Cellular and Molecular Biology of the Kidney


The kidney is one of the most highly differentiated organs in the body. Nearly 30 different cell types can be found in the renal interstitium or along segmented nephrons, blood vessels, and filtering capillaries at the conclusion of embryological development. This panoply of cells 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 fuel or 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.

Embryological Development
The kidney develops from within the intermediate mesoderm under the timed or sequential control of a growing number of genes, described in Fig. 271-1. The transcription of these genes is guided by morphogenic cues that invite ureteric buds to penetrate the metanephric blastema, where they induce primary mesenchymal cells to form early nephrons. This induction involves a number of complex signaling pathways mediated by c-Met, fibroblast growth factor, transforming growth factor , glial cell–derived neurotrophic factor, hepatocyte growth factor, epithelial growth factor, and the Wnt family of proteins.
The ureteric buds derive from the posterior nephric ducts and mature into collecting ducts that eventually funnel to a renal pelvis and ureter. Induced mesenchyme undergoes mesenchymal-epithelia transitions to form comma-shape bodies at the proximal end of each ureteric bud leading to the formation of S-shape nephrons that cleft and enjoin with penetrating endothelial cells derived from sprouting angioblasts. Under the influence of vascular endothelial growth factor 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 produces 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. In the latter case, a failure to complete the last one or two rounds of branching leads to smaller kidneys and increased risk for hypertension and cardiovascular disease later in life.
Figure 271-1
Genes controlling renal nephrogenesis. A growing number of genes have been identified at various stages of glomerulotubular development in 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. GDNF, giant cell line–derived neutrophilic factor; FGFR2, fibroblast growth factor receptor 2; WT-1, Wilms tumor gene 1; FGF-8, fibroblast growth factor 8; VEGF–A/Flk-1, vascular endothelial growth factor–A/fetal liver kinase-1; PDGFB, platelet-derived growth factor B; PDGFR, PDGF receptor; SDF-1, stromal-derived factor 1; NPHS1, nephrin; NCK1/2, NCK-adaptor protein; CD2AP, CD2-associated protein; NPHS2, podocin; LAMB2, laminin beta-2.

Glomeruli evolved as complex capillary filters with fenestrated endothelia. Outlining each capillary is a basement membrane covered by epithelial podocytes. Podocytes attach by special foot processes and share a slit-pore membrane with their neighbor. The slit-pore membrane is formed by the interaction of nephrin, annexin-4, CD2AP, FAT, ZO-1, P-cadherin, podocin, and neph 1–3 proteins. These glomerular capillaries seat in a mesangial matrix shrouded by parietal and proximal tubular epithelia forming Bowman's capsule. Mesangial cells have an embryonic lineage consistent with arteriolar or juxtaglomerular cells and contain contractile actin-myosin fibers. These cells make contact with glomerular capillary loops, and their matrix holds them in condensed arrangement. Between nephrons lies the renal interstitium. This region forms the 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 segments during embryological development into a proximal tubule, descending and ascending limbs of the loop of Henle, distal tubule, and the collecting duct. These classic tubular segments have subsegments recognized by highly unique epithelia serving regional physiology. All nephrons have the same structural components, but there are two types whose structure depends 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 use separate 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 a hyperosmolar gradient that allows for the production of concentrated 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 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 as 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 (peritubular capillaries) surrounding the cortical tubules (Fig. 271-2A). Thus, the cortical nephron has two capillary beds arranged in series separated by the efferent arteriole that regulates the hydrostatic pressure in both capillary beds. The peritubular capillaries empty into small venous branches, which coalesce into larger veins to eventually form the renal vein.
 Figure 271-2. A,B,C
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 angiotensin II
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 before reaching the efferent arteriole. Approximately 20% of the renal plasma flow is filtered into Bowman's 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. 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 elevations in systolic pressure.
Tubuloglomerular feedback changes the rate of filtration and tubular flow by reflex vasoconstriction or dilatation of the afferent arteriole. Tubuloglomerular feedback 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 flow of tubular fluid. With high tubular flow rates, a proxy for an inappropriately high filtration rate, there is increased solute delivery to the macula densa (Fig. 271-2B), which evokes vasoconstriction of the afferent arteriole causing the GFR to return to normal. One component of the soluble signal from the macula densa is adenosine triphosphate (ATP), which is released by the cells during increased NaCl reabsorption. ATP is metabolized in the extracellular space by ecto-5'-nucleotidase to generate adenosine, a potent vasoconstrictor of the afferent arteriole. Direct release of adenosine by macula densa cells also occurs. During conditions associated with a fall in filtration rate, reduced solute delivery to the macula densa attenuates the tubuloglomerular response, allowing afferent arteriolar dilatation and restoring glomerular filtration to normal levels. Loop diuretics block tubuloglomerular feedback by interfering with NaCl reabsorption by macula densa cells. Angiotensin II and reactive oxygen species enhance, while nitric oxide blunts tubuloglomerular feedback.
The third component underlying autoregulation of filtration rate 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. 271-2B). 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. 271-2C). 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. 271-3). 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. These specialized junctions also divide the cell membrane into discrete domains: the apical membrane faces the tubular lumen, and the basolateral membrane faces the interstitium. This physical separation of membranes allows cells to allocate membrane proteins and lipids asymmetrically to different regions of the membrane. Owing to this feature, renal epithelial cells are said to be polarized. The asymmetrical assignment of membrane proteins, especially proteins mediating transport processes, provides the structural machinery for directional movement of fluid and solutes by the nephron.

Figure 271-3 
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. The 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- and 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 components mediate specific types of transport activities, including active transport (pumps), passive transport (channels), facilitated diffusion (transporters), and secondary active transport (co-transporters). Different cell types in the mammalian nephron are endowed with distinct combinations of proteins that serve specific transport functions. Active transport requires metabolic energy generated by the hydrolysis of ATP. The classes of protein that mediate active transport ("pumps") are ion-translocating ATPases, including the ubiquitous Na+/K+-ATPase, the H+-ATPases, and Ca2+-ATPases. Active transport can create asymmetrical 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 utilized to drive transport through other mechanisms (secondary active transport).
Pumps are often electrogenic, meaning they can create an asymmetrical 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. Examples in the kidney include water channels (aquaporins), K+ channels, epithelial Na+ channels, and Cl– channels. Facilitated diffusion is a specialized type of passive transport mediated by simple transporters called carriers or uniporters. For example, a family of hexose transporters (GLUTs 1–13) mediates glucose uptake by cells.
These transporters are driven by the concentration gradient for glucose, which is highest in extracellular fluids and lowest in the cytoplasm due to rapid metabolism. Many transporters operate by translocating two or more ions/solutes in concert either in the same direction (symporters or co-transporters) 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 271-1).

Table 271-1 Inherited Disorders Affecting Renal Tubular Ion and Solute Transport
Disease or Syndrome
Disorders Involving the Proximal Tubule
Proximal renal tubular acidosis
Sodium bicarbonate co-transporter
(SLC4A4, 4q21)
Faconi-Bickel syndrome
Glucose transporter-2
(SLC2A2 3q26.1-q26.3)
Isolated renal glycosuria
Sodium glucose co-transporter

Cystinuria, type I
Cystine, dibasic and neutral amino acid transporter

(SLC3A1, 2p16.3)
Cystinuria, non-type I
Amino acid transporter, light subunit

(SLC7A9, 19q13.1)
Lysinuric protein intolerance
Amino acid transporter
(SLC7A7, 4q11.2)
Hereditary hypophosphatemic rickets with hypercalcemia
Sodium phosphate co-transporter
(SLC34A3, 9q34)

Renal hypouricemia
Urate-anion exchanger

(SLC22A12, 11q13)
Dent disease
Chloride channel, ClC-5

(CLCN5, Xp11.22)
X-linked recessive nephrolithiasis with renal failure
Chloride channel, ClC-5
(CLCN5, Xp11.22)

X-linked recessive hypophosphatemic rickets
Chloride channel, ClC-5
(CLCN5, Xp11.22)
Disorders Involving the Loop of Henle
Bartter syndrome, type 1
Sodium potassium-chloride co-transporter
Bartter syndrome, type 2
Potassium channel, ROMK

(KCNJ1, 11q24)
Bartter syndrome, type 3
Chloride channel, ClC-Kb
(CLCNKB, 1p36)
Bartter syndrome with sensorineural deafness
Chloride channel accessory subunit, barttin

(BSND, 1p31)
Autosomal dominant hypocalcemia with Bartter-like syndrome
Calcium-sensing receptor

(CASR, 3q13.3-q21)
Familial hypocalciuric hypercalcemia
Calcium-sensing receptor
(CASR, 3q13.3-q21)
Primary hypomagnesemia
Claudin-16 or paracellin-1

(CLDN16 or PCLN1, 3q27)
Isolated renal magnesium loss
Sodium potassium ATPase, 1-subunit
(ATP1G1, 11q23)
Primary hypomagnesemia with secondary hypocalcemia
Melastatin-related transient receptor potential cation channel 6
(TRPM6, 9q22)
Disorders Involving the Distal Tubule and Collecting Duct
Gitelman's syndrome
Sodium-chloride co-transporter
(SLC12A3, 16q13)
Pseudoaldosteronism (Liddle's syndrome)
Epithelial sodium channel and subunits
(SCNN1B, SCNN1G, 16p13-p12)
Recessive pseudohypoaldosteronism type 1
Epithelial sodium channel, , , and subunits
(SCNN1A, 12p13; SCNN1B, SCNN1G, 16p13-p12)
Pseudohypoaldosteronism type 2 (Gordon hyperkalemia-hypertension syndrome)
Kinases WNK-1, WNK-4
(WNK1, 12p13; WNK4, 17q21-q22)
X-Linked nephrogenic diabetes insipidus
Vasopressin V2 receptor
(AVPR2, Xq28)
Nephrogenic diabetes insipidus (autosomal)
Water channel, aquaporin-2
(AQP2, 12q13)
Distal renal tubular acidosis, autosomal dominant
Anion exchanger-1
(SLC4A1, 17q21-q22)
Distal renal tubular acidosis, autosomal recessive
Anion exchanger-1
(SLC4A1, 17q21-q22)
Distal renal tubular acidosis with neural deafness
Proton ATPase, 1 subunit
Distal renal tubular acidosis with normal hearing
Proton ATPase, 116-kD subunit
(ATP6N1B, 7q33-q34)

Segmental Nephron Functions
Each anatomic segment of the nephron has unique characteristics and specialized functions that enable selective transport of solutes and water (Fig. 271-3). Through sequential events of reabsorption and secretion along the nephron, tubular fluid is progressively conditioned into final urine for excretion. 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 utilizes 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 comparatively leaky tight junctions further 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. Physiologic adjustments in GFR made by changing efferent arteriolar tone cause proportional changes in reabsorption, a phenomenon known as glomerulotubular balance. For example, vasoconstriction of the efferent arteriole by angiotensin II will increase glomerular capillary hydrostatic pressure but lower pressure in the peritubular capillaries. At the same time, increased GFR and filtration fraction cause a rise in oncotic pressure near the end of the glomerular capillary. These changes, a lowered hydrostatic and increased oncotic pressure, increase the driving force for fluid absorption by 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. 271-3A). 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 co-transporters such as Na+-glucose and the Na+-phosphate. 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. In addition, small, local osmotic gradients close to plasma membranes generated by cellular Na+ reabsorption are likely responsible for driving directional water movement across proximal tubule cells.
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 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 reform carbonic acid. Finally, intracellular carbonic acid dissociates into free protons and bicarbonate anions, and bicarbonate exits the cell through a basolateral Na+/HCO3– co-transporter. This process is saturable, resulting in renal 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.
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– co-transporter.
Reabsorption of glucose is nearly complete by the end of the proximal tubule. Cellular transport of glucose is mediated by apical Na+-glucose co-transport 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, 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. Certain drugs like cimetidine and trimethoprim compete with endogenous compounds for transport by the organic cation pathways. These drugs elevate levels of serum creatinine, but this change does not reflect changes in the 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, 2-microglobulin, and other small proteins, are taken up by the proximal tubule through a process of absorptive endocytosis and are degraded in acidified endocytic vesicles or lysosomes. Acidification of these vesicles depends on a "proton pump" (vacuolar H+-ATPase) and a Cl– channel. Impaired acidification of endocytic vesicles because of mutations in a Cl– channel gene (CLCN5) causes low-molecular-weight proteinuria in Dent's disease. Renal ammoniagenesis from glutamine in the proximal tubule provides a major tubular fluid buffer to ensure excretion of secreted H+ ion as NH4+ by the collecting duct. Cellular K+ levels inversely modulate ammoniagenesis, and in the setting of high serum K+ from hypoaldosteronism, reduced ammoniagenesis facilitates the appearance of Type IV renal tubular acidosis.

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 well 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 a critically important role in urinary concentrating ability 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 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– co-transporter on the apical membrane in series with basolateral Cl– channels and Na+/K+-ATPase (Fig. 271-3B). The Na+/K+/2Cl– co-transporter is the primary target for loop diuretics. Tubular fluid K+ is the limiting substrate for this co-transporter (tubular concentration of K+ is similar to plasma, about 4 meq/L), but it is maintained by K+ recycling through an apical potassium channel. An inherited disorder of the thick ascending limb, Bartter's syndrome, results in a salt-wasting renal disease associated with hypokalemia and metabolic alkalosis. Loss-of-function mutations in one of four distinct genes encoding components of the Na+/K+/2Cl– co-transporter (NKCC2), apical K+ channel (KCNJ1), or basolateral Cl– channel (CLCNKB, BSND) can cause the syndrome.
Potassium recycling also contributes to a positive electrostatic charge in the lumen relative to the interstitium, which promotes divalent cation (Mg2+ and Ca2+) reabsorption through the 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 utilizing 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 exocellular Ca2+. Mutations in CLDN16 encoding paracellin-1, a transmembrane protein located within the tight junction complex, leads to familial hypomagnesemia with hypercalcuria and nephrocalcinosis, suggesting that the ion conductance of the paracellular pathway in the thick limb is regulated. Mutations in TRPM6 encoding a Mg2+ permeable ion channel also cause familial hypomagnesemia with hypocalcemia. A molecular complex of TRPM6 and TRPM7 proteins is critical for Mg2+ reabsorption in the thick ascending limb of Henle.
The loop of Henle contributes to urine concentrating ability by establishing a hypertonic medullary interstitium, which promotes water reabsorption by a more distal nephron segment, the 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 the interstitial fluid surrounding the thick ascending limb. 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 utilizes an apical membrane, electroneutral thiazide-sensitive Na+/Cl– co-transporter in tandem with basolateral Na+/K+-ATPase and Cl– channels (Fig. 271-3C). 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– co-transport 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– co-transporter cause Gitelman's 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's 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– co-transporter 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.

Collecting Duct
The collecting duct regulates the final composition of the 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 a high-resistance epithelia with two cell types. Principal cells are the main Na+ reabsorbing cells and the site of action of aldosterone, K+-sparing diuretics, and spironolactone. The other cells are type A and B intercalated cells. Type A intercalated cells mediate acid secretion and bicarbonate reabsorption. 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 with basolateral exit via the Na+/K+-ATPase (Fig. 271-3E). This Na+ reabsorptive process is tightly regulated by aldosterone. 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 sodium reabsorption. Activating mutations in this epithelial Na+ channel increase Na+ reclamation and produce hypokalemia, hypertension, and metabolic alkalosis (Liddle's syndrome). The potassium-sparing diuretics amiloride and triamterene block the epithelial Na+ channel causing reduced Na+ reabsorption.
Principal cells secrete K+ through an apical membrane potassium channel. Two forces govern the secretion of K+. First, the high intracellular K+ concentration generated by Na+/K+-ATPase creates a favorable concentration gradient for K+ secretion into tubular fluid. Secondly, 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 cations. When Na+ reabsorption is blocked, the electrical component of the driving force for K+ secretion is blunted. K+ secretion is also promoted by fast tubular fluid flow rates (which might occur during volume expansion or diuretics acting "upstream" of the cortical collecting duct), and the presence of relatively nonreabsorbable anions (including bicarbonate and penicillins) that contribute to the lumen-negative potential. Principal cells also participate in water reabsorption by increased water permeability in response to vasopressin; this effect is explained more fully below for the inner medullary collecting duct.
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– exchanger. 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 anion exchanger for mediating bicarbonate reabsorption (Fig. 271-3E). 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. 271-3F). 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 levels of cyclic AMP. This signaling cascade ultimately 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. Thus, the nephron separates NaCl from water so that considerations of volume or tonicity can determine whether to retain or excrete water.
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 pre-prohormone 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 is permeable to urea, allowing urea to diffuse into 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. 271-4A), and extracellular blood volume is regulated by Na+ balance (Fig. 271-4B). The kidney is a critical modulator for both of these physiologic processes.
Figure 271-4
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 osmols in the body divided by the total body H2O (TB H20), 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. When water metabolism is disturbed and total-body water increases, hyponatremia, hypotonicity, and water intoxication occurs; when total-body water decreases, hypernatremia, hypertonicity, and dehydration occurs. B. Extracellular blood volume and pressure are an integrated function of total body Na+ (TB Na+), total body H20 (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 naturetic 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; AP2, aquaporin-2.

Water Balance
Tonicity depends on the variable concentration of effective osmoles inside and outside the cell that cause 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. 271-4A).
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 reaching 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. While all cells expressing mechanosensitive TRPV4 channels respond to changes in tonicity by altering their volume and Ca2+ concentration, only TRPV4+ neuronal cells connected to the supraoptic and paraventricular nuclei in the hypothalamus are osmoreceptive; that is, they alone, because of their neural connectivity, modulate the 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, 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 their regulation of renal water excretion. The ability to concentrate urine to an osmolality exceeding that of plasma enables water conservation, while the ability to produce urine more dilute than plasma promotes excretion of excess water. Cell membranes are composed of lipids and other hydrophobic substances that are intrinsically impermeable to water. In order for water to enter or exit a cell, the cell membrane must express water channel aquaporins. In the kidney, aquaporin 1 is constitutively active in all water-permeable segments of the proximal and distal tubules, while aquaporins 2, 3, and 4 are regulated by vasopressin in the collecting duct. Vasopressin interacts with the V2 receptor on basolateral membranes of collecting duct cells and signals the insertion of new water channels into apical membranes to promote 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 the extracellular volume. Na+ and its anions are the most abundant extracellular effective osmoles, and together they support a blood volume around which pressure is generated. Under normal conditions, this volume is regulated by sodium balance (Fig. 271-4B), 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 naturetic 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 1-adrenergic stimulation to the afferent arteriole, input from the macula densa, and prostaglandins. Renin and ACE activity eventually produce angiotensin II, which 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 Na+ reabsorption. Finally, angiotensin II inhibits renin secretion through a negative feedback loop.
Aldosterone is synthesized and secreted by granulosa cells in the adrenal cortex. It binds to cytoplasmic mineralocorticoid receptors in principal cells of the collecting duct that increase the activity of the apical membrane Na+ channel, 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 epithelial Na+ channel 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 epithelial Na+ channel, leading to increased channel density at the plasma membrane and increased capacity for Na+ reabsorption by the collecting duct.
Chronic overexpression of 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 naturetic peptides, which lose their effectiveness in the clinical settings of heart failure, nephrotic syndrome, and cirrhosis, leading to severe Na+ retention and volume overload.

Further Readings

  1. Ballermann BJ: Glomerular endothelial cell differentiation. Kidney Int 67:1668, 2005 [PMID: 15840009]
  2. Giebisch G et al: New aspects of renal potassium transport. Pflugers Arch 446:289, 2003 [PMID: 12684792]
  3. Kopan R et al: Molecular insights into segmentation along the proximal–distal axis of the nephron. J Am Soc Nephrol 18:2014, 2007 [PMID: 17568016]
  4. Mange K et al: Language guiding therapy: The case of dehydration versus volume depletion. Ann Inten Med 127: 848, 1997 [PMID: 9382413]
  5. O'Neil RG, Heller S: The mechanosensitive nature of TRPV channels. Pflugers Arch-Eur J Physiol 451:193, 2005 [PMID: 15909178]
  6. Ribes D et al: Transcriptional control of epithelial differentiation during kidney development. J Am Soc Nephrol 14:S9, 2003
  7. Schrier RW, Ecder T: Gibbs memorial lecture: Unifying hypothesis of body fluid volume regulation. Mt Sinai J Med 68: 350, 2001 [PMID: 11687862]
  8. Wagner CA et al: Renal acid-base transport: Old and new players. Nephron Physiol 103:1, 2006 
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