Toxicologic Pathology http://tpx.sagepub.com/ Kidney Morphology: Update 1985 Ruth Ellen Bulger Toxicol Pathol 1986 14: 13 DOI: 10.1177/019262338601400103 The online version of this article can be found at: http://tpx.sagepub.com/content/14/1/13 Published by: http://www.sagepublications.com On behalf of: Society of Toxicologic Pathology Additional services and information for Toxicologic Pathology can be found at: Email Alerts: http://tpx.sagepub.com/cgi/alerts Subscriptions: http://tpx.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://tpx.sagepub.com/content/14/1/13.refs.html >> Version of Record - Jan 1, 1986 What is This? Downloaded from tpx.sagepub.com at PENNSYLVANIA STATE UNIV on March 4, 2014 TOXICOLOGIC PATHOLOGY ISSN:Ol92-6233 SYMPOSIUM Renal Pathology and Toxicity Volume 14, Number 1. 1986 Copyright 0 1986 by thc Society of Toxicologic Pathologists Kidney Morphology: Update 1985* RUTHELLENBULGER Graduate School of Bioniedical Sciences, The University of Texas Health Science Center at Hoiuton. iloirston. Texas 77030 ABSTRACT Many new observations havc been made correlating changes in renal morphology with changes in renal function. These changes have led to a better definition of the various segments which make up the renal tubule. These morphological patterns vary in different species as is documented by morphologicstudies and by differences in the patterns of enzymes in various nephron segments. The subdivision of cells located in the mesangial region of the glomerulus into several types may provide new areas to study with respect to disease processes. . INTRODU(TTION “. . To all stiiderits for whoin the ever-widenirig horizons and increasing details of medicine make the art of healing more diJiciilt and yet more certain . . .**Homer W.Smith (97). The relentless drive of scientists to unravel the complexities of the relationship between renal structure and function has led to a number of important observations and conceptual advances. First, there has arisen a better definition of ncphron types classified according to their position and tubular configuration in the kidney. Second, an increasing number ofsubdivisions have bccn and are being identified in the urinary tubule. Concomitantly, an appreciation of marked species differences of the various tubular subdivisions in both form and function has evolved. For example, Morel (74) has graphically and dramatically demonstrated the difference in patterns produced by measuring hormonc-dcpcndent adenylate cyclase activity in various nephron segments. Lastly, the identification ofpreviously undescribed resident cell types within the glomerulus promises to open new avenues for fruitful investigation in the future. A synthesis of these “increasing details of medicine” have made it clear that a dynamic interplay exists between kidney form and function. Disuse can lead to atrophy (27). Functional stresses can lead to * Presented at the Fourth International Symposium of thc Society of Toxicologic Pathologists, Junc 5-7, 1985 in Washington, D.C. Address corrcspondcncc to Dr. Ruth Ellen Bulger, Renal Rcsearch, h1.S.hi.B. 7242, The University ofTexas Medical School, P.O. BOX20708, Houston, Texas 77225. 13 hypertrophy, and, some studies indicate that after a certain degree of nephron loss occurs, nephron injury progresses (1 6). The urinary tubule of the long-looped nephrons is presently divided into the following regions: the renal corpuscle, the S,, S2,and S3 regions of the proximal tubule, the upper descending region of the thin limb, the lower descending region of the thin limb, the ascending thin limb, the medullary ascending thick (MAT) region of the distal tubule (in the inner stripe and outer stripe of the outer medulla), the cortical ascending thick (CAT) region of the distal tubule, the macula densa, the post macula densa segment ofthc ascending thick limb, the distal convoluted tubule, the connecting piece, the cortical collecting duct, the outer medullary collecting duct, and the inner medullary collecting duct. Short-looped nephrons have all the same segments except that they have only one type of thin limb segment and it comprises a portion of the descending limb of Henle’s loop. ’ Our understanding of the function of each ofthese tubular divisions has increased immensely, partly because of the study of isolated perfused segments. The whole ofrenal function, however, is greater than the sum of the individual parts. Recently, we have learned much about the interrelations between the elaborate shape of the renal pelvis and the adjacent renal parenchyma, and suggestions have been made concerning the role these structures play in the mechanism of urinary concentration. Furthermore, the functional interactions of various nephron scgments located in specific zones within the kidney are now also receiving increased interest. Downloaded from tpx.sagepub.com at PENNSYLVANIA STATE UNIV on March 4, 2014 14 BULGER TOXICOLOGIC PATHOLOGY FIG.1.-Electron micrograph from a renal.corpuscle showing a capillary loop (C), podocytes (P), and rnesangial cells (M). ~6,300. Nephrons are typed as superficial, midcortical, or juxtamedullary on the basis of the position of their renal corpuscle within the cortex, and on the anatomy of their postglomerular blood supply (5, 6, 1 1, 12,46, 59). Nephrons are classified as short-looped if their loops of Henle turn in the outer medulla, or long-looped if the loops of Henle turn in the inner medulla. This paper will stress new findings and assumes that the reader possesses a basic knowledge of renal anatomy. RENALCORPUSCLE The renal'corpuscle, the initial part of the nephron, is a eltration device which forms an ultrafiltrate of plasma (Fig. 1). The double-walled capsule (Bowman's capsule) consists of an outer parietal layer of flattened cells and an inner visceral layer of epithelial cells, known as podocytes, which possess an elaborate octopus-like shape; the capillary lining cells have a fenestrated endothelium consisting of large pores usually lacking diaphragms. A population of mesangial cells is located in the hilar region of each capillary loop in a-position similar to pericytes of other small vessels. A subpopulation of these mesangal cells which display Ia antigens on their ce1.I surface can also be identified. Various cxtraccllular materials contribute to the molecular composition of the glomcrular basement membrane and mesangial matrix. The glomerular basement membrane (GBM) is a complex structure consisting of several type-IV collagens and a type-V (AB2) collagen (82), collagenous plus noncollagenous glycoproteins, and proteoglycans. Two glycoproteins, laminin and fibronectin, have been localized in the glomerulus (1, 66). Laminin was localized in the mesangial matrix, the lamina rara-interna, and adjacent areas of the lamina densa of the GBM, as well as throughout the tubular basement membranes. Fibronectin, secmingly involved in mesenchymal cell adhesion, was found within the mcsangial matrix. A negatively-charged glycoprotein which coats the glomerular epithelial cell (the so-called glomerular polyanion) appears to be involved in podocyte cell shape maintenance. Seiler et al(95,96) demonstrated podocyte cell shape changes after in vivo administration ofpolycations which appeared to neutralize the fixed negative charges of this polyanion. Removal of sialic acid by neuraminidase digestion also resulted in cell shape changes (2). Detachment of the visceral epithelial cells from the GBM could be induced by perfusion of neuraminidase or treatment with puromycin aminonucleoside (52). Concomitant with this detachment, a change in GBM permeability was seen (52). A reduction in glomerular Downloaded from tpx.sagepub.com at PENNSYLVANIA STATE UNIV on March 4, 2014 Vol. 14, NO. 1, 1986 RENAL MORPHOLOGY 15 FIG.2.-Electron micrograph of a proximal convoluted tubule (S, region). Note the extensive microvillus border and interdigitated epithelium. x 9,150. polyanion staining was also seen in certain glomcrular diseases (14), and in aminonucleoside nephrosis (73). This glomerular polyanion has been identified, characterized, and named podocalyxin by Kerjaschki et a1 (53). Using aminonucleoside nephrosis as a model, Kerjaschki et a1 ( 5 5 ) have demonstrated that the loss of epithelial foot processes and filtration slit organization is accompanied by a biochemical defect in sialylation of podocalyxin. Proteoglycans also form an integral part of the filtration bamer and appear to be important in the permeability of the GBM. These molecules consist of a core protein and covalently bound glycosaminoglycans. Using a cationic probe, Kanwar and Farquhar (50) identified a regular lattice-like network of sulfated glycosaminoglycans with a spacing of 60 nm within the lamina rara of the GBM and in the mesangial matrix. To assess the role of these molecules in GBM permeability, irz situ vascular perfusion of glycosaminoglycan-degrading enzymes (heparinase) was done (5 1). Subsequent perfusion with native fenitin demonstrated that a dramatic increase in GBM permeability had occurred. A recent hypothesis suggests that contraction of intraglomerular mesangial cells can effect glomerular function. Contraction of mesangial cells was noted in 1969 by Burnick (1 7). Becker (10) suggested that effects on tuft size and surface area could be caused by mesangial contraction. More recently, Ausiello et a1 (3) showed contraction of cultured Downloaded from tpx.sagepub.com at PENNSYLVANIA STATE UNIV on March 4, 2014 16 TOXICOLOGIC PATHOLOGY BULGER FIG.3.-Electron micrograph of a proximal pars recta tubule (S, region). Note the extensive microvillus border and the cuboidal epithelium. mesangial cells in response to either angiotensin I1 or vasopressin. This evidence correlated with the identification of specific angiotensin I1 receptors on mesangial cells (98). Angiotensin I1 has been postulated as a regulator of intraglomerular blood flow by Schor et a1 (89) since both angiotensin I1 and arginine vasopressin can lead to a decrease in glomerular ultrafiltration coefficient. Streptozotocininduced diabetic rats have a decrease in angiotensin I1 receptor sites (4)which might underlie the hyperfiltration seen in this situation. Kreisberg (57) has demonstrated that cultured mesangial cells do not contract without insulin. Since catecholamines can influence glomerular hemodynamics, Kreisberg et a1 (58) exposed mesangial cells in culture to hi norepinephrine, epinephrine or isoprotcronol. These agents elevated intraccllular cyclic AMP levels nearly threefold. More than half of the cells underwent a shape change with this exposure. PGE, restored or inhibited the cell shape and attenuated the cyclic AMP generation. . A subpopulation of glomcrular mesangial cells, which resemble Kupffer cells, has been recently identified by Schreiner and Unanue (90) in rats. These cells are phagocytic, display Ia surface antigens, can take up antigen, and stimulate lympho- cytes. Total body irradiation induced progressive loss of these cells after three days; however, the cells were restored by transplantation of syngeneic bone marrow (90). The role of these cells in various disease processes has been investigated (9 1). TUBULE The nomenclature which divides the proximal tubule into a convoluted and straight portion has been largely replaced by one using three specific segments designated S,,S,, and S, (or PI, P,, and P,) on the basis of cell height; cell shape and organelle content (71). The part designated as the proximal convoluted tubule includes the entire S, region and the first part of the S, region (Fig. 2). The pars recta, seen in the medullary ray and outer stripe of the outer zone of the medulla, includes the last part of S, and the entire S3segment (Fig. 3). This new nomenclature is more specific and allows for clearer definitions of relationships between structure and function. For example, it has long been known that the pars recta was involved in para-aminohippuric acid (PAH) secretion but only recently has it been shown that the cortical S, segment of the pars recta is a much more efficient pump then either the S, or S3 segments (107). There is a marked amount of PROXIMAL Downloaded from tpx.sagepub.com at PENNSYLVANIA STATE UNIV on March 4, 2014 Vol. 14,No. 1, 1986 RENAL MORPHOLOGY species variation in morphology seen in the proximal tubule, so cross species generalizations can lead to erroneous interpretations. The S , and S , segments are both composed of cells with. extensive lateral interdigitating projections which contain numerous mitochondria. This arrangement results in the formation ofan extensive system of lateral intercellular membranes adjacent to the cell mitochondria. The cells are held together by shallow tight junctional regions at their apical borders. These junctions and the lateral intercellular spaces form a low resistance shunt pathway. Thus, it was believed that the proximal tubule reabsorbed isosmotic fluid by utilizing a standing gradient hypothesis. Newer evidence from several la6oratories has shown that small but important osmotic gradients develop across the entire proximal tubule, and that these gradients can drive transepithelial volume flow (7, 32, 65, 84). The extensive reabsorption of glucose, amino acids and bicarbonate by the brush border membrane generates a luminal hypotonicity which serves as an osmotic driving force for water reabsorption. Kerjaschki et a1 (54), using a monoclonal antibody for maltase, localized this glycoprotein to the lateral surface of proximal tubule microvilli. The Na+K+ATPasein the basolateral membrane maintains the sodium electrochemical gradient. The proximal tubulc is frequently the site ofinjury after various insults. A common site within the proximal tubule is in the S, segment, within the outer stripe of the medullary outer zone. Agents which preferentially induce necrosis in this region include mercuric chloride (1, 19, 3 3 , uranyl nitrate (28, 37, loo), cis-platinum (22), renal arterial occlusion in rats (30, 31, 103, 104) and hemorrhagic shock (2 1). With high doses of many of these agents, necrosis Will extend up the ray and into the proximal convolutions. One possible explanation for these findings might be related to blood supply. The majority of the capillary vessels in the outer stripe region have been said to be ascending vasa recta which contain venous blood from the inner medulla (6, 59). However, recently Yamamoto et a1 (108), using resin casts instead of silicone rubber casts, has demonstrated a rich capillary network in the outer stripe. T I i I N Llh1B.S Four kinds of thin limb regions have been identified (8, 9, 20, 24, 59, 61, 93, 94): descending thin limbs of short-looped ncphrons, upper descending thin limbs of long-looped nephrons, lower descending thin limbs of long-looped nephrons, and ascending thin limbs of long-looped'nephrons. Their characteristics differ from each other in the following ways: 1) the number of intramembranous par- 17 ticles in the cell membranes (94), since the density of these particles is thought to be related to transepithelial water flux; 2) the depth (number ofstrands) of the tight junction is perhaps related to ion permeability; 3) the degree ofcell interdigitation which is related to the overall length of the paracellular pathway and presumably to ion permeability; 4) the cellular organelles which will influence cell function such as the number of mitochondria being related to the degree of energy production, the amount of basolateral cell membrane to the number of Na+K+ATPasesites, and the number of microvilli related to some aspect of surface transport. The descending thin limb of short-looped nephrons from all species studied has a relatively small diameter and is lined by flat, simple non-interdigitating cells with few microvilli, few mitochondria, a tight junction with several strands (94), and few intramembranous particles. Such an epithelium would be expected to have a low permeability to sodium chloride and water, and be fairly inactive in transport processes. The small diameter would be consistent with a low flow per nephron. In some species which are good concentrators such as rat (60), mouse (62), Psantnionzys (48), and Perognathus (73,the descending thin limbs of short-looped nephrons lie in the vascular bundles in close approximation to ascending vasa recta where exchange of substances such as urea could easily occur. In other species, they surround the vascular bundles or lie in the interbundle region, Morphologic differences have been reported in thc upper descending thin limb of long-looped nephrons of various species. In the rat, mouse, and desert rodents (8,9, 20, 62, 75, 93, 94), the epithelial cells which line this segment are joined by shallow tight junctions and have extensive intercellular interdigitations, numerous microvilli, and many mitochondria (Fig. 4). They run in the interbundle region. This region stains positively for Na+K+ATPase(69), and carbonic anhydrase in mouse (23). The cells have a high density-of intramembranous particles (94). This region of the thin limb epithelium would be expected to have an extensive paracellular shunt pathway, the ability to transport solutes, and a high water permeability. In other species, such as the rabbit (46), a less interdigitated epithelium containing fewer organelles and a deeper tight junctional region is seen. Carbonic anhydrase activity was seen fa-intly in the lumen (23). As the long-looped thin limb descends into thc inner medulla it assumes a simplified form lined by flat, less interdigitating cells with multiple strands in the tight junction, few microvilli, and an intermediate number of intramembranous particles. This morphology would bc consistent with a relatively Downloaded from tpx.sagepub.com at PENNSYLVANIA STATE UNIV on March 4, 2014 18 BULGER TOXICOLOGIC PATHOLOGY FIG. 4.-Electron micrograph of an upper descending thin limb segment characterized by an elaborately-shaped epithelium with interdigitating processes. x 13,100. FIG.5.-EElectron micrograph ofa medullary thick segment from the distal tubule. x 12,600. high permeability to water, but a decreased passage of sodium chloride. In animals on reduced dietary protein, Schmidt-Nielsen et a1 (88) showed a significant thinning in the wall of the descending limbs of long-looped nephrons. The ascending thin limb, present only in long-looped nephrons, usually begins just prior to the bend in the loop and is lined by a highly interdigitated epithelium containing few mi- Downloaded from tpx.sagepub.com at PENNSYLVANIA STATE UNIV on March 4, 2014 Vol. 14, No. 1, 1986 RENALMORPHOLOGY tochondria and joined by relatively shallow but tight junctions with single thick strands. It is similar in all species studied. The prominent paracellular pathway of this epithelium would indicate a high ion permeability but not with extensive active transport. This would be consistent with the passive efflux of sodium chloride postulated for this region. DISTAL TUBULE The distal tubule is now generally divided into an MAT which runs through the inner and outcr stripe regions of the outer medulla, a CAT, and a distal convoluted tubule (DCT). The macula densa is a specialized region near the end of the CAT. It is continuous with a short post-macula densa segment which converts to the distal convoluted tubule (46). The MAT and the CAT differ both in morphology and function. The MAT, especially in the inner stripe, is characterized by tall cells which are highly interdigitated and have shallow tight junctions (Fig. 5). Numerous mitochondria fill the interdigitating cell projections. The MAT traverses the inner stripe region, gradually decreases in cell height in the outer stripe region, and becomes the CAT in the medullary ray. The CAT therefore has a lower cell height and more simplified cell shape. The MAT and CAT demonstrate several physiological differences, especially with respect to hormone responsiveness (1 5 , 18,38,39, 102). The MAT region has a high density of Na+K+ATPase(72). Hebert et al(42) have shown that ADH increased the transepithelial voltage and net chloride absorption in the MAT (but not CAT) of the mouse. Kone et a1 (56) has quantitated the morphology of the ascending thick limb in the inner stripe, outer stripe, and inner cortex in rat kidney. The ascending thick region functions in the flowdependent absorption of sodium chloride in which there is co-transport of Na+2CI K+ (33, 34). The MAT and CAT vary in basal transport rates and susceptibility to hormone stimulation. Sasaki and Imai (83), and Hebert et a1 (42) have shown that sodium chloridc reabsorption is stimulated by antidiuretic hormone. The DCT (Fig. 6) can reabsorb sodium chloride against a steep chemical gradient. It contains the greatest amount of Na+K+ATPase(72, 85), which is present on its basolateral plasma membrane (26). This region does not appear to be sensitive to ADH (36, 44, 106). Recent work indicates that the DCT does not respond to aldosterone (25, 70). Proliferation of the DCT has been shown to correlate with an increase in active sodium reabsorption (45). Recently, Kaissling et a1 (49) demonstrated a marked structural adaptation of the distal convoluted tubule to an increased sodium load produced by furosemide administration over a 6-day period. The kidney responded by enlargement of the 19 cortex, proliferation of the distal convoluted tubules, and an increase in DCT basolateral cell membrane volume. CONNEC~ING TUBULE A well-dcfined connecting tubule (CnT) has been identified between the DCT and the cortical collecting duct (CCT) in the rabbit kidney (46). Similar segments appear to be present, although less well demarcated, in other species. Each superficial nephron empties directly into a cortical collecting duct via a connecting tubulc. The arcades formed by deeper nephrons are also considered to be connecting tubules. Two cell types comprise this segment. The connecting tubule cell is characterized by extensive true infoldings of the basal cell membrane which extend deep into the cells separated by the mitochondria. The intercalated cell of the connecting tubule is similar to its namesake seen in the collecting duct system. There is controversy as to whether the connecting tubule is part of the DCT of thc nephron (derived from metanephric blastema) or part of the collecting duct system (derived from the ureteric bud). Oliver (77), Potter (80), and Neiss (76) support the metanephric blastema as the source, while Peter (78) believes that the arcades arise from the ureteric bud. The morphology of the CnT, however, more closely resembles the collecting duct. Morel (74) demonstrated differences between argininc vasopressinsensitive, parathyroid-sensitive, and synthetic calcitonin-sensitive adenyl cyclase activity in the rabbit between the DCT and CnT. The CnT cell displays an amplification of basolateral cell membrane area in situations with a low sodium and high potassium intake and a high plasma aldosterone level. Stanton et al (99) using rats and Kaissling and Le Hir (47) using rabbits have shown an increase in membrane arca of the CnT. When an inhibitor of aldosterone production (canrenoatc K) was administered in the rabbit experiment cited above, the membrane amplification was still present in the beginning of the CnT but not near the end. COLLEC~ING Ducrs The collecting ducts are divided into cortical collecting ducts, outer medullary collecting ducts, and inner medullary collecting ducts. The cortical collecting ducts are lined by principal (light) cells and intercalated (dark) cells (Fig. 7). The collecting ducts. are the final regulators of fluid and electrolyte balance and play key roles in the handling of sodium, chloride, potassium and acid-base balance. The collectingduct system is a major site ofaction for ADH, and hence plays a critical role in urine concentration. Downloaded from tpx.sagepub.com at PENNSYLVANIA STATE UNIV on March 4, 2014 20 BULGER TOXICOLOGIC PATHOLOGY F ~ G6.-Electron . micrograph from a distal convoluted tubule. This segment contains abundant mitochondria, and intcrdigitating epithelial cells. x 7,750. FIG.7.-Electron micrograph of a collecting duct lined by intercalated cells (I) and principal cells (P). x 8,000. Downloaded from tpx.sagepub.com at PENNSYLVANIA STATE UNIV on March 4, 2014 Vol. 14, No. 1, 1986 RENAL MORPHOLOGY The cortical collecting duct is the targct tissue for aldosterone (70). The principal (light) cell is most numcrous. It has pale cytoplasm with a few oval mitochondria, frequent infoldings of the basal cell membrane, short apical microvilli, and relatively long tight junctions. Dramatic increascs in basolatcral membrane surface density have bcen measured in principal cells after potassium adaptation or by high endogenous or cxogenous mincralocorticoid levels which increase potassium sccretion along the collecting ducts (47, 81, 99, 105).The second cell type called the intercalated cell is prescnt in both the CnT and CCT. Thcy are mainly seen in cortical and outer medullary regions of the collecting duct system; however, occasional dark cells arc present even in the inner medulla of some species. Kaissling and Kritz (46) estimate 33% intercalated cells in the rabbit cortical collecting duct, and 50% in the outer medullary collecting duct. The intercalated cells generally are characterized by lum i n d extensions (microvilli or microplicac), a cytoplasm with more ribosomes, and more mitochondria than seen in the light cells, which leads to their darker staining characteristics. Two morphological variants of the intercalated cell have been identified (46,60) in the rabbit. The grey manifestation stained lighter and contained many spherical or flat cytoplasmic vesicles while the black manifestation stained more densely. Medullary intercalated cells in rats on a high potassium diet have a small luminal membrane area and the cell apcx contains numerous vesicles (8 1). However, when rats are fed a low potassium diet there is an increase in luminal membrane area and fewer apical vesicles (101). These changes would be consistent with a function for some of the intcrcalated cells of potassium reabsorption. The intercalated cells ofthe cortcx, however, respond to dietary potassium in a different manner (47). Similar increases in the amount of apical plasma membrane with a decrease in tubulovesicular profiles within the apical cytoplasm were seen in intercalated cells of the outer medulla in acute respiratory acidosis (67) and in chronic metabolic acidosis (68) in rats. These authors postulated that hydrogen ion pumps were inscrtcd into the luminal membrane by the fusion of thc apical vesicles with the apical cell mcmbranc. The inner collecting duct is lined almost entirely by light cells which contain fcw mitochondria and only a fcw small basal intcrdigitations. In spite of this rather simple structure, inner medullary collccting ducts can reabsorb ions from the urine and secrete potassium and hydrogen ions against high concentration gradients (1 3, 43). A dose-related increase in the number of clusters of intramembrane particles has bcen dcmonstratcd, 21 using freezc-etch tcchniqucs, in the luminal membrane of the papillary collecting duct after antidiuretic hormone treatment (40, 41). The renal pelvis, major and minor calyces, and their blind ending fornices have been viewed mainly as passive receptacles, but it is becoming clear that they play a vital rolc in renal concentrating me’chanisms. Pfeiffer (79) divided animals into those with renal pelves of simple and complex shape. Species with complex shaped renal pelves had the ability to increasc urine concentration in response to dietary protein. This complex shape was associated with the increase in surface area of rcnal medulla exposed to thc pelvic urine. In fact, Lacy (63) has demonstrated that the area of pelvic surface in a variety of rodents correlates with the urine concentrating ability. Although the functional significance to the concentration process is not yet clearly understood, a variety of investigators are involved in research aimed at understanding these interrelationships (29, 64,86,87,92). 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