulated primarily by changing tonicity and secondarily by other nonosmotic signals such as variable blood volume, stress, pain, nausea, and some drugs. The release of vasopressin by the posterior pituitary increases linearly as plasma tonicity rises above normal, although this varies, depending on the perception of extracellular volume (one form of cross-talk between mechanisms that adjudicate blood volume and osmoregulation). Changing the intake or excretion of water provides a means for adjusting plasma tonicity; thus, osmoregulation governs water balance.

The kidneys play a vital role in maintaining water balance through the regulation of renal water excretion. The ability to concentrate urine to an osmolality exceeding that of plasma enables water conservation, whereas the ability to produce urine more dilute than plasma promotes excretion of excess water. For water to enter or exit a cell, the cell membrane must express aquaporins. In the kidney, aquaporin-1 is constitutively active in all water-permeable segments of the proximal and distal tubules, whereas vasopressin-regulated aquaporin-2, -3, and -4 in the inner medullary collecting duct promote rapid water permeability. Net water reabsorption is ultimately driven by the osmotic gradient between dilute tubular fluid and a hypertonic medullary interstitium.

SODIUM BALANCE

The perception of extracellular blood volume is determined, in part, by the integration of arterial tone, cardiac stroke volume, heart rate, and the water and solute content of extracellular fluid. Na+ and accompanying anions are the most abundant extracellular effective osmoles and together support a blood volume around which pressure is generated. Under normal conditions, this volume is regulated by sodium balance (Fig. 332e-4B), and the balance between daily Na+ intake and excretion is under the influence of baroreceptors in regional blood vessels and vascular hormone sensors modulated by atrial natriuretic peptides, the renin-angiotensin-aldosterone system, Ca2+ signaling, adenosine, vasopressin, and the neural adrenergic axis. If Na+ intake exceeds Na+ excretion (positive Na+ balance), then an increase in blood volume will trigger a proportional increase in urinary Na+ excretion. Conversely, when Na+ intake is less than urinary excretion (negative Na+ balance), blood volume will decrease and trigger enhanced renal Na+ reabsorption, leading to decreased urinary Na+ excretion.

The renin-angiotensin-aldosterone system is the best-understood hormonal system modulating renal Na+ excretion. Renin is synthesized and secreted by granular cells in the wall of the afferent arteriole. Its secretion is controlled by several factors, including β1-adrenergic stimulation to the afferent arteriole, input from the macula densa, and prostaglandins. Renin and ACE activity eventually produce angiotensin II that directly or indirectly promotes renal Na+ and water reabsorption. Stimulation of proximal tubular Na+/H+ exchange by angiotensin II directly increases Na+ reabsorption. Angiotensin II also promotes Na+ reabsorption along the collecting duct by stimulating aldosterone secretion by the adrenal cortex. Constriction of the efferent glomerular arteriole by angiotensin II indirectly increases the filtration fraction and raises peritubular capillary oncotic pressure to promote tubular Na+ reabsorption. Finally, angiotensin II inhibits renin secretion through a negative feedback loop. Alternative metabolism of angiotensin by ACE2 generates the vasodilatory peptide angiotensin 1-7 that acts through Mas receptors to counterbalance several actions of angiotensin II on blood pressure and renal function (Fig. 332e-2C).

Aldosterone is synthesized and secreted by granulosa cells in the adrenal cortex. It binds to cytoplasmic mineralocorticoid receptors in the collecting duct principal cells that increase activity of ENaC, apical membrane K+ channel, and basolateral Na+/K+-ATPase. These effects are mediated in part by aldosterone-stimulated transcription of the gene encoding serum/glucocorticoid-induced kinase 1 (SGK1). The activity of ENaC is increased by SGK1-mediated phosphorylation of Nedd4-2, a protein that promotes recycling of the Na+ channel from the plasma membrane. Phosphorylated Nedd4-2 has impaired interactions with ENaC, leading to increased channel density at the plasma membrane and increased capacity for Na+ reabsorption by the collecting duct.

Chronic exposure to aldosterone causes a decrease in urinary Na+ excretion lasting only a few days, after which Na+ excretion returns to previous levels. This phenomenon, called aldosterone escape, is explained by decreased proximal tubular Na+ reabsorption following blood volume expansion. Excess Na+ that is not reabsorbed by the proximal tubule overwhelms the reabsorptive capacity of more distal nephron segments. This escape may be facilitated by atrial natriuretic peptides that lose their effectiveness in the clinical settings of heart failure, nephrotic syndrome, and cirrhosis, leading to severe Na+ retention and volume overload.

 

333e  

Adaptation of the Kidney to Injury

Joseph V. Bonventre


Many years ago Claude Bernard (1878) introduced the concepts of milieu extérieur (the environment where an organism lives) and a milieu intérieur (the environment in which the tissues of that organism live). He argued that the milieu intérieur varied very little and that there were vital mechanisms that functioned to maintain this internal environment constant. Walter B. Cannon later extended these concepts by recognizing that the constancy of the internal state, which he termed the homeostatic state, was evidence of physiologic mechanisms that act to maintain this minimal variability. In higher animals, the plasma is maintained remarkably constant in composition both within an individual and among individuals. The kidney plays a vital role in this constancy. The kidney changes the composition of the urine to maintain electrolyte and acid-base balance and can produce hormones that can maintain constancy of blood hemoglobin and mineral metabolism. When the kidney is injured, the remaining functional mass responds and attempts to continue to maintain the milieu intérieur. It is remarkable how well the residual nephrons can perform in this task so that in many cases homeostasis is maintained until the glomerular filtration rate (GFR) drops to very low levels. At this point, the functional tissue can no longer compensate. In this chapter, we will discuss a number of these compensatory adaptations that the kidney makes in response to injury in an attempt to protect itself and protect the milieu intérieur. A theme that permeates, however, is that these adaptive processes can often be maladaptive and contribute to enhanced renal dysfunction, facilitating a positive feedback process that is inherently unstable.

RESPONSES OF THE KIDNEY TO REDUCED NUMBERS OF NEPHRONS DURING DEVELOPMENT

Renal disease is associated with a reduction in functional nephrons. The rest of the kidney adapts to this reduction by increasing blood flow to and the size of the remaining glomeruli and increasing size and function of the remaining tubules. Robert Platt, in 1936, argued that “…a high glomerular pressure, together with loss of nephrons (destroyed by disease) [is] an explanation of the peculiarities of renal function in this stage of kidney disease.” The raised glomerular pressure will increase the amount of filtrate produced by each nephron and thus compensate for a time for the destruction of part of the kidney. But eventually there are too few nephrons remaining to produce an adequate filtrate, even though they may work under the highest possible pressure, associated with a high systemic blood pressure. The responses to kidney injury can be both adaptive and maladaptive, and in many cases, the early adaptive responses can become maladaptive over time, leading to progressive decline in the anatomic and functional integrity of the kidney. As described previously, the early responses are likely in many cases motivated by attempts to maintain the constancy of the milieu intérieur for the survival of the organism (Claude Bernard).

Barry Brenner in the 1960s and 1970s carried out micropuncture experiments to define the pressures in glomerular capillaries as well as afferent and efferent resistances and modeled the behavior of the factors that governed glomerular filtration in health and disease. According to the Brenner Hyperfiltration Hypothesis, a reduction in the number of nephrons results in glomerular hypertension, hyperfiltration, and enlargement of glomeruli and this hyperfiltration results in damage to those glomeruli over time and ultimately decreased kidney function. According to this hypothesis, a positive feedback process is set into motion whereby injury to the glomeruli will result in further hyperfiltration to other glomeruli and hence more accelerated injury to those glomeruli. Since nephrons are not generated after 34–36 weeks of gestation or after birth (if earlier than 34–36 weeks) in humans, this hypothesis implies a deterministic effect of low nephron numbers at birth. There is over a 10-fold variation in the number of nephrons per kidney in the population (200,000 to over 2.5 million). This variation is not explained by kidney size in the adult. Children born with low birth weights would be more prone to kidney disease as adults. There are many reasons why there might be reduced nephron numbers at birth: developmental abnormalities, genetic predisposition, and environmental factors, such as malnutrition. There are thought to be interactions between these various factors. Reduced nephron mass can also occur with chronic kidney disease (CKD) in the adult, and the response of the kidney is similar qualitatively with hyperfiltration of the remaining nephrons.

Developmental Abnormalities    There are many congenital abnormalities of the kidney and urinary tract (CAKUT). Dysplastic kidneys have varying degrees of abnormalities that interfere with their function. Anatomically abnormal kidneys can be associated with abnormalities of the lower urinary tract. Urinary tract abnormalities resulting in obstruction or vesicoureteric reflux can dramatically alter the normal development of the kidney nephrons. Dysplastic or hypoplastic kidneys can be cystic in patterns that are distinct from polycystic kidney disease. Of course, autosomal recessive kidney disease can result in widespread cyst formation.

Hypoplastic kidneys are characterized by a reduced number of functional nephrons. One definition of hypoplastic kidneys is as follows: “Kidney mass below two standard deviations of that of age-matched normal [individuals] or a combined kidney mass of less than half normal for the patient’s age.” Renal agenesis and cystic dysplasia often affects only one kidney. This results in hypertrophy of the other kidney if it is unaffected by any congenital abnormality itself. Although there is hypertrophy in size, it is not clear if this is associated with an increase in the number of nephrons on the contralateral side.

The prevalence of CAKUT has been generally found to be between 0.003 and 0.2%, depending on the population studied. This excludes fetuses with transient upper renal tract dilatation likely related to the high rate of fetal urine flow rate. In the adult U.S. Renal Data System (USRDS) of patients with end-stage kidney disease, approximately 0.6% are listed as having dysplastic or hypoplastic kidneys as a primary cause of the disease. This is likely an underestimate, however, because many patients with “small kidneys” may be misdiagnosed with chronic glomerulonephritis or chronic pyelonephritis.

Environmental Contributions to Reduced Nephron Mass    The most important environmental factor responsible for reduced nephron number is growth restriction within the uterus. This has been associated with disease processes such as diabetes mellitus in the mother, but there also is a strong genetic disposition. Low-birth-weight children are more likely to be born to mothers who, themselves, were born with low birth weight. There are clearly other environmental factors. Caloric restriction during pregnancy in humans has been associated with altered glucose as adults and increased risk for hypertension. In one study, it was found that if women were calorie restricted in midgestation, the time of most rapid nephrogenesis, there was a threefold incidence of albuminuria in their children when they were tested as adults. Factors such as deficiency in vitamin A, sodium, zinc, or iron have been implicated as predisposing to abnormal kidney development. Other environmental factors that can influence kidney development are medications taken by the mother, such as dexamethasone, angiotensin-converting enzyme inhibitors, and angiotensin receptor antagonists (Table 333e-1). Protein restriction in mice during pregnancy can reduce lifespan of the offspring by 200 days. Obesity may play an important role in determining kidney outcome long term in patients with reduced kidney mass. It has been shown in mice fed a high-fat diet that the rodents that had reduced nephron number had a greater incidence of hypertension and renal fibrosis.

TABLE 333e-1

DRUGS THAT INHIBIT NEPHROGENESIS


  Dexamethasone

  Angiotensin-converting enzyme inhibitors

  Angiotensin receptor blockers

  Gentamicin

  Nonsteroidal anti-inflammatory drugs


Implications of Low Nephron Number at Birth    David Barker was the first to describe the association between low birth weight and later cardiovascular death. This was followed by studies relating low birth weight to risk for diabetes, stroke, hypertension, and CKD. It has been found that there is an inverse relationship between nephron number and blood pressure in adults. This relationship was found in Caucasians but not in African Americans. Approximately one-third of children with a single functioning kidney at the age of 10 years had signs of renal injury as determined by the presence of hypertension, albuminuria, or the use of renoprotective drugs. Another study revealed that 20–40% of patients born with a single functional kidney had renal failure requiring dialysis by 30 years of age.

ADAPTIVE RESPONSES OF THE KIDNEY TO REDUCED KIDNEY MASS THAT CHARACTERIZES CHRONIC KIDNEY DISEASE

In the early stages of CKD, there are many adaptations structurally and functionally that limit the consequences of the loss of nephrons on total-body homeostasis. In later stages of disease, however, these adaptations are insufficient to counteract the consequences of nephron loss and in fact often become maladaptive.

Counterbalance    Renal counterbalance was defined by Hinman in 1923 as “an attempt on the part of the less injured or uninjured portion (of the kidney) to take over the work of the more injured portion.” Hinman defined “renal reserve” to be of two types: “native reserve, which is the normal physiological response to stimulation … and acquired reserve, which involves growth or compensation due to overstimulation.” It was known that removal of one kidney results in an increase in size of the contralateral kidney. If, instead of nephrectomy, one kidney is rendered ischemic and the other left intact, there is a resultant atrophy of the postischemic kidney. If the contralateral kidney is removed, however, before the atrophy becomes too severe, then the postischemic kidney increases markedly in size. With the contralateral kidney in place, there is vasoconstriction and reduced renal blood flow to the postischemic kidney. This is rapidly reversed, however, when the contralateral normal kidney is removed. The factors responsible for the persistent initial (prenephrectomy) vasoconstriction and those responsible for the rapid vasodilation and enhanced growth after contralateral nephrectomy are unknown.

Hypertrophy    Because nephrons of mammals, in contrast to those of fish, cannot regenerate, the loss of functional units of the kidney, either due to disease or surgery, results in anatomic and functional changes in the remaining nephrons. As described above, there is increased blood flow to remaining glomeruli with potentially adverse effects over time of the resultant increased size of the remaining glomeruli and hyperfiltration (Fig. 333e-1). In addition, there is hypertrophy of the tubules. Some of the mediators of this hypertrophy of the remaining functional tubules are listed in Table 333e-2. In the adult, within a few weeks after unilateral nephrectomy for donation of a kidney, the GFR is approximately 70% of the prenephrectomy value. It then remains relatively stable for most patients over 15–20 years. The hyperfiltration is related to an increase in renal blood flow likely secondary to dilatation of the afferent arterioles potentially due to increases in nitric oxide (NO) production. The rate of increase in GFR is slower in the adult than it is in the young after nephrectomy. There are a number of factors that have been implicated at the cellular and nephron level to account for the compensatory hypertrophy that ensues after removal of functional nephrons (Table 333e-2).

image

FIGURE 333e-1   Some of the pathophysiologic mechanisms involved with the maladaptive response to a reduction in the number of functional nephrons due to prenatal factors or postnatal disease processes.

TABLE 333e-2

FACTORS IMPLICATED IN COMPENSATORY RENAL GROWTH AFTER NEPHRON LOSS


Increased renal blood flow

Increased tubular absorption of Na with decreased distal delivery and decreased afferent arterial resistance due to adaptive tubuloglomerular feedback

Hepatocyte growth factor

Glucose transporters

Increased renal nerve activity

Insulin-like growth factor

Mammalian target of rapamycin (mTOR) signaling pathway activation

p21Waf1, p27kip1, and p57kip2

Transforming growth factor β


With increased blood flow to the kidney, there is glomerular hypertension (i.e., an increase in glomerular capillary pressure). There is increased wall tension and force on the capillary wall that is counteracted by contractile properties of the endothelium and elastic properties of the glomerular basement membrane. The force is conveyed to podocytes, which adapt by reinforcing cell cycle arrest and increasing cell adhesion in an adaptive attempt to maintain the delicate architecture of the interdigitating foot processes. Over time, however, these increased forces due to glomerular hypertension lead to podocyte damage and glomerulosclerosis.

Other Systemic and Renal Adaptations to Reduced Nephron Function    With reduced functional nephrons, as is seen in CKD, there are many other systemic adaptations that occur to preserve the milieu intérieur because the kidney is involved in so many regulatory networks that are then stressed when there is dysfunction. In the 1960s, Neil Bricker introduced the “intact nephron hypothesis.” According to his concept, with decreases in the number of functioning nephrons, each remaining nephron has to adapt to carry a larger burden of transport, synthetic function, and regulatory function.

POTASSIUM    Under normal and abnormal conditions, most of the filtered potassium is reabsorbed in the proximal tubule so that excretion is determined by secretion by the distal nephron. Potassium handling is altered in CKD protecting the organism somewhat from lethal hyperkalemia. Hyperkalemia is a common feature of individuals with CKD. Hyperkalemia (if not severe and dangerous) is adaptive in that it promotes potassium secretion by the principal cells of the collecting duct. When patients with CKD are given a potassium load, they can excrete it at the same rate as patients with normal renal function except that they do so at a higher serum potassium, consistent with the view that the hyperkalemia facilitates potassium excretion. The direct effect of hyperkalemia on potassium secretion by the distal nephron is independent of changes in aldosterone levels, but “normal” levels of aldosterone are necessary to see the effect of hyperkalemia on potassium excretion. Elevated potassium stimulates the production of aldosterone, and this effect is also seen in patients with CKD. Aldosterone increases the density and activity of the basolateral Na+-K+ ATPase and the number of Na+ channels in the apical membrane of the collecting duct. In CKD, the excretion of the dietary load of potassium occurs at the expense of an elevation in serum potassium concentrations.

SODIUM    As renal function is reduced with CKD, there is a reduced ability to excrete sodium. Thus, patients with advanced kidney disease are often fluid overloaded. In early disease, however, there are functional adaptations that the kidney assumes to help to maintain the milieu intérieur. With loss of functional nephrons, the remaining nephrons are hyperperfused and are hyperfiltering in a manner that can be influenced by dietary protein intake. Although protein restriction can decrease this compensatory hyperperfusion, there is generally more sodium and water filtered and delivered to the remaining nephrons. There is some preservation of glomerulotubular balance with increased proximal tubule sodium and water reabsorption associated with increased levels of the Na/H exchanger in apical membranes of the tubule. The tubuloglomerular feedback (TGF) of the remaining nephrons is sensitive to sodium intake. With high sodium intake in normal renal function, a negative feedback process occurs by which increased distal delivery results in reduced GFR and hence filtration of sodium. In CKD, the TGF becomes a positive feedback process by which increased distal delivery results in increased filtration so that the need to excrete an increased amount of sodium per nephron is achieved. This conversion from a negative feedback process to a positive feedback process may be due to conversion of an adenosine-dominated vasoconstrictive feedback on the afferent arteriole of the glomerulus to a NO-dominated vasodilatory feedback. Like so many of these adaptive responses, this one may turn maladaptive, resulting in higher intraglomerular hydrostatic pressures with increased mechanical strain on the glomerular capillary wall and podocytes and increased glomerulosclerosis as a consequence.

ACID-BASE HOMEOSTASIS The kidneys excrete approximately 1 mEq/kg per day of dietary acid load under normal dietary conditions. With decreased kidney functional mass, there is an adaptive response to increase H+ excretion by the remaining functional nephrons. This takes the form of enhanced nephron ammoniagenesis and increased distal nephron H+ ion secretion, which is mediated by the renin-angiotensin system and endothelin-1. NH3 is produced by deamidization of glutamine in the proximal tubule. NH3 is converted to NH4+ in the collecting duct, where it buffers the secreted H+. It has been argued, however, that these mechanistic attempts to enhance H+ secretion can be maladaptive in that they can contribute to kidney inflammation and fibrosis and hence facilitate the progression of CKD.

MINERAL METABOLISM In CKD, there is a decrease in the ability of the kidney to excrete phosphate and produce 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. There is a resultant increase in serum phosphate and reduction in serum calcium (Fig. 333e-2). In response, the body adapts by increasing production of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) in an attempt to increase phosphaturia. The elevated levels of PTH act on bone to increase bone resorption and on osteocytes to increase FGF-23 expression. Elevated levels of PTH increase FGF-23 expression by activating protein kinase A and wnt signaling in osteoblast-like cells. There are a number of other factors that increase bone FGF-23 production in CKD including systemic acidosis, altered hydroxyapatite metabolism, changes in bone matrix, and release of low-molecular-weight FGFs. Although the production of PTH and FGF-23 initially are adaptive attempts to maintain body phosphate levels by enhancing excretion by the kidney, they become maladaptive due to systemic effects on the cardiovascular system and bone, as renal function continues to deteriorate. PTH and FGF-23 decrease the kidney’s ability to reabsorb phosphate by decreasing the levels of the sodium-phosphate cotransporters NaPi2a and NaPi2c on the apical and basolateral membranes of the renal tubule. FGF-23 also reduces the ability of the kidney to generate 1,25(OH)2D3. In the parathyroid gland, the FGF-23 receptor, the klotho-fibroblast growth factor 1 complex, is downregulated with a consequent loss of the normal action of FGF-23 to downregulate PTH production. PTH and FGF-23 have been implicated in the cardiovascular disease that is so characteristic of patients with CKD. With CKD, there is less klotho expression in the kidney and the parathyroid glands. Klotho deficiency contributes to soft tissue calcifications in CKD. FGF-23 has been associated with increased mortality in CKD and has been reported to be involved causally in the development of left ventricular hypertrophy. PTH also has been reported to directly affect rat myocardial cells, increasing calcium entry into the cells and contributing to death of the cells.

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FIGURE 333e-2   Modification of the trade-off hypothesis of Slatopolsky and Bricker as it relates to the adaptation of the body to decreased functional renal mass in an attempt to maintain calcium and phosphate stores and serum levels. 1,25(OH)2D3, 1,25-dihydroxy-vitamin D3; FGF-23, fibroblast growth factor-23; GI, gastrointestinal; PTH, parathyroid hormone.

THE EFFECTS OF ACUTE KIDNEY INJURY ON SUSCEPTIBILITY TO SUBSEQUENT INJURY (PRECONDITIONING)

Preconditioning represents activation by the organism of intrinsic defense mechanisms to cope with pathologic conditions. Ischemic preconditioning is the phenomenon whereby a prior ischemic insult renders the organ resistant to a subsequent ischemic insult. Renal protection afforded by prior renal injury was described approximately 100 years ago, in 1912, by Suzuki, who noted that the kidney became resistant to uranium nephrotoxicity if the animal had previously been exposed to a sublethal dose of uranium. This resistance of the renal epithelium to recurrent toxic injury was proposed to be a defense mechanism of the kidney. There have been a number of studies over the years demonstrating that preconditioning with a number of renal toxicants leads to protection against injury associated with a second exposure to the same toxicant or to another nephrotoxicant. It is not, however, a universal finding that toxins confer resistance to subsequent insults.

Kidney ischemic preconditioning is the conveyance of protection against ischemia due to prior exposure of the kidney to sublethal episodes of ischemia. In some experiments in rodents, these prior exposures were short (e.g., 5 min) and repeated or longer. Subsequent protection was generally found at 1–2 h or up to 48 h, but there has been a report of protection in the mouse for up to 12 weeks after the preconditioning exposures. Unilateral ischemia, with the contralateral kidney left alone, was also protective against a subsequent ischemic insult to the postischemic kidney, revealing that systemic uremia was not necessary for protection.

Remote Ischemic Preconditioning    Remote ischemic preconditioning is a therapeutic strategy by which protection can be afforded in one vascular bed by ischemia to another vascular bed in the same organ or a different organ. A large number of studies have demonstrated that ischemia to one organ protects against ischemia to another. There are very few mechanistic studies of remote preconditioning in the kidney. In one study, naloxone blocked preconditioning in the kidney, implicating opiates as effectors. Remote preconditioning induced by ischemia to the muscle of the arm induced by a blood pressure cuff can result in protection of the kidney against a subsequent insult, such as one related to contrast agents in humans. Some of the cellular processes and signaling mechanisms proposed to explain preconditioning in the kidney and other organs are listed in Table 333e-3. These protective processes, most of which have been identified in the heart, involve multiple signaling pathways that affect decreased apoptosis, inhibition of mitochondrial permeability transition pores, activation of survival pathways, autophagy, and other pathways involved in reducing energy consumption or reactive oxygen production. In a study from our laboratory, inducible NO synthase was found to be an important contributor to the adaptive response to kidney injury, which results in protection against a subsequent insult. Identification of the responsible protective factor(s) mediating the advantageous adaptive response to remote ischemic preconditioning would provide a therapeutic approach for prevention of acute kidney injury or facilitation of a protective adaptation to kidney injury.

TABLE 333e-3

FACTORS AND PROCESSES IMPLICATED AS PROTECTIVE MEDIATORS OF ISCHEMIC PRECONDITIONING


Adenosine

AKT (protein kinase B)

Antioxidants

Autophagy

Bradykinin

Decrease in genes regulating inflammation (cytokine synthesis, leukocyte chemotaxis, adhesion, exocytosis, innate immune signaling pathways)

Extracellular signal-related kinase (ERK)

Heat shock proteins

Hypoxia-inducible factors (HIFs)

JAK-STAT pathway

Jun N-terminal kinase (JNK)

Mitochondrial ATP-sensitive potassium channel (K+ ATP channel)

Mitochondrial connexin 43

Nitric oxide

Opioids

Protein kinase C (PKC)

Sirtuin activity (SIRT1)


ADAPTIVE RESPONSE OF THE KIDNEY TO ACUTE INJURY

Adaptive Response to Hypoxic Injury    Hypoxia plays a role in ischemic, septic, and toxic acute kidney injury. Many conditions result in a global or regional impairment of oxygen delivery. This is particularly important in the outer medulla where there is baseline reduced oxygen tension and a complex capillary network that, by its nature, is susceptible to interruption. In addition, the S3 segment of the proximal tubule is very dependent on oxidative metabolism, whereas the medullary thick ascending limb of the nephron that also traverses the outer medulla can adapt to hypoxia by converting to glycolysis as a primary energy source.

One proposed adaptive response to hypoxia is a reduction in glomerular filtration with consequent reduction in “work” requirement for reabsorption of solutes by the tubule. This was termed acute renal success by Thurau many years ago. The importance of this has been questioned, however, because there is no significant reduction in renal oxygen consumption in post–cardiac surgery patients with acute kidney injury in the setting of reduced GFR and renal blood flow.

If hypoxia or other influences, such as toxins, damage the proximal tubule and interfere with reabsorption of sodium and water, it is important that the kidney adapt in such a way so that there is not a large natriuresis that might compromise intravascular volume and blood pressure. This is accomplished, at least in part, by tubuloglomerular feedback (TGF). The increased distal delivery of salt and water results in a homeostatic adaptation to decrease glomerular filtration and hence decrease tubular delivery of salt and water through the glomerulus and reduce the delivery to the distal nephron. This adaptive response to acute injury is different from the role of TGF in CKD, as we have discussed previously in this chapter. In chronic disease with reduced nephron function, there is a steady-state need to increase excretion of sodium, whereas with acute injury, excretion of sodium is reduced.

Many genes are activated by hypoxia that are adaptive in serving to protect the cell and organ. With hypoxia, hypoxia-inducible factor (HIF) 1α rapidly accumulates due to the inhibition of the HIF prolyl-hydroxylases, which normally promote HIF1α proteasomal degradation. HIF1α then dimerizes with HIF1β and the dimer moves to the nucleus, where it upregulates a number of genes whose protein products are involved in energy metabolism, angiogenesis, and apoptosis, enhancing oxygen delivery and metabolic adaptation to hypoxia. This takes the form of a complex interplay among factors that regulate perfusion, cellular redox state, and mitochondrial function. For example, upregulation of NO production by sepsis results in vasodilatation and reduction in mitochondrial respiration and oxygen consumption. In addition, HIF1 activation in endothelial cells may be important for adaptive preservation of the microvasculature during and after hypoxia. Better understanding of the role that the HIFs play in protective adaptation has led to an aggressive development of HIF prolyl-hydroxylase inhibitors by biotechnology and pharmaceutical companies for clinical use.

Adaptive Response to Toxic Injury Specific to the Proximal Tubule    One can model an acute kidney injury by genetically inserting a Simian diphtheria toxin (DT) receptor into the proximal tubule and then adding either a single dose of DT or multiple doses of the toxin. Repair of the kidney after a single dose of DT can be shown to be adaptive with few longer term sequelae. There is a very robust proliferative response of the proximal tubule cells to replace the cells that die as a result of the DT. Ultimately the inflammation resolves, and there is little, if any, residual interstitial inflammation, expansion, or matrix deposition.

Maladaptive Response of the Kidney to Acute Injury

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