858 SECTION VII Pediatric Critical Care Renal sympathetic a1 receptors, myogenic contraction, and vasoactive mediators that control vascular resistance and provide regulation of renal blood flow Maint[.]
Vascular Development The development of the kidney vasculature is an area of active investigation Markers of early vascular development are expressed in undifferentiated metanephric mesenchyme, which suggests that the blood supply to the nephron develops at least partially from precursors inherent to the developing kidney.12 Migration of committed endothelial cells into the developing glomerulus occurs in response to secreted factors such as vascular endothelial growth factor, which is secreted under the transcriptional regulation of the oxygen-sensitive hypoxic inducible factor.13 Other factors that have been shown to coordinate and control vascular development in the mammalian kidney include the renin-angiotensin system, transforming growth factor-b, platelet-derived growth factor, angiopoietins, sphingosine-1-phosphate pathway, and Notch signaling.14 The Nephron The nephron is the functional unit of the kidney, with structurally and functionally defined areas that refine glomerular filtrate into urine The nephron consists of a glomerular capillary tuft within the Bowman capsule and the renal tubule, which is divided into anatomically and functionally distinct areas, including the proximal convoluted tubule, loop of Henle, distal tubule, and collecting duct (Fig 70.3) Nephron Development Metanephric nephron development occurs through a complex, interactive series of processes beginning at around weeks’ gestation, with cessation of nephrogenesis at around 34 weeks’ gestation.3–5 Nephron development begins with the outpouching of ureteric epithelium, the ureteric bud, from the mesonephric duct This precursor to the collecting duct encroaches on undifferentiated metanephric mesenchyme in the caudal retroperitoneal space and induces the development of an epithelial cell condensate, which is the precursor to the glomerulus and tubule (Fig 70.4) Simultaneously, factors within the metanephric mesenchyme induce the ureteric bud to continue branching The epithelial condensate forms a vesicle that convolutes progressively into a comma-shaped body and then an S-shaped body, signifying the development of the urinary space and early tubule segments The ureteric bud eventually evolves into the collecting ducts, calyces, renal pelvis, and ureters The mechanisms by which the ureteric bud epithelial derivatives link to the corresponding mesenchymal derivatives in the distal nephron remain unknown but may involve mesenchymal to epithelial cell transitioning under the Efferent arteriole Afferent arteriole Cortical nephron Juxtamedullary nephron Outer stripe Inner stripe Outer zone Interlobular artery vein Interlobar artery vein Collecting duct Inner zone sympathetic a1-receptors, myogenic contraction, and vasoactive mediators that control vascular resistance and provide regulation of renal blood flow Maintenance of glomerular filtration rate at the level of the glomerulus occurs by action of vasoactive mediators such as angiotensin II, which induces smooth muscle contraction and prostacyclin, which relaxes afferent arterioles There are significant developmental variations in the levels of vasoactive mediators and receptor characteristics Circulating angiotensin II, for example, is elevated in the neonate,9 as are corresponding vasodilators.10 The end result of these maturational differences in the infant is a decreased capacity to regulate renal blood flow and subsequent susceptibility to renal ischemia and acute kidney injury, particularly in hypovolemic or hypotensive states.11 Cortex S E C T I O N V I I Pediatric Critical Care: Renal Medulla 858 Vasa recta Thick loop of Henle Thin loop of Henle Ducts of Bellini • Fig 70.3 The nephron structure with cortical and juxtamedullary neph- rons in relation to arterioles, peritubular capillaries, and vasa rectae (From Guyton A Formation of urine by the kidney: I Renal blood flow, glomerular filtration, and their control In: Wonsiewicz M, ed Textbook of Medical Physiology 8th ed Philadelphia: WB Saunders; 1991.) control of glial cell line–derived neurotrophic factor.15 The glomerular capillary loops form through the angiogenic processes of committed endothelial cells,12 and supporting mesangial cells develop from committed metanephric mesenchyme with myoblastic characteristics.16 Glomerulus Glomerular Anatomy The glomerulus is a tuft of capillaries located within the Bowman capsule It is unique among mammalian vascular beds by having two sets of arterioles, both proximal and distal to the capillary bed Approximately 80% to 85% of glomeruli are in the cortical region, while the remaining 15% to 20% are juxtamedullary The location of the glomerulus in either the cortical or juxtamedullary region dictates the tubular length and function of the nephron with regard to salt and water reabsorption capacity and contribution to generation of steep osmotic gradients for production of a concentrated urine, discussed in detail later The cell types within the glomerulus include extensively fenestrated endothelial cells; podocytes, which are highly specialized epithelial cells; and supporting mesangial cells Epithelial cells also form the urinary compartment into which ultrafiltrate passes (Bowman space) Endothelial cells and podocytes sit on opposite sides of the glomerular basement membrane, the entirety of which forms the filtration apparatus (Fig 70.5) Glomerular endothelial cells on the blood side of the filtration barrier are highly fenestrated, promoting efficient solute and fluid transfer across the glomerular basement membrane The epithelial side is characterized by fingerlike extensions of the podocyte cell membrane that interdigitate to form a mesh on the glomerular basement membrane CHAPTER 70 Renal Structure and Function Loose mesenchyme Condensation Epithelial ureter bud A Mesenchyme B Comma-shape S-shape Distal Proximal C D Tubule elongation Podocyte folding Distal Podocyte E G Proximal Capsule F • Fig 70.4 Branching morphogenesis of the developing kidney (A–B) The ureteric epithelium interacts with the metanephric mesenchyme, inducing condensation of the mesenchyme (1, ureteric epithelium; 2, vasculature; 3, undifferentiated mesenchyme; 4, condensed mesenchyme [precursor to epithelium]) (C–D) Infolding of the glomerular epithelium forms a comma-shaped body, followed by development of an S-shaped body (E–F) Infolding of the glomerular epithelium and vascular structures and elongation of the tubular elements form the completed nephron The mature glomerular capillary network is likely initiated during C and D (G) Fluorescent microscopy of branching morphogenesis in organ culture (A–F, From Gomez RA, Norwood VF Recent advances in renal development Curr Opin Pediatr 1999;11:136 G, Courtesy John Bertram, Kidney Development and Research Group.) 859 860 S E C T I O N V I I Pediatric Critical Care: Renal Parietal epithelial cell Urinary space Podocyte cell body Slit diaphragm Podocyte foot processes Filtration slit (40 nm) GBM Glycocalyx Fenestra Glomerular capillary lumen Endothelial cell • Fig 70.5 Glomerular filtration apparatus GBM, Glomerular basement membrane (From Jefferson JA, Alpers CE, Shankland SJ Podocyte biology for the bedside Am J Kidney Dis 2011;58[5]:835–845.) Glomerular Filtration Afferent arteriole Efferent arteriole Glomerular capillary Blood flow (protein) Hydrostatic pressure Oncotic pressure (protein) Tubular hydrostatic pressure Urinary space • Fig 70.6 Forces affecting glomerular filtration in the isolated nephron Mesangial cells form the supporting network of the glomerular structure, provide some phagocytic function, and participate in control of glomerular filtration.17 Glomerular Function Filtration is the primary function of the glomerulus.18 Filtration requires a gradient across the glomerular basement membrane favoring the movement of water and solute to a low-pressure area There are generally four factors that contribute to the pressure gradient and determine the quantity of filtrate obtained across the glomerular basement membrane (Fig 70.6) First, hydrostatic pressure in the glomerular capillary drives filtration of fluid across the glomerular basement membrane If the blood flow to the glomerulus decreases, the hydrostatic pressure also drops, which necessitates an increase in efferent vascular resistance to maintain glomerular perfusion pressure Angiotensin II, prostaglandins, and renal sympathetic activity control afferent and efferent vascular tone to carefully regulate glomerular vascular resistance The second factor controlling the pressure gradient is the oncotic pressure of the blood entering the glomerulus As blood is filtered and water leaves the vascular compartment, the oncotic pressure in the blood compartment rises, limiting the passage of additional fluid across the glomerular basement membrane In situations of low oncotic pressure, such as nephrotic syndrome, the initial rate of ultrafiltrate formation is increased because of low oncotic pressure with preserved hydrostatic pressure However, over time, low systemic oncotic pressure causes a redistribution of intravascular volume into peripheral tissue spaces, resulting in decreased intravascular hydrostatic pressure and forcing ultrafiltrate production to drop The third factor affecting ultrafiltrate formation is tubular hydrostatic pressure, or the resistance within the urinary space In urinary tract obstruction, tubular hydrostatic pressure limits ultrafiltrate generation as it rises above the hydrostatic pressure of the blood compartment, thereby negatively affecting glomerular filtration rate The last factor in the determination of ultrafiltrate formation is the available glomerular basement membrane surface area and related filtration efficiency Physiologically, the functional size of the glomerular basement membrane can be determined at the whole kidney level or at the glomerular level At the whole kidney level, the number of nephrons receiving adequate blood supply determines glomerular basement membrane area available for filtration For example, shunting of blood from the cortex into the medulla, as seen in hepatorenal syndrome, effectively decreases the available glomerular basement membrane area by reducing the number of actively filtering nephrons Within the glomerulus, glomerular basement membrane area can be altered by mesangial cell function In hypovolemic states, mesangial cell contraction is thought to decrease glomerular basement membrane area in response to hormonal mediators, resulting in decreased filtration and preservation of intravascular volume.19 The efficiency of basement membrane filtration is also affected by disease states, including immune complex deposition, fibrosis, or complement activation, which disrupt the integrity and efficiency of the membrane Finally, selectivity of the filtration barrier is determined by the ability of the basement membrane to permit water and smaller solutes (such as sodium, chloride, and urea) to pass into the urinary space while restricting others (such as cells and larger proteins) to remain in the blood compartment The glomerular filtration barrier provides both charge and size selectivity that ultimately involves the compound influences of endothelial fenestrae, glomerular basement membrane structure, and podocyte structure and function The effects of altered podocyte function on the integrity of filtration are most commonly seen in the various forms of nephrotic syndromes.20 Tubular Anatomy Proximal Tubule The proximal tubule consists of polarized epithelia with structurally and functionally defined areas that are key to the primary function of reabsorption of filtered solute and water The polarity of the cells is maintained by the presence of cell-cell adhesion complexes called tight junctions, which separate apical transport proteins from the gradient-generating basolateral membrane proteins CHAPTER 70 Renal Structure and Function The apical surface of the proximal tubular cell has a distinctive brush border that increases the luminal surface area of the cell, maximizing contact with the tubular ultrafiltrate Increased surface area facilitates reabsorption of solutes and water, which occurs through a wide array of sodium-coupled transporters The apical brush border membrane also contains numerous ion channels and ion exchange proteins that maintain electrochemical gradients The basolateral aspects of the proximal tubular cells contain membrane-bound sodium-potassium adenosine triphosphatase (Na1/K1-ATPase) proteins and a high density of intracellular mitochondria along with additional ion channels and ion exchange proteins It is through the Na1/K1-ATPase that favorable sodium and electrochemical gradients are generated to facilitate transcellular and paracellular transport of solutes and water 861 Distal tubule Macula densa cells Afferent arteriole Efferent arteriole Granular cells Loop of Henle The loop of Henle, whether cortical or juxtamedullary, is characterized by a long tubule extending from the proximal tubule toward the medulla with a hairpin turn extending back out toward the cortex The structural and functional properties of the epithelial cells change throughout the length of the loop of Henle The proximal portions have cells with prominent microvilli and permeable cell junctions that permit passage of fluid via aquaporin-1 channels.21 The distal sections of the loop of Henle consist of flat epithelia lacking microvilli and are devoid of aquaporin-1 channels; the thin ascending limb of the loop of Henle is impermeable to water and urea but transports other solutes, particularly chloride, and is important in assisting with the establishment of medullary concentration gradients.22 An abrupt transition occurs at the beginning of the thick ascending limb of the loop of Henle (TALH) The TALH is impermeable to water owing to a dense network of tight junctions The TALH is the site of solute transport in an active, ATP-dependent manner, and these cells have dense localization of mitochondria and Na1/K1-ATPase at the basolateral membrane that generate chemical gradients for solute transport across the luminal surface Compared with the proximal tubule, the TALH basolateral surface is larger than the luminal surface and accommodates a larger number of Na1/K1-ATPase pumps.23,24 At the distal end of the TALH, the tubule courses back toward its originating glomerulus Here, a small plaque of tall, narrow tubular epithelial cells, the macula densa, contacts the vascular pole and extraglomerular mesangial cells (Fig 70.7) The primary function of the macula densa cells appears to be the detection of tubular chloride content and the regulation of glomerular filtration via activation of the reninangiotensin system and additional vasoactive hormones.25 Distal Nephron The distal nephron segment from the TALH to the beginning of the collecting duct has three distinct regions that fine-tune the filtrate contents.26 The first region is the distal convoluted tubule, where the luminal sodium chloride transporter (NCC2, or thiazide-sensitive transporter) is located along with the highest density of mitochondria in the nephron The basolateral membranes of this segment are composed of interdigitating membranes from adjacent cells, giving the appearance of membranous convolutions This composition maximizes the basolateral surface area to accommodate the high density of mitochondria and allow for high levels of Na1/K1-ATPase function Moving distally, the tubule contains transitional cells that have a smaller basolateral surface area and fewer mitochondria at the basolateral membrane Glomerulus • Fig 70.7 Structure of the macula densa and juxtaglomerular apparatus (Modified from The kidney and urinary system In: Ritter JM, Flower R, Henderson G, Rang H, eds Rang & Dale’s Pharmacology 9th ed Philadelphia: Elsevier; 2020:382–394.) Transitional cells express both the NCC2 channel and luminal epithelial sodium channel (ENaC), with the quantities of ENaC increasing and NCC2 decreasing with distal progression along the segment The next segment is the connecting tubule, where cells have even fewer mitochondria and smaller basolateral membranes These cells are distinguished by a more flattened appearance, an increased expression of ENaC, and a luminal potassium channel (ROMK), but not NCC2 The basolateral membrane is expanded to some degree by infoldings of the basal membrane, but there is no interdigitation from neighboring cells These cells also contain magnesium transporters and calcium transporters, indicating their role in divalent cation regulation.27,28 The final segment in the distal nephron is the collecting duct.29 The primary cells of this segment, the principal cells, have apical vacuoles, some of which store aquaporin-2 channels (Fig 70.8) Cells in the collecting duct also contain mineralocorticoid receptors and apical sodium channels that function in sodium and potassium balance In the medullary portions of the collecting duct, urea transporters again appear Two forms of intercalated cells, type A and non–type A, exist as single cells interspersed throughout the distal nephron (see Fig 70.8) These cells have high densities of mitochondria and express several important membrane proteins, including luminal hydrogen adenosine triphosphatase (H1-ATPase) and hydrogenpotassium adenosine triphosphatase (H1/K1-ATPase) along with cytoplasmic carbonic anhydrase, thereby serving an integral role in acid-base balance The essential difference between type A and non–type A intercalated cells is that cell polarity is opposite in the two cell types In type A intercalated cells, the apical membrane contains a H1/K1-ATPase, whereas the basolateral membrane contains AE1, a bicarbonate/chloride exchanger that provides a mechanism for proton secretion The non–type A intercalated cells have vacuolar H1-ATPase on the basolateral and apical surfaces and a chloride bicarbonate exchanger, pendrin, on the apical surface, allowing for both bicarbonate secretion and proton reabsorption.30 Generally, the number of type A and non–type A intercalated cells can vary to accommodate the acid-base status in the blood.31 862 S E C T I O N V I I Pediatric Critical Care: Renal Lumen Blood – Principal cell H2O AQP2 Na+ ENaC Vasopressin 3Na+ ROMK H2PO4– Type A intercalated cell (A-IC) K+ ATPase A11 HPO42– + H+ ATPase H+ K+ H+ H Cl– NHE1 NKCC1 H+ H2O CAII CO2 + OH– + NH3 + ATPase HCO–3 AE1 2K+ Na+ K+ Na+ 2Cl– Cl– RhCG NH+4 HCO–3 Type B intercalated cell (B-IC) Na+ Cl– 2H+ NDCBE Pendrin Cl– HCO–3 3HCO3– Na+ ATPase AE4 • Fig 70.8 Collecting duct cell types: the principal cell, type A intercalated cell (A-IC), and type B interca- lated cell (B-IC) The principal cell (PC) is responsive to vasopressin When vasopressin binds the V2 receptor, an intracellular cascade leads to phosphorylation of intravesicular aquaporins, which are then targeted to the luminal membrane PC also expresses epithelial sodium channel (ENaC) When ENaC is active, a lumen negative potential favors secretion of potassium from the renal outer medullary potassium channel The electronegative lumen also promotes H1 secretion from the type A-IC This results in the generation of “new bicarbonate,” which is extruded from the basolateral membrane by anion exchanger (AE1) The secreted hydrogen can be excreted with titratable acids or ammonia The type B-IC secretes bicarbonate while reabsorbing NaCl (Modified from Hoening MP, Hladik GA Overview of kidney structure and function In: Gilbert S, Welner D, eds National Kidney Foundation Primer on Kidney Diseases, 7th ed Published Philadelphia: Elsevier; 2018:2–18.) Tubular Function Although the function of the glomerulus is filtration, the function of the tubule is to modify the ultrafiltrate to maintain metabolic balance The distinct segments of the tubule carry out unique functions that culminate in the production of the final urine that is quantitatively and qualitatively appropriate for maintaining homeostasis Proximal Tubule Solute and water are transported in the proximal tubule via both paracellular and transcellular routes (Fig 70.9) Paracellular transport allows water and solute travel between cells along chemical or electrical gradients generated by the basolateral Na1/K1ATPase with relatively efficient energy expenditure The mechanism for high-flux movement of sodium out of the lumen is explained by a net luminal positive charge generated by the basolateral Na1/K1-ATPase and net anion reabsorption Therefore the bulk of the sodium follows an electrochemical gradient through paracellular pathways into the blood space The same principle applies to other cations, such as calcium, which are reabsorbed down electrochemical gradients in the proximal tubule Neutrally charged solutes move between cells following concentration gradients, the transport becoming less effective in the distal segments as the concentration gradient dissipates Water movement generally follows sodium movement and is facilitated by the high oncotic pressure of the peritubular capillary network This favorable osmotic gradient allows for reabsorption of approximately 70% of the filtered water in the adult proximal tubule Transcellular movement of solute is a high-resistance method of sodium-coupled transport that results from electrochemical and concentration gradients established by the basolateral Na1/ K1-ATPase (see Fig 70.9) The Na1/K1-ATPase pumps three intracellular sodium molecules into the basolateral extracellular milieu against a concentration gradient and imports two potassium molecules into the cell against a concentration gradient The process, which is ATP dependent, establishes a low intracellular ... forcing ultrafiltrate production to drop The third factor affecting ultrafiltrate formation is tubular hydrostatic pressure, or the resistance within the urinary space In urinary tract obstruction,... chloride transporter (NCC2, or thiazide-sensitive transporter) is located along with the highest density of mitochondria in the nephron The basolateral membranes of this segment are composed of... Henle consist of flat epithelia lacking microvilli and are devoid of aquaporin-1 channels; the thin ascending limb of the loop of Henle is impermeable to water and urea but transports other solutes,