863CHAPTER 70 Renal Structure and Function sodium concentration and permits luminal sodium entry along a concentration gradient coupled with solutes such as phosphate, glucose, amino acids, and organi[.]
CHAPTER 70 Renal Structure and Function Lumen Capillary Solute/H2O Solute H2O H2O Solute 320 Cortex K Na Na 2K 3Na 2K 3Na 400 Outer medulla 600 300 400 NaCl 320 800 1000 NaCl and Urea Inner medulla Loop of Henle The loop of Henle plays an important role in establishing the osmotic gradients facilitating water reabsorption in the kidney and 300 400 400 NaCl 200 600 400 H2O 800 800 1200 Vasa recta 1000 1200 Interstitial fluid 300 400 600 300 320 H2O 400 600 H2O 600 H2O 800 800 800 H2O 800 NaCl 800 Urea H2O and Urea 1000 1000 1000 1000 1000 1200 1200 1200 600 600 800 320 600 1000 1000 sodium concentration and permits luminal sodium entry along a concentration gradient coupled with solutes such as phosphate, glucose, amino acids, and organic acids In a similar fashion, protons are exported from the luminal membrane by an Na1/H1 exchanger that exploits the intracellular movement of sodium to facilitate the export of protons Bicarbonate is indirectly absorbed through the activity of luminal carbonic anhydrase and the Na1/ H1 exchanger The high oncotic pressure of the blood in the arterioles and early vasa recta drives transcellular water reabsorption in the proximal tubular cells via constitutively expressed aquaporin-1 channels located in both apical and basolateral membranes that permit water to flow from lumen to vasculature.32,33 Some proximal solute reabsorption is modifiable by hormone activity Parathyroid hormone binding to the proximal tubule receptors activates several second messenger systems that ultimately result in decreased sodium-phosphate transporter activity and increased urinary phosphate excretion.34 The proximal tubule is also a site of hormone production, with 1a-hydroxylase activity converting 25-hydroxyvitamin D to the active 1,25-dihydroxy form This conversion permits vitamin D to act in calcium and phosphate metabolism Maturational development of the proximal tubule imparts functional differences in neonatal proximal tubules compared with those in adult kidneys The relatively low outer cortical nephron blood flow in infancy results in a generalized decrease in proximal tubule resorptive capacity because fewer nephrons participate in active solute and water reabsorption In the neonate, the proximal tubule also expresses specific neonatal isoforms of the Na1/H1 exchanger, which has decreased chloride permeability, and expresses different permeability proteins (claudins) in the transcellular space As a result, neonatal reabsorptive capacity is reduced compared with adults.35 In addition, hormone receptors are expressed in fewer numbers or may have higher thresholds for activation in the neonate For example, isoforms of sodium-phosphate transporters of the premature neonate exhibit a relatively low sensitivity to parathyroid hormone but a high transport capacity for phosphate, resulting in lower urinary excretion of phosphate and higher serum phosphate levels than those seen in adults.36 300 400 400 600 NaCl • Fig 70.9 Proximal tubule transport of solute and water Apical solute reabsorption (urea, bicarbonate, glucose, phosphate, organic acids, urea and amino acids) is coupled to sodium and follows the electrochemical gradient produced by the basolateral sodium-potassium adenosine triphosphatase 300 H2O 200 Solute/H2O Solute 863 Loop of Henle Interstitial fluid Collecting duct • Fig 70.10 Countercurrent amplification mechanism facilitating urinary concentration (From Guyton A Renal and associated mechanisms for controlling extracellular fluid osmolality and sodium In: Wonsiewicz M, ed Textbook of Medical Physiology 8th ed Philadelphia: WB Saunders; 1991.) the subsequent production of high osmolar urine In the descending limb of the loop of Henle, the tubular epithelium is permeable to water but impermeable to solute Therefore, as ultrafiltrate passes down the descending loop of Henle, water leaves the luminal space, resulting in an increasingly hyperosmolar ultrafiltrate Water permeability decreases, however, in the ascending loop and solute transporters become more prevalent, allowing the filtrate to become hypoosmolar by the time it reaches the outer cortex The thick ascending loop of Henle is responsible for roughly 25% of the total sodium reclamation in the kidney, primarily by the NKCC2 channel transportation of one sodium, one potassium, and two chloride ions from the tubular lumen into the cell.37 Potassium subsequently leaks back into the lumen via the ROMK potassium channel, causing the lumen to become positively charged This electrochemical gradient permits paracellular reabsorption of cations such as calcium and magnesium as they are propelled out of the tubular lumen The reabsorption of sodium in the TALH also helps establish osmotic gradients in the renal interstitium by the countercurrent amplification mechanism (Fig 70.10) Although sodium, potassium, and chloride are absorbed into the interstitium, back leak of ions occurs into the descending limb of the loop of Henle, thereby increasing the concentration of solute in the descending limb tubular fluid As this fluid passes into the ascending loop of Henle, the higher sodium content is also reabsorbed into the interstitium, augmenting the osmotic gradient in the medulla Under normal conditions, ultrafiltrate leaving the ascending loop of Henle is more dilute than that entering the descending loop because of the proficient solute reabsorption in the late ascending limb Loop diuretics, such as bumetanide or furosemide, block the NKCC2 channel function and impair the ability both to establish osmotic gradients and to reabsorb solute The result is the 864 S E C T I O N V I I Pediatric Critical Care: Renal production of large volumes of urine that is isotonic to plasma In the immature kidney, the loop of Henle is relatively short and impedes the ability to set up steep osmotic gradients In the setting of stable vasopressin levels, neonatal urinary concentrating ability is relatively weak compared with that of the mature adult kidney.38 The thick ascending loop of Henle returns to its glomerulus of origin where the tubular epithelium is attached to the triangle between the efferent and afferent arteriole The tubular epithelium in contact with the glomerulus contains about 15 to 20 cells in the form of a plaque, called the macula densa (see Fig 70.7) The macula densa actively reabsorbs sodium, potassium, and chloride through the NKCC2 channel and, in doing so, acts as a sensor of tubular chloride concentration.39 This sensing mechanism is integral to the functioning of the juxtaglomerular apparatus, which consists of the macula densa, the afferent arteriole containing renin-producing granular cells, the efferent arteriole, and the extraglomerular mesangium In response to low tubular chloride, such as in hypovolemia, the macula densa secretes chemical mediators (prostaglandins, nitric oxide, adenosine, and ATP) that trigger renin release from the granular cells in the afferent arteriole Similar effects can be induced by sympathetic nervous system stimulation and arteriolar baroreceptor activation.40 Renin activity ultimately leads to the production of the potent vasoconstrictor angiotensin II, vascular smooth muscle contraction in the efferent arteriole, increased efferent arteriolar vascular resistance, and a rise in glomerular perfusion pressure.39 The macula densa also signals the mesangial cells and neighboring smooth muscle cells to contract through a process that involves gap junction signaling and calcium flux This contraction results in increased vascular tone and decreased effective filtration area of the glomerular basement membrane.41,42 Distal Tubule The distal convoluted tubule is also a site of active sodium reabsorption and helps fine-tune the urinary filtrate to form the final urine When tubular fluid enters the distal convoluted tubule, it is relatively dilute because of active solute reabsorption in the TALH Thus, reabsorption of sodium and chloride in this segment occurs against a concentration gradient Sodium and chloride are actively reabsorbed through the luminal thiazide-sensitive cotransporter (NCCT) following electrochemical gradients generated by the basolateral Na1/K1-ATPase However, regulation of the NCCT—and, hence, sodium flux—is modifiable through a series of modulator kinases, such as WNK-1 and WNK-4.43 Approximately 10% of filtered calcium is also reabsorbed from the lumen of the distal convoluted tubule through parathyroid hormone activation of ATP-dependent TRPV5 calcium channels.44 Once inside the cell, calcium is sequestered by calbindin-D28k, a protein that facilitates the transport of calcium to the basolateral membrane Calcium exits the cell through either a basolateral sodium-calcium exchanger, NCX1, or the plasma membrane calcium efflux ATPase.44 Collecting Duct The collecting duct fine-tunes the final composition of the renal ultrafiltrate, adjusting sodium, potassium, water content, and acid-base balance Approximately 5% of the filtered sodium is reabsorbed at this location and occurs through active transport Sodium enters the cell through apical ENaCs and generates a luminal electronegative gradient.45 Consequently, the excretion of cations such as potassium (principal cell) or protons (A-type intercalated cell) is favored (see Fig 70.8) Because relatively little potassium is in the tubular fluid when it reaches this segment, potassium excretion is facilitated down both concentration and charge gradients As potassium is excreted, urine flow keeps the concentration in the tubular fluid low and the favorable gradient is maintained In states of low urine flow, the tubular potassium concentration rises, the gradient is reduced, and potassium excretion decreases Potassium excretion and sodium reabsorption are also enhanced by the presence of aldosterone Binding of aldosterone to its receptor and subsequent translocation to the cell nucleus induces transcription of the luminal sodium channel and basolateral Na1/K1-ATPase.45 Increased efficiency and numbers of ENaCs on the luminal membrane tend to increase cell permeability to sodium; this increase allows the tubular fluid to become more negatively charged after the influx of sodium This process is facilitated by the increased activity and number of Na1/K1-ATPase pumps at the basolateral membrane, which creates larger electrical gradients The net result is an increased capacity to excrete potassium or, in the hypokalemic state, an increased capacity to excrete protons, resulting in alkalosis The electrical gradient in the collecting duct also favors proton secretion into the tubular lumen, but the chemical gradient does not; the pH in the lumen can be as low as 5, whereas that of the intracellular space is 7.3 Excretion of protons occurs through an apical H1-ATPase in the A-type intercalated cells and is also increased by aldosterone action in principal cells, as previously described Protons secreted into the lumen are bound by ammonia (NH3) to form NH41 or are bound by other titratable acids, such as phosphate or sulfate This sequestration lowers the concentration of free protons in the ultrafiltrate, prevents diffusion of protons back into the intracellular space, and ultimately promotes acid secretion.46 The collecting duct is also responsible for establishing the final concentration of the urine by controlling water reabsorption At the beginning of the medullary collecting duct, the ultrafiltrate remains relatively dilute, and the cells are relatively impermeable to water and solute In the setting of hypovolemia or hyperosmolarity, arginine vasopressin binds to V2 vasopressin receptors on the basolateral membrane of the medullary collecting duct cell V2 receptor signaling results in aquaporin-2 channel migration from intracellular vesicles to the apical surface; this migration increases tubular permeability to water Because of the high interstitial osmolality, water is reabsorbed through the aquaporin channels along an osmotic gradient into the blood space, causing increased urinary concentration.47 Although largely established by active sodium reabsorption in the TALH, the medullary osmotic gradient is also maintained by the presence of urea gradients generated in the collecting duct (see Fig 70.10) As tubular fluid moves down the collecting duct, the water entering the interstitium allows the urine to become more concentrated and the urea concentration to rise The interstitial osmolarity, however, decreases with the influx of water As the distal tubular permeability to urea increases distally, urea moves from an area of high concentration (the lumen) into an area of lower urea concentration (the interstitium) via the UT-1 urea transporters.48 The interstitium becomes more hyperosmolar with the influx of urea, and the concentrating mechanism of the interstitium is preserved CHAPTER 70 Renal Structure and Function 865 Interstitium Summary Development Structural development of the human kidney supports the observation that renal physiologic processes change with maturation Perfusion, tubular function, and hormonal responses are unique in young patients and affect renal responses in health and disease Understanding the functions of the pediatric kidney at various stages of development is important for predicting therapeutic responsiveness in the critically ill child and for monitoring recovery from illness Developmentally, the interstitium may not arise from a single progenitor, but possibly from both mesenchymal and neural crest origin.49 During metanephric development, the interstitium differentiates to form the larger inner and outer medullary interstitium and the smaller cortical interstitium In the inner medulla, the interstitium is involved in growth and branching of the collecting duct In the outer medulla, the interstitium is involved in the elongation of the loops of Henle of the corticomedullary nephrons Although the mechanisms for both processes remain unclear, the developmental role of the interstitium appears to be in the promotion of growth/branching and attachment, respectively occurring through the secretion of growth factors and matrix proteins.50 Structure and Function The renal interstitium is a composite of cells, fluid, matrix proteins, and fibrils that form a network supporting the function of tubules.49 In the cortex, the interstitium contains two dominant components: fibroblasts and dendritic cells Cortical interstitial fibroblasts provide both structural support of the kidney and a synthetic role in the synthesis of erythropoietin and production of adenosine, which functions in tubuloglomerular feedback.50 The dendritic cells appear to originate from bone marrow and function largely in an immune capacity, presenting antigen in major histocompatibility complex class II molecules to surveying cells of the immune system.50,51 In the medulla, the interstitium is the site where the steep osmotic gradients are maintained Additionally, some evidence supports a role for medullary interstitium in the secretion of vasopressors The role of these depressors on either a local or systemic effect requires further study.51 The interstitium is also a target of disease, with the result often being interstitial fibrosis The development of interstitial fibrosis in response to injury is modulated by dendritic cell activity and subsequent cytokine release, as well as the synthesis of matrix by fibroblasts, most notably via the actions of transforming growth factor b A number of chronic inflammatory processes may induce chronic renal insufficiency through the development of interstitial fibrosis, a phenomenon that remains an area of active study.50 Key References Brenner BM, Humes HD Mechanics of glomerular ultrafiltration N Engl J Med 1977;297(3):148-154 Costantini F Genetic controls and cellular behaviors in branching morphogenesis of the renal collecting system Wiley Interdiscip Rev Dev Biol 2012;1(5):693-713 Ferenbach DA, Bonventre JV Kidney tubules: intertubular, vascular, and glomerular cross-talk Curr Opin Nephrol Hypertens 2016;25(3): 194-202 Gattineni J, Baum M Developmental changes in renal tubular transportan overview Pediatr Nephrol 2015;30(12):2085-2098 Holmes RP The role of renal water channels in health and disease Mol Aspects Med 2012;33(5-6):547-552 Kurihara H, Sakai T Cell biology of mesangial cells: the third cell that maintains the glomerular capillary Anat Sci Int 2017;92(2):173-186 McMahon AP Development of the mammalian kidney Curr Top Dev Biol 2016;117:31-64 Mohamed T, Sequeira-Lopez MLS Development of the renal vasculature Semin Cell Dev Biol 2019;91:132-146 Nawata CM, Pannabecker TL Mammalian urine concentration: a review of renal medullary architecture and membrane transporters J Comp Physiol B 2018;188(6):899-918 Nielsen S, Frøkiaer J, Marples D, Kwon TH, Agre P, Knepper MA Aquaporins in the kidney: from molecules to medicine Physiol Rev 2002;82(1):205-244 Subramanya AR, Ellison DH Distal convoluted tubule Clin J Am Soc Nephrol 2014;9(12):2147-2163 Zeisberg M, Kalluri R Physiology of the renal interstitium Clin J Am Soc Nephrol 2015;10(10):1831-1840 The full reference list for this chapter is available at ExpertConsult.com e1 References Schedl A Renal abnormalities and their developmental origin Nat Rev Genet 2007;8(10):791-802 Dorko F, Tokarcik J, Vyborna E Congenital malformations of the ureter: anatomical studies Anat Sci Int 2016;91(3):290-294 McMahon AP Development of the Mammalian Kidney Curr Top Dev Biol 2016;117:31-64 Krause M, Rak-Raszewska A, Pietila I, Quaggin SE, Vainio S Signaling during Kidney Development Cells 2015;4(2):112-132 Dressler GR, Patel SR Epigenetics in kidney development and renal disease Transl Res 2015;165(1):166-176 Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE Human nephron number: implications for health and disease Pediatr Nephrol 2011;26(9):1529-1533 Negromonte G, Bandeira R, Farias RD, et al Standardization of the nomenclature of anatomical variants of the renal arteries – a conciliatory proposal Acta Scientiae Anatomica 2018;1(1):40-48 Musso CG, Ghezzi L, Ferraris J Renal physiology in newborns and old people: similar characteristics but different mechanisms Int Urol Nephrol 2004;36(2):273-276 Nobilis A, Kocsis I, Toth-Heyn P, et al Variance of ACE and AT1 receptor gene does not influence the risk of neonatal acute renal failure Pediatr Nephrol 2001;16(12):1063-1066 10 Lucke T, Kanzelmeyer N, Kemper MJ, Tsikas D, Das AM Developmental changes in the L-arginine/nitric oxide pathway from infancy to adulthood: plasma asymmetric dimethylarginine levels decrease with age Clin Chem Lab Med 2007;45(11):1525-1530 11 Jetton JG, Boohaker LJ, Sethi SK, et al Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study Lancet Child Adolesc Health 2017;1(3):184-194 12 Robert B, Abrahamson DR Control of glomerular capillary development by growth factor/receptor kinases Pediatr Nephrol 2001;16(3):294-301 13 Freeburg PB, Abrahamson DR Hypoxia-inducible factors and kidney vascular development J Am Soc Nephrol 2003;14(11): 2723-2730 14 Mohamed T, Sequeira-Lopez MLS Development of the renal vasculature Semin Cell Dev Biol 2019;91:132-146 15 Costantini F Genetic controls and cellular behaviors in branching morphogenesis of the renal collecting system Wiley Interdiscip Rev Dev Biol 2012;1(5):693-713 16 Betsholtz C, Lindblom P, Bjarnegard M, Enge M, Gerhardt H, Lindahl P Role of platelet-derived growth factor in mesangium development and vasculopathies: lessons from platelet-derived growth factor and platelet-derived growth factor receptor mutations in mice Curr Opin Nephrol Hypertens 2004;13(1):45-52 17 Kurihara H, Sakai T Cell biology of mesangial cells: the third cell that maintains the glomerular capillary Anat Sci Int 2017;92(2):173186 18 Carlstrom M, Wilcox CS, Arendshorst WJ Renal autoregulation in health and disease Physiol Rev 2015;95(2):405-511 19 Brenner BM, Humes HD Mechanics of glomerular ultrafiltration N Engl J Med 1977;297(3):148-154 20 Schell C, Huber TB The Evolving Complexity of the Podocyte Cytoskeleton J Am Soc Nephrol 2017;28(11):3166-3174 21 Holmes RP The role of renal water channels in health and disease Mol Aspects Med 2012;33(5-6):547-552 22 Nawata CM, Pannabecker TL Mammalian urine concentration: a review of renal medullary architecture and membrane transporters J Comp Physiol B 2018;188(6):899-918 23 Zacchia M, Capolongo G, Rinaldi L, Capasso G The importance of the thick ascending limb of Henle’s loop in renal physiology and pathophysiology Int J Nephrol Renovasc Dis 2018;11:81-92 24 Sands JM, Layton HE The physiology of urinary concentration: an update Semin Nephrol 2009;29(3):178-195 25 Friis UG, Madsen K, Stubbe J, et al Regulation of renin secretion by renal juxtaglomerular cells Pflugers Arch 2013;465(1):25-37 26 Subramanya AR, Ellison DH Distal convoluted tubule Clin J Am Soc Nephrol 2014;9(12):2147-2163 27 Curry JN, Yu ASL Magnesium Handling in the Kidney Adv Chronic Kidney Dis 2018;25(3):236-243 28 Zhou Y, Greka A Calcium-permeable ion channels in the kidney Am J Physiol Renal Physiol 2016;310(11):F1157-F1167 29 Roy A, Al-bataineh MM, Pastor-Soler NM Collecting duct intercalated cell function and regulation Clin J Am Soc Nephrol 2015;10(2): 305-324 30 Wagner CA, Devuyst O, Bourgeois S, Mohebbi N Regulated acidbase transport in the collecting duct Pflugers Arch 2009;458(1): 137-156 31 Schwartz GJ, Tsuruoka S, Vijayakumar S, Petrovic S, Mian A, Al-Awqati Q Acid incubation reverses the polarity of intercalated cell transporters, an effect mediated by hensin J Clin Invest 2002; 109(1):89-99 32 Nielsen S, Frokiaer J, Marples D, Kwon TH, Agre P, Knepper MA Aquaporins in the kidney: from molecules to medicine Physiol Rev 2002;82(1):205-244 33 Li Y, Wang W, Jiang T, Yang B Aquaporins in Urinary System Adv Exp Med Biol 2017;969:131-148 34 Blaine J, Weinman EJ, Cunningham R The regulation of renal phosphate transport Adv Chronic Kidney Dis 2011;18(2):77-84 35 Gattineni J, Baum M Developmental changes in renal tubular transport-an overview Pediatr Nephrol 2015;30(12):2085-2098 36 Spitzer A, Barac-Nieto M Ontogeny of renal phosphate transport and the process of growth Pediatr Nephrol 2001;16(9):763-771 37 Castrop H, Schiessl IM Physiology and pathophysiology of the renal Na-K-2Cl cotransporter (NKCC2) Am J Physiol Renal Physiol 2014;307(9):F991-F1002 38 Nyul Z, Vajda Z, Vida G, Sulyok E, Frokiaer J, Nielsen S Urinary aquaporin-2 excretion in preterm and full-term neonates Biol Neonate 2002;82(1):17-21 39 Ferenbach DA, Bonventre JV Kidney tubules: intertubular, vascular, and glomerular cross-talk Curr Opin Nephrol Hypertens 2016; 25(3):194-202 40 Welch WJ The pathophysiology of renin release in renovascular hypertension Semin Nephrol 2000;20(5):394-401 41 Yao J, Zhu Y, Morioka T, Oite T, Kitamura M Pathophysiological roles of gap junction in glomerular mesangial cells J Membr Biol 2007;217(1-3):123-130 42 Peti-Peterdi J Calcium wave of tubuloglomerular feedback Am J Physiol Renal Physiol 2006;291(2):F473-F480 43 Hoorn EJ, Ellison DH WNK kinases and the kidney Exp Cell Res 2012;318(9):1020-1026 44 Boros S, Bindels RJ, Hoenderop JG Active Ca(21) reabsorption in the connecting tubule Pflugers Arch 2009;458(1):99-109 45 Feraille E, Dizin E Coordinated Control of ENaC and Na1,K1ATPase in Renal Collecting Duct J Am Soc Nephrol 2016;27(9):25542563 46 Weiner ID, Verlander JW Role of NH3 and NH41 transporters in renal acid-base transport Am J Physiol Renal Physiol 2011;300(1): F11-F23 47 Hasler U Controlled aquaporin-2 expression in the hypertonic environment Am J Physiol Cell Physiol 2009;296(4):C641-C653 48 Weiner ID, Mitch WE, Sands JM Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion Clin J Am Soc Nephrol 2015;10(8):1444-1458 49 Zeisberg M, Kalluri R Physiology of the Renal Interstitium Clin J Am Soc Nephrol 2015;10(10):1831-1840 50 Kaissling B, Le Hir M The renal cortical interstitium: morphological and functional aspects Histochem Cell Biol 2008;130(2): 247-262 51 Alcorn D, Maric C, McCausland J Development of the renal interstitium Pediatr Nephrol 1999;13(4):347-354 e2 Abstract: The kidneys are paired organs located in the retroperitoneum on either side of the spine at the T12–L3 vertebrae The kidneys function in the maintenance of multiple homeostatic processes in the organism Kidneys regulate water, electrolyte, and acid-base composition of both the intracellular and extracellular compartments, excretion of waste products and toxins, blood pressure via hormonal actions on retention of sodium and water, circulating blood volume by production of erythropoietin, and serum calcium and phosphorus levels through production of active 1,25-hydroxyvitamin D in response to parathyroid hormone These functions are not fully maximized at birth, making the youngest children the most vulnerable to alterations in physiologic balance during illness Key words: kidney, nephron, development, vasculature, glomerulus, tubule, interstitium, homeostasis ... reabsorption of sodium and chloride in this segment occurs against a concentration gradient Sodium and chloride are actively reabsorbed through the luminal thiazide-sensitive cotransporter (NCCT)... tend to increase cell permeability to sodium; this increase allows the tubular fluid to become more negatively charged after the influx of sodium This process is facilitated by the increased activity... muscle cells to contract through a process that involves gap junction signaling and calcium flux This contraction results in increased vascular tone and decreased effective filtration area of the