Urinary System Anatomy and Physiology PDF

11/29/2023 URINARY SYSTEM Dr Neha Mishra Kumar V, Abbas AK, & Astor, JC. Robbins Basic Pathology, 10th edition Zachary JF, and McGavin MD. Pathologic Basis of Veterinary Disease, 6th edition, Elsevier, 2017 Young et al. Wheater’s Functional Histology: A Text and Colour Atlas, 5th or 6th ed. 1 Uri...

11/29/2023 URINARY SYSTEM Dr Neha Mishra Kumar V, Abbas AK, & Astor, JC. Robbins Basic Pathology, 10th edition Zachary JF, and McGavin MD. Pathologic Basis of Veterinary Disease, 6th edition, Elsevier, 2017 Young et al. Wheater’s Functional Histology: A Text and Colour Atlas, 5th or 6th ed. 1 Urinary system anatomy • Divided into upper and lower urinary tract – Upper urinary tract: kidneys – Lower urinary tract: ureters, urinary bladder and urethra • Kidney provides for elimination of excess water and electrolytes in the form of urine • Ureters, bladder and urethra serve as the storage and outflow tract – No modification of the urine occurs after it leaves the kidneys • Blood supply by one main branch from the aorta: renal arteries • Blood drains via renal veins to the inferior vena cava 2 3 1 11/29/2023 Functions of the kidney • Maintenance of water and electrolyte balance = osmoregulation (regulation of osmotic concentration of blood plasma and hence all other body fluids) – Eliminates or conserves water and electrolytes • Regulation of acid-base balance • Excretion of toxic metabolic waste products – urea and creatinine • Hormonal and metabolic functions – Synthesis of renin, which regulates blood pressure via reninangiotensin-aldosterone system – Synthesis of erythropoietin, which regulates erythropoiesis – Conversion to active form of vitamin D, which regulates calcium balance 4 General Structure of the kidney 5 General Structure of the kidney • Cortex – Outer zone covered by fibrous capsule – contains the renal corpuscles and proximal and distal segments of tubules of nephrons • Medulla – Inner zone forms one or more coneshaped pyramids (depending on species) – Apex of each pyramid is a renal papilla – Nephrons arise in the cortex, loop down into medulla (loop of Henle), return to cortex, then drain into collecting ducts that descend into the medulla and discharge at the renal papilla (via ducts of Bellini) 6 2 11/29/2023 General Structure of the kidney • Hilus, pelvis, calyx – Hilus is indented area of the kidney where the blood vessels and ureter enter and exit – Pelvis is the enlarged, funnelshaped proximal portion of the ureter – Calyx is a branching portion of the pelvis that collects the urine in a multilobular (multipyramidal) kidney – =Pelvicalyceal system: urinary collection system of the kidney consisting of pelvis and its branches • Renal Sinus – Space around pelvis and between calyces filled with fatty tissue 7 Lobulation • Varies by species • Lobe = discrete regions of cortex and medulla (pyramid plus overlying cortex) • Multilobular (multipyramidal) = kidney divided by fissures into smaller individual units containing cortex and medulla – e.g. bovids – In adult humans and pig, cortex is fused but medulla is separated • Unilobular (unipyramidal) = no anatomic subdivision into lobes – e.g. sheep, goat, horse, dog, cat, rodents – Papillae fused into ridge also called the renal crest 8 9 3 11/29/2023 The Nephron • Basic functional unit of the kidney • Consists of (1) the renal corpuscle and (2) the renal tubule – 1-4 million per kidney • Renal corpuscle consists of Bowman’s capsule and the glomerulus • Renal tubule extends from Bowman’s capsule to junction with collecting duct – consists of four segments: • (1) proximal convoluted tubule (PCT) • (2) loop of Henle • (3) distal convoluted tubule (DCT) • (4) collecting tubule 10 11 Renal vasculature • Renal artery & vein: enter and exit at the hilus • Interlobar: to corticomedullary junction • Arcuate: parallel with cortical surface at corticomedullary junction • Cortical radial (interlobular): radiate into cortex, give rise to the afferent arterioles of the glomerulus • Afferent arterioles: enter glomerulus  glomerular capillary bed • Efferent arterioles: exit glomerulus  peritubular capillary plexus or vasa recta – Peritubular capillary plexus: arise from efferent arterioles of glomeruli in outer cortex – Vasa recta: capillary loops arise from efferent arterioles of glomeruli near corticomedullary junction • penetrate deep into medulla around the loops of Henle and collecting ducts 12 4 11/29/2023 13 14 15 5 11/29/2023 Renal cortex • Identified by presence of renal corpuscles (NOT found in the medulla) • Bulk of the cortex is from PCT and DCT • Bundles of collecting tubules and ducts extend through cortex to medulla as medullary rays • Arcuate arteries and veins at corticomedullary junction also demarcate cortex from medulla 16 17 Renal corpuscle Consists of Bowman’s capsule and the glomerulus • Bowman’s capsule is derived from a blind-ended metanephric tubule that dilates and surrounds the glomerulus • Glomerulus is a mesoderm-derived tuft of anastomosing capillaries formed between the afferent and efferent arterioles, which invaginates into the blindended developing tubule – Becomes covered with an epithelial layer and its associated basement membrane derived from the tubule: visceral layer of Bowman’s capsule 18 6 11/29/2023 Renal corpuscle • • Has a vascular pole where arterioles enter and exit and an opposite urinary pole where glomerular filtrate drains into proximal convoluted tubule (PCT) Bowman’s capsule consists of a parietal (outer) and visceral (inner) layer of flattened epithelial cells resting on a basement membrane – Parietal layer is simple squamous epithelium • continuous with epithelium of PCT at urinary pole – Visceral layer is simple epithelium with specialized features • Composed of podocytes – Layers are continuous at the vascular pole – Space between visceral and parietal layers is Bowman’s space • Collects the glomerular filtrate • Exiting efferent arteriole has smaller diameter than entering afferent arteriole – creates a pressure gradient to drive filtration of the plasma into Bowman’s space 19 20 Glomerulus • Afferent and efferent arterioles • afferent arteriole branches to form capillary tuft • Capillaries • lined by fenestrated endothelium • Glomerular basement membrane • shared by BOTH capillary endothelium and podocytes • Mesangium • basement membrane-like material between capillary loops with embedded mesangial cells • PAS-positive 21 7 11/29/2023 22 23 Glomerular filtration barrier • Filtration of plasma from glomerular capillaries into the renal tubule forms the glomerular ultrafiltrate – Composed of water and low molecular weight molecules – Processed into urine in the tubule • Filtrate passes through 3 layers: 1. capillary endothelium 2. glomerular basement membrane (GBM) 3. podocyte layer 24 8 11/29/2023 Glomerular filtration barrier • Capillary endothelium – Contains numerous 70-100 nm diameter fenestrations – Fenestrations lack diaphragms – Luminal surface of endothelium is negatively charged due to surface layer of glycoprotein, called podocalyxin 25 Glomerular filtration barrier • Glomerular Basement Membrane (GBM) – Derived from capillary endothelium and podocytes – Thicker than other basement membranes – Composed of type IV collagen, structural glycoproteins (fibronectin, laminin) and proteoglycans (heparin sulphate) – 3 layers on EM: central thick lamina densa with thin lamina rara on either side • Lamina rarae are negatively charged 26 Glomerular filtration barrier • Podocytes – Podocytes have long cytoplasmic extensions called primary processes that cover capillaries and give rise to secondary foot processes (pedicels) – Secondary foot processes of adjacent podocytes interdigitate – Gaps between adjacent foot processes known as filtration slits • Have a uniform 40 nm width • Slit diaphragms bridge filtration slits – Urinary surface also covered by podocalyxin 27 9 11/29/2023 28 Glomerular filtration barrier • Macromolecules >MW 68 KDa are retained in the plasma, whereas those <MW 68 KDa or smaller pass through the barrier – e.g. free hemoglobin passes but albumin does not • Three factors determine permeability for macromolecules: (1) electrical charge, (2) size and (3) configuration – Negatively charged coat on endothelial cell plasma membrane and BM blocks negatively charged molecules – Lamina densa of GBM discriminates by size and configuration (i.e. shape) – Water movement controlled by slit diaphragms of podocytes and colloidal osmotic pressure of retained albumin in capillaries 29 30 10 11/29/2023 Mesangium • Spaces between capillary loops filled by basement membrane-like material called mesangium – Continuous with capillary side of glomerular basement membrane • Has embedded mesangial cells – cells with dark nuclei and irregular shapes – have long cytoplasmic processes that ramify through the mesangium and form cell junctions with processes of other mesangial cells – Functions: • • • • Support capillaries Secrete mesangial matrix Secrete vasoactive chemical mediators Phagocytic and contractile 31 32 33 11 11/29/2023 Glomerulonephritis 34 Duck with mycobacteriosis 35 Amyloidosis 36 12 11/29/2023 http://www.renaldigest.com/cgibin/nephrology/book_perm 37 Renal Tubule • Extends from Bowman’s capsule to junction with collecting duct – consists of four segments: • (1) proximal convoluted tubule (PCT) • (2) loop of Henle • (3) distal convoluted tubule (DCT) • (4) collecting tubule • Forms urine from glomerular ultrafiltrate • PCT, DCT and collecting tubule found in cortex 38 Proximal convoluted tubule • Confined to the cortex • Longest and most convoluted segment of renal tubule • Reabsorbs ~65% of glomerular filtrate (water, ions, glucose, amino acids, protein) – Epithelium structured to allow maximum reabsorption: • Simple cuboidal w/ prominent brush border consisting of long microvilli – PAS-positive since surfaces of microvilli coated by a glycocalyx • Numerous mitochrondria to make energy for absorption processes • Lysosomes to degrade reabsorbed protein • Prominent pinocytotic vesicles and endocytic vesicles • Surrounded by rich capillary network arising from efferent arteriole (peritubular capillary plexus) – reabsorbed molecules returned to circulation • Segment of tubule highest in cytochrome P450, major detoxification enzyme 39 13 11/29/2023 40 Ultrastructure of PCT • Lining cells have multiple lateral processes that interdigitate to form the complex lateral intercellular space – lateral intercellular space has the plasma membrane area equivalent to that of the luminal space – separated from the lumen by ring of junctional complexes near the luminal surface • Mitochondria in these processes are elongated and stacked vertically (can give striated appearance to cell) – supply ATP for Na-K-ATPase pump to actively transport Na+ into the intercellular space – movement of Na+ out of cell is accompanied by facilitated transport of Na+, glucose and amino acids into the PCT cells – almost 100% of filtered glucose and amino acids are reabsorbed by PCT – water follows Na+ so that most of the filtrate water is reabsorbed as well 41 42 14 11/29/2023 43 Distal convoluted tubule • Found in the cortex amongst the proximal convoluted tubules • Continuation of thick ascending limb of Henle after its return to cortex • First part forms the macula densa (chemoreceptor portion of juxtaglomerular apparatus) • Compared to PCT, DCT has: – – – – Short cuboidal epithelium, NO microvilli Larger, more clearly defined lumen More nuclei per cross-section and paler cytoplasm Fewer numbers seen in sections • Main function is maintenance of acid-base balance through reabsorption of Na+ in exchange for H+ or K+ – Acid-base maintenance by DCT controlled by aldosterone (produced by adrenal cortex) 44 45 15 11/29/2023 Ultrastructure of DCT • Similar to PCT – Lateral cell interdigitations – Large numbers of mitochondria • BUT lacks a brush border • Na+/K+ ATPase in basolateral membrane • Drives exchange of Na+ and K+ or H+ at the apical surface 46 Juxtaglomerular apparatus • Specialization of the glomerular afferent arteriole and DCT of the same nephron • Regulation of systemic blood pressure via reninangiotensinaldosterone system (RAAS) • Composed of: DCT comes in close proximity to glomerulus. DCT cells become modified to macula densa Juxtaglomerular cells of the afferent arteriole – (1) juxtaglomerular cells of the afferent arteriole – (2) macula densa of DCT – (3) extraglomerular mesangial cells Lacis cells 47 Juxtaglomerular apparatus (JGA) • Macula densa are darker staining, taller epithelial cells of the DCT located adjacent to vascular pole of glomerulus • Juxtaglomerular cells are modified smooth muscle cells of afferent arteriole just before entering glomerulus • Extraglomerular mesangial cells lie between afferent and efferent arterioles and macula densa 48 16 11/29/2023 49 Renin-Angiotensin-Aldosterone System • JGA acts as both baroreceptor and chemoreceptor – Macula densa detects decreased sodium concentration of fluid in DCT – indicates decreased glomerular filtration rate (GFR) – Juxtaglomerular cells detect decreased blood pressure in afferent arteriole  secretion of renin from juxtaglomerular cells • Renin (enzyme) converts angiotensinogen to angiotensin I in blood • Angiotensin converting enzyme (ACE) in the lung converts angiotensin I to angiotensin II • Angiotensin II raises BP by: (1) peripheral vasoconstriction, (2) promoting release of aldosterone, (3) promoting Na+ (and water) reabsorption in DCT expands plasma volume & increases BP 50 Macula densa role: baroreceptor, will recognize pressure and also osmoreceptor Renal medulla • Consists of closely packed tubules of two types: • (1) the loop of Henle and • (2) the collecting tubules and ducts • Also contains the vasa recta (capillary network around loop of Henle) • Collecting ducts empty at the papilla into the pelvicalyceal system 51 17 11/29/2023 Loop of Henle • Composed of four parts that dive into the medulla: – Thick descending limb (AKA pars recta of the proximal tubule; proximal straight tubule) – Thin descending limb – Thin ascending limb – Thick ascending limb (AKA pars recta of distal tubule; distal straight tubule) • Cortical nephrons have short loops that reach into the outer medulla • Juxtamedullary nephrons have long thin loops extending into the inner medulla 52 Loop of Henle • Function of loop of Henle is production of an increasing osmotic gradient in medulla by countercurrent multiplier mechanism • Thin descending limb is freely permeable to water BUT impermeable to Na+ and Clwater flows into the medullary interstitium making urine hyperosmolar 53 Loop of Henle • Thick ascending limb is impermeable to water and actively transports Na+ and Cl- into medullary interstitium against a concentration gradient  leads to build-up of Na+ in the medulla that produces hyperosmolar environment (high osmotic pressure) – Glycocalyx composed of Tamm-Horsfall protein (glycoprotein unique to the thick ascending limb) 54 18 11/29/2023 Loop of Henle • Limbs of loops of Henle are closely associated with the capillary loops of the vasa recta in the medulla • vasa recta recovers water from medullary interstitium and carries it to general circulation maintains high ion 55 Medulla • Thin limbs lined by a simple squamous epithelium – Similar to capillaries, but no erythrocytes in lumen • Thick limbs lined by a low cuboidal epithelium • Collecting tubules lined by low cuboidal epithelium similar to thick ascending limb • Collecting ducts lined by cuboidal to columnar epithelium – Large diameter 56 57 19 11/29/2023 Collecting tubules and ducts • Collecting tubules (connecting segment) join distal convoluted tubule to collecting duct – Several collecting tubules empty into each collecting duct • Collecting ducts are long straight tubules that connect nephron to renal papilla – Collecting ducts descend through cortex in parallel bundles known as medullary rays – Ducts progressively merge in medulla to form ducts of Bellini, which drain urine from papilla into pelvis • Renal pelvis lined by transitional epithelium (extension of ureter) 58 Renal Papilla 59 Urine Concentration • Epithelial cells of collecting tubules and ducts have tight junctions to retain water • Antidiuretic hormone (ADH, vasopressin) secreted by pituitary gland in response to dehydration increases water permeability in collecting tubules and ducts – water flows into hyperosmolar medulla – results in passive water reabsorption from filtrate  more concentrated urine – vasa recta returns water to circulation • Hyperosmolarity of medulla produced by action of loop of Henle and passive diffusion of urea into interstitium from collecting duct • Hyperosmolarity of medulla and ADH provide means of making urine that is hyperosmotic to plasma, i.e. conserving water 60 20 11/29/2023 61 Lower urinary tract • Includes renal pelvis and calyces, ureters, urinary bladder, urethra • Passage/storage of urine – NO modification after leaving kidney • Ureter – Muscular tubes carry urine from kidney to bladder – Lined by transitional epithelium (AKA urothelium) – Lamina propria underlies epithelium – 2-3 layers of smooth muscle (may be difficult to distinguish from each other) – Outer layer is adventitia 62 Urinary Bladder • • • • Lined by transitional epithelium Substantial elastic fibers in lamina propriasubmucosa 3 variably distinct layers of smooth muscle Outer adventitia 63 21 11/29/2023 64 Urethra • Passage from bladder to external • Short in females; long penile urethra in males • Transitional epithelium near bladder  stratified cuboidal or pseudostratified columnar  stratified squamous at the external orifice • Paraurethral glands in subepithelial stroma produce mucoid secretion Can see change from transitional epithelium to cuboidal At external opening → stratified squamous Keeps area lubricated; is tougher epithelium Near the opening → stratified cuboidal or pseudostratified columnar Near bladder is transitional epithelium 65 Renal Disease • Disease of the kidney are divided into those that affect four basic anatomic components – – – – Glomeruli Tubules Interstitium Blood vessels • Damage to one component often secondarily affects another • All forms of chronic disease ultimately damage all four anatomic components, culminating in end stage kidney disease 66 22 11/29/2023 Clinical Manifestations of Renal Disease • Azotemia refers to an elevation of blood urea nitrogen and creatinine levels and is largely related to decreased glomerular filtration rate (GFR) – Prerenal azotemia refers to the occurrence of azotemia from conditions that exert their effect prior to the formation of urine and in the absence of parenchymal damage • hypoperfusion of the kidneys which decreases GFR (e.g. shock) – Postrenal azotemia refers to the occurrence of azotemia from conditons that exert their effect after the formation of urine • urine flow is obstructed below level of kidney (e.g. calculus) • Uremia occurs when azotemia progresses and is characterized not only by failure of renal excretory function but also metabolic and endocrine alterations – Uremic gastritis, peripheral neuropathy, pericarditis 67 Uremia → seeing uric damage; ulceration on tongue; mineralization on lining of stomach; all damage that excess uric acid can do Most common is prerenal azotemia: can result from shock, hypotension; Exam: absence of parenchymal damage in prerenal azotemia Major Renal Syndromes • Acute nephritic syndrome • Nephrotic Syndrome – glomerular syndrome; acute onset hematuria, mild to moderate proteinuria, azotemia, edema, hypertension – glomerular syndrome; severe proteinuria, hypoalbuminemia, severe edema, hyperlipidemia, lipiduria • Asymptomatic hematuria or proteinuria • Rapidly progressive glomerulonephritis • Acute renal failure – Manifestation of subtle or mild glomerular abnormalities – loss of renal function in days or few weeks; microscopic hematuria and red blood cells casts – oligouria or anuria; recent azotemia; results from lesions to any of 4 anatomic components of the kidney • Chronic renal failure • Urinary tract infection • Nephrolithiasis – prolonged signs of uremia; end result of all chronic renal diseases – bacteriuria and pyuria; pyelonephritis or cystitis Nephritis of pelvic area Gastric ulcers, hemorrhages Anemia due to lack of erythropoietin – stones; signs include renal colic, hematuria In urethra, kidney, etc. 68 Glomerular Diseases •Glomerular diseases are a major problem in nephrology •Chronic glomerulonephritis (GN) is one of most common causes of chronic kidney disease •Nephrin is the major glycoprotein component of the slit diaphragms and maintains the glomerular barrier function 69 23 11/29/2023 70 Pathogenesis of Glomerular Diseases • Primary glomerular diseases are those in which the kidney is the only or predominant organ involved • Secondary glomerular diseases are those in which glomeuli are injured in the course of systemic diseases • Immune mechanisms underlie most types of primary glomerular diseases and many secondary glomerular diseases • Two forms of antibody-associated injury – Injury resulting from deposition of soluble circulating antigenantibody complexes in glomerulus – Injury by antibodies reacting in situ within the glomerulus, either with intrinsic fixed glomerular antigens or with extrinsic molecules planted within the glomerulus 71 Nephritis caused by circulating immune complexes • Complexes are formed in circulation and trapped in the glomeruli where they activate complement and recruit leukocytes • Glomerular lesions usually consist of leukocyte infiltration (exudation) into glomeruli and proliferation of endothelial, mesangial, and parietal epithelial cells • Electron microscopy reveals immune complexes as electrondense deposits or clumps that lie at one of three sites: – in the mesangium, – between endothelial cells and GBM (subendothelial) – between outer surface of GBM and podocytes (subepithelial) • Using fluorescent labeling with anti-Ig or anti-complement antibodies, the immune complexes are seen as granular deposits throughout the glomerulus 72 24 11/29/2023 Nephritis caused by in situ immune complexes • Antibodies react directly with fixed or planted antigens in the glomerulus • Anti-GBM antibody glomerulonephritis – Antibodies directed against fixed antigens of GBM – Deposition of these antibodies creates a linear pattern of staining when visualized with immunofluorescence compared to granular pattern – Basement membrane antigen responsible for classic anti-GBM antibody GN is a component of the noncollagenous domain of the alpha3 chain of collagen type IV • Cross-react with basement membrane of alveoli resulting in simultaneous lung and kidney lesions, aka Goodpasture syndrome • Antibodies also react in situ with “planted” nonglomerular antigens that localize to GBM – DNA (affinity for GBM), endostreptosin (Group A streptococci) – Induce a granular pattern of immunofluorescence • Localization of Ag-Ab complexes determines glomerular response – Proximal zone versus distal zones of the GBM 73 74 75 25 11/29/2023 76 Mediators of Immune Injury • • • • • The principal pathway of antibody-mediated glomerular injury is complement-leukocyte-mediated Complement leads to generation of chemotactic agents and recruitment of neutrophils and monocytes – Release proteases, reactive oxygen species, arachidonic acid Also, complement-dependent but not neutrophil-dependent injury due to the effect of the membrane attack complex (C5-C9) – Injury to epithelial cells – Upregulates TGF-beta receptors on podocytes  synthesis of ECM  altered GBM composition and thickening Antibodies directed to glomerular cells may be directly cytotoxic Other mediators – Monocytes and macrophages – Platelets which aggregate and release prostaglandins and growth factors – Resident glomerular cells can be stimulated to secrete cytokines, arachidonic metabolites, growth factors, NO, and endothelin – Fibrin-related products cause leukocyte infiltration, and glomerular cell proliferation 77 78 26 11/29/2023 Nephrotic Syndrome • Initial event is derangement in capillary wall of glomeruli resulting in increased permeability to plasma proteins • A clinical complex that includes: – – – – – Massive proteinuria, e.g. 3.5gm or more daily Hypoalbuminemia, with plasma levels less than 3gm/dL Edema, progressing to anasarca (generalized edema) Hyperlipidemia and lipiduria AT ONSET, little or no azotemia, hematuria, or hypertension 79 Nephrotic Syndrome • Causes of nephrotic syndrome vary according to age – In children, the cause is almost always a primary lesion of the kidney, e.g. FSGS and minimal-change disease – In adults, almost always due to renal manifestations of a systemic disease, e.g. diabetes, amyloidosis, SLE • Four primary glomerular lesions characteristically lead to nephrotic syndrome: • • • • MCD: Minimal change disease FSGS: Focal and segmental glomerulosclerosis Membranous Glomerulopathy Membranoproliferative GN 80 Minimal change disease (MCD)aka Lipoid Nephrosis •Glomeruli appear normal by light microscopy •GBM appears normal by TEM •Uniform and diffuse effacement of foot processes of podocytes •Cytoplasm of podocytes appears flattened over the GBM •Cells of PCT are laden with protein droplets and lipids (lipoid nephrosis) •No hypertension and normal renal function •Steroid-responsive 81 27 11/29/2023 Focal and segmental glomerulosclerosis •Affects only some glomeruli and initially the juxtaglomerular glomeruli (focal) •Affects some tufts of the glomerulus and not others (segmental) •Lesion is one of increased mesangial matrix, obliterated capillary lumens, and deposits of hyaline masses (hyalinosis) and lipid droplets •Occasional glomeruli are completely affected (global sclerosis) •Nonspecific trapping of IgM and complement in areas of hyalinosis •Effacement of podocyte foot processes seen on TEM •Progresses to global sclerosis, tubular atrophy and interstitial fibrosis •Injury to podocytes is thought to represent the initiating event of primary FSGS 82 Membranous nephropathy •Most common between 30 and 50 years of age •Slowly progressive disease •Characteristic light microscopic change is diffuse thickening of GBM •Caused by subepithelial deposits along the GBM separated by spikelike protrusions of GBM matrix (spike and dome pattern) •As progresses, deposits get incorporated into GBM and there is effacement of foot processes •Granular deposits of Ig and complement along GBM with immunofluorescent staining •Form of chronic immune complex nephritis induced by antibodies reacting to endogenous or planted glomerular antigens, or DNA in SLE 83 84 28 11/29/2023 85 Membranoproliferative Glomerulonephritis •Manifested histologically by alterations in GBM and mesangium and by proliferation of glomerular cells •Type I MPGN seems to result from circulating immune complexes •Type II MPGN seems to be linked to excessive complement activation •By light microscopy, both types have large glomeruli with accentuated lobular appearance, porliferation of mesangial and endothelial cells, infiltrating leukocytes •GBM is thickened, and capillary wall shows double contour – caused by inclusion of processes of glomerular or inflammatory cells 86 •Type I MPGN characterized by subendothelial electrondense deposits •Immunofluorescent labeling of C3 deposited in an irregular granular pattern (immune complex pathogenesis) •Type II MPGN characterized by lesions in the lamina densa and subendothelial space of the GBM, transforming these into a ribbon-like electrondense structure dense deposit disease •C3 is present in irregular deposits 87 29 11/29/2023 88 Nephritic Syndrome • Clinical complex, usually of acute onset, characterized by – – – – Hematuria, with dysmorphic RBCs and RBC casts in urine Oliguria and azotemia Hypertension Proteinuria (but mild, i.e. not severe as in nephrotic syndrome) • Glomerular lesions have in common (1) proliferation of cells in glomeruli accomapnied by (2) leukocyte infiltration • Inflammation cause injury to capillary wall allowing RBCs to escape into urine – Hemodynamic changes result in reduction of GFR • Reduced GFR is manifest as oliguria, fluid retention, and azotemia • Reduced GRF leads to renin release, with fluid retention, results in hypertension 89 Acute Postinfectious (Poststreptococcal) GN • Classic case develops in children 1-4 weeks after recovery from group A streptococcal infection • Characteristic change is fairly unifrom increased cellularity of glomerular tufts that affects nearly all glomeruli (diffuse) due to proliferration of endothelial and mesangial cells and infiltration of neutrophils and monocytes • Most often subepithelial deposits of immune complexes, aka subepithelial humps • Granular deposits of IgG and complement within capillary walls and mesangium 90 30 11/29/2023 IgA Nephropathy (Berger Disease) • Affects children and young adults and occurs as an episode of gross hematuria within 1-2 days of upper respiratory tract infection • Hematuria lasts several days, then subsides, but then recurs every few months • One of the most common causes of recurrent microscopic or gross hematuria and is the most common glomerular disease revealed by renal biopsy • Pathogenic hallmark is deposition of IgA in mesangium • Characteristic immunofluorescent labeling of mesangial deposition of IgA, with C3 and proteins 91 92 Rapidly Progressive (Crescentic) GN • RPGN is a clinical syndrome and not a specific form of GN • Characterized clinically by rapid and progressive loss of renal function with features of nephritic syndrome, severe oliguria, and if untreated, death from renal failure • Regardless of cause, histologic picture is characterized by crescents – Produced by proliferation of parietal epithelial cells of Bowman’s capsule and by infiltration of monocytes and macrophages • Three types of RPGN 93 31 11/29/2023 94 Rapidly Progressive (Crescentic) GN • RPGN is a clinical syndrome and not a specific form of GN • Characterized clinically by rapid and progressive loss of renal function with features of nephritic syndrome, severe oliguria, and if untreated, death from renal failure • Regardless of cause, histologic picture is characterized by crescents – Produced by proliferation of parietal epithelial cells of Bowman’s capsule and by infiltration of monocytes and macrophages • Three types of RPGN 95 • Pauci-Immune (Type III) Crescentic GN – Defined by lack of anti-GBM antibodies or significant immune complex deposition detectable by immunofluorescence – Anti-neutrophil cytoplasmic antibodies in serum – No deposits detectable by EM or by immunofluorescence 96 32 11/29/2023 • Anti-Glomerular Basement Membrane Antibody (Type I) Crescentic GN – Characterized by linear deposits of IgG and C3 along the GBM – Antibodies to collagen type IV antigen endogenous to GBM – Anti-GBM antibodies also bind to pulmonary alveolar capillary basement membranes, aka Goodpasture syndrome – Kidneys are enlarged and pale, often with petechiae hemorrhages on cortical surface – Glomeruli show segmental necrosis and GBM breaks Will be picture on this in exam 97 PAS stain Goodpasture syndrome 98 99 33 11/29/2023 • Immune Complex-Mediated (Type II) Crescentic GN – Complications of any immune complex nephritides, including Poststreptococcal GN, SLE, and IgA Glomelur nephritis nephropathy – Severe glomerular injury with segmental necrosis and GBM breaks – Immunofluorescence reveals granular (“lumpy bumpy”) pattern of the GBM and/or mesangium for Ig and/or complement 100 • Pauci-Immune (Type III) Crescentic GN – Defined by lack of anti-GBM antibodies or significant immune complex deposition detectable by immunofluorescence – Anti-neutrophil cytoplasmic antibodies in serum – No deposits detectable by EM or by Electron micrography immunofluorescence 101 Chronic Glomerulonephritis Chronic renal failure. • Important cause of end-stage kidney disease presenting as chronic renal failure • At the time of diagnosis, glomerular changes so advanced that it is difficult to discern the nature of the original lesion • Kidneys are symmetrically contracted and surfaces are red brown and diffusely granular • Common features histologically are advanced scarring of glomeruli to point of complete sclerosis – Obliteration of glomeruli • Marked interstitial fibrosis associated with atrophy and loss of tubules • Hypertension leads to thickening of walls of small muscular arteries Basement membrane irregular or expanded by collagen deposition. Also blood vessels • Lymphocytic infiltrates in fibrous interstitium 102 34 11/29/2023 Obsolete glomeruli Fibrosis Expande d inflamma tory cells Collagen and inflammatory cells interstitial this is interstitial nephritis 103 Diseases Affecting Tubules and Interstitium • • • • • 104 Diseases characterized by one of the following: 1. Inflammatory involvement of the tubules and interstitium 2. Ischemic or toxic tubular injury leading to acute tubular necrosis and acute renal failure Tubulointerstitial nephritis (TIN) refers to group of inflammatory diseases of the kidneys that primarily involve the interstitium and tubules In most cases of TIN caused by bacterial infection, the renal pelvis is prominantly involved, hence, pyelonephritis, (from Common cause is over consuming Tylenol or ibuprofen pyelo, “pelvis”) Interstitial nephritis is a term reserved for cases of TIN that are nonbacterial in origin Two routes by which bacteria reach the kidney Pyelonephritis affects the pelvic region. 105 35 11/29/2023 Acute Pyelonephritis • Common suppurative inflammation of the kidney and renal pelvis caused by bacterial infection – Enteric gram-negative rods, e.g. E. coli • Great majority associated with infection of the lower urinary tract (cystitis, prostatitis, urethritis) • Discrete, yellowish, raised abscesses are grossly visible on renal surface • Characteristic histologic feature is suppurative necrosis or abscess formation within the renal parenchyma • Large masses of intratubular neutrophils give rise to characteristic white cell casts 106 Bilaterallly, lesions, white raised lesions, pyogenic. Multifocal and disseminated diffusely 107 Chronic Pyelonephritis and Reflux Nephropathy • • • • • Characterized by interstitial inflammation and uneven scarring of the renal parenchyma Hallmark is scarring involving the pelvis or calyces, leading to papillary blunting and marked deformity of pelvicalyceal system Can be divided into two forms Chronic Obstructive Pyelonephritis – Recurrent infections superimposed on diffuse or localized obstructive lesions Chronic Reflux-Associated Pyelonephritis – Rresults from superimposition of UTI on congenital vesicourteral reflux and intrarenal influx 108 36 11/29/2023 Drug-Induced Interstitial Nephritis • Drugs have emerged as an important cause of renal injury • Two forms of TIN caused by drugs are recognized Analgesic Nephropathy •Consumption of large quantities of non-steriodal anti-inflammatory drugs •Development of chronic interstitial nephritis associated with renal papillary necrosis and progressive renal dysfunction •Aspirin and acetominophen are principal drugs involved •Papillary necrosis is the initial event, and the interstitial nephritis is secondary •Pathognomonic gross features of papillary necrosis is sharply defined graywhite to yellow-brown necrosis of the apical two-thirds of the renal pyramids; one or several papillae may be affected •Histologic findings consist of coagulative necrosis with a surrounding neutrophilic infiltrate and basement membrane thickening of blood vessels •Aspirin, phenylbutazone (horses) inhibit prostaglandin synthesis which predisposes the pyramid to ischemia by reducing the vasodilatory state of venous tone of the medulla normally under prostaglandins 109 110 Pyramidal necrosis caused by analgesics (black necrotic regions) Acute Drug-Induced Interstitial Nephritis •Adverse reaction to any of a large number of drugs •Most often occurs with synthetic penicillins (methicillin, ampicillin), other synthetic antibiotics (rifampin), diuretics (thiazides), NSAIDs, cimetidine •Immune mechanism of hypersensitivity is suspected as clinical signs include fever, eosinophilia and rash •Lesion is in the interstitium, which shows edema and infiltration of lymphocytes and macrophages, also eosinophils and neutrophils (often in large numbers) 111 37 11/29/2023 Acute Tubular Necrosis (ATN) • ATN is characterized by damage to tubular epithelial cells and acute suppression of renal function • Most common cause of acute renal failure – Urine flow falls to less than 400 mL per day • ATN is a reversible renal lesion – Can be due to trauma, acute pancreatitis, septicemia • ATN associated with shock is called ischemic ATN due to hypoperfusion of organs, and resultant hypotension • Nephrotoxic ATN is caused by heavy metals, organic solvents, or drugs that exert toxic effect on tubular epithelium • Morphologically characterized by necrosis of tubular segments (especially PCT), proteinaceous casts in distal tubules and interstitial edema 112 113 114 38 11/29/2023 • Ischemic ATN is characterized by necrosis of short segments of the renal tubules, particularly the PCT and ascending limb • Histologically a variety of tubular injuries seen, e.g. attentuation of PCT brush border, vacuolation of cells, detachment of cells, proteinaceous casts in distal tubules and collecting ducts – Tamm-Horsfall protein normally secreted with hemoglobin, myoglobin and plasma proteins – Mild interstitial infiltrate of mixed inflammatory cells • Toxic ATN is characterized by more prominnent necrosis in proximal tubules and sparing of basement membranes • Tubular epithelium can regenerate if organs can be maintained and basement membrane damage is minimized – Regeneration begins about one week after injury 115 Diseases Involving Blood Vessels • Systemic vascular diseases also involve renal blood vessels Benign Nephrosclerosis •Renal changes in benign hypertension and is associated with hyaline arteriosclerosis •Kidneys are symmetrically atrophic, with a surface of diffuse granularity •Basic microscopic anatomic change is hyaline thickening of the walls of small arteries and arterioles, aka hyaline arteriolosclerosis, at expense of vessel lumen  ischemia Arcuate artery 116 • Malignant Hypertension and Malignant Nephrosclerosis – – – – – Kidneys may be normal in size or slightly smaller Small pinpoint petechial hemorrhages on cortical surface Damage to small vessels manifests as fibrinoid necrosis Vessel walls have a granular eosinophilic appearance Larger vessels have an onion-skin appearance due to proliferation of intimal cells, aka hyperplastic arteriolosclerosis 117 39 11/29/2023 Cystic Diseases of the Kidney • Group of heterogeneous diseases including hereditary, developmental but not hereditary, and acquired • Reasonably common and present diagnostic challenges • Some are major causes of chronic renal failure • Can be confused with malignant tumors • Emerging theme in the study of hereditary cystic diseases is that the underlying defect is in the cilia-centrosome complex of tubular epithelial cells, which may interfere with fluid balance or cellular maturation • Simple Cysts – generally innocuous lesions occurring as multiple or single cystic spaces that vary in diameter, are translucent, lined by a gray glistening smooth membrane, and filled with clear fluid – Microscopically membranes are single layer of cuboidal epithelium which may be atrophic – Cysts are usually confined to cortex – Importance of cysts lies in their differentiation from kidney tumors 118 Autosomal Dominant (Adult) Polycystic Kidney Disease • Characterized by multiple expanding cysts of both kidneys that ultimately destroy the parenchyma • Autosomal dominant disease caused by mutations in the genes encoding polycystin-1 or -2 • Accounts for ~ 10% of cases of chronic renal failure in adults • Kidneys are very large and palpable abdominally • Grossly, kidneys seems to be replaced by numerous, variablysized cysts with no intervening parenchyma – Cysts are thin-walled and can contain fluid that may be clear, turbid or hemorrhagic • Microscopically, reveals narrow bands of normal parenchyma between cysts • Cysts may arise at any level of the nephron, and are lined by a cuboidal to flattened or atrophic epithelium • Pressure of expanding cysts causes ischemic atrophy of intervening renal parenchyma • One-third of patients have liver (biliary) cysts (asymptomatic) 119 120 40 11/29/2023 • Autosomal Recessive (Childhood) Polycystic Kidney Disease – Caused by mutations in the gene encoding fibrocystin – Strongly associated with liver abnormalities – Numerous small cysts in the cortex and medulla giving the kidney a sponge-like appearance • Medullary Cystic Disease – Nephronophthisis-medullary cystic disease complex usually begins in childhood – Being recognized as a cause of chronic renal failure in children and young adults – Associated with mutations in several genes that encode epithelial proteins called nephrocystins – Small contracted kidneys with numerous small cysts lined by flattened or cuboidal epithelium 121 Urinary Outflow Obstruction Renal Stones • Urolithiasis refers to calculus (stone) formation at any level in the urinary collecting system, but most often in kidney • Common sites are renal pelvis and calyces and the bladder • The most important cause of stone formation is increased urine concentration of stone’s constituents in excess of their solubility in urine • Prevalence of different types of stones varies – Calcium oxalate and/or calcium phosphate comprise 80% of all stones in humans – Other types, e.g. struvite (Mg, NH3, Ca, Po4), uric acid, cysteine 122 Hydronephrosis • Dilation of renal pelvis and calyces, accompanied by atrophy of the parenchyma • Caused by obstruction to the outflow of urine anywhere from urethra to renal pelvis • Congenital – atresia of urethra, valve formations in ureter or urethra, renal artery compressing on ureter, kinking of ureter • Acquired – foreign bodies (calculi), tumors, inflammation, neurogenic, pregnancy 123 41 11/29/2023 Tumors 124 Renal Cell Carcinoma • • • • • • Most common malignant tumor of the kidney Derived from renal tubular epithelium and, hence, located predominantly in cortex Three most common forms are the following… Clear Cell Carcinomas – Most common, accounting for 70-80% of renal cancers – Cut surface of carcinoma is yellow to orange to gray-white, with prominent areas of cystic softening or of hemorrhage – Made up of cells with clear or granular cytoplasm – Associated with homozygous loss of the VHL tumor suppressor gene – Often invade the renal vein Papillary Renal Cell Carcinomas – Tumors are multifocal and bilateral – Formation of papillae varies from tumor to tumor – Associated with overexpression and activating mutations of the MET oncogene Chromophobe Renal Carcinomas – Arise from intercalating cells of collecting ducts – Grossly tan-brown, cells have clear flocculent cytoplasm with prominent cell membranes 125 126 42 11/29/2023 Wilms’ Tumor, aka nephroblastoma • The most common renal neoplasm of childhood • The third most common organ cancer in children younger than 10 years-of-age • Can arise spontaneously or be familial • Patient’s with Wilms’ tumors often have abnormalities of the Wilms’ tumor 1 (WT1) gene, which is critical to normal renal and gonadal development • Grossly appears as a large, solitary, well circumscribed mass with a soft, multi-lobulated, bulging, tan, cut surface • Microscopically, tumor is characterized by attempts to recapitulate different stages of nephrogenesis, i.e. triphasic combination of blastemal (small blue cells), stromal and epithelial cell types (abortive tubules or glomeruli) 127 128 Tumors of Bladder and Collecting System • Entire urinary collecting system from renal pelvis to urethra is lined with transitional epithelium; so, its epithelial tumors assume similar morphologic patterns • Tumors above bladder are uncommon, those in bladder are very common • Clinical significance depends on histologic grade and differentiation, and depth of invasion of lesion (most important) – Benign papillomas – Urothelial (transitional) cell carcinoma – Squamous cell carcinoma 129 43 11/29/2023 Wilms’ Tumor, aka nephroblastoma • The most common renal neoplasm of childhood • The third most common organ cancer in children younger than 10 years-of-age • Can arise spontaneously or be familial • Patient’s with Wilms’ tumors often have abnormalities of the Wilms’ tumor 1 (WT1) gene, which is critical to normal renal and gonadal development • Grossly appears as a large, solitary, well circumscribed mass with a soft, multi-lobulated, bulging, tan, cut surface • Microscopically, tumor is characterized by attempts to recapitulate different stages of nephrogenesis, i.e. triphasic combination of blastemal (small blue cells), stromal and epithelial cell types (abortive tubules or glomeruli) 127 128 Tumors of Bladder and Collecting System • Entire urinary collecting system from renal pelvis to urethra is lined with transitional epithelium; so, its epithelial tumors assume similar morphologic patterns • Tumors above bladder are uncommon, those in bladder are very common • Clinical significance depends on histologic grade and differentiation, and depth of invasion of lesion (most important) – Benign papillomas – Urothelial (transitional) cell carcinoma – Squamous cell carcinoma 129 43 11/29/2023 Wilms’ Tumor, aka nephroblastoma • The most common renal neoplasm of childhood • The third most common organ cancer in children younger than 10 years-of-age • Can arise spontaneously or be familial • Patient’s with Wilms’ tumors often have abnormalities of the Wilms’ tumor 1 (WT1) gene, which is critical to normal renal and gonadal development • Grossly appears as a large, solitary, well circumscribed mass with a soft, multi-lobulated, bulging, tan, cut surface • Microscopically, tumor is characterized by attempts to recapitulate different stages of nephrogenesis, i.e. triphasic combination of blastemal (small blue cells), stromal and epithelial cell types (abortive tubules or glomeruli) 127 128 Tumors of Bladder and Collecting System • Entire urinary collecting system from renal pelvis to urethra is lined with transitional epithelium; so, its epithelial tumors assume similar morphologic patterns • Tumors above bladder are uncommon, those in bladder are very common • Clinical significance depends on histologic grade and differentiation, and depth of invasion of lesion (most important) – Benign papillomas – Urothelial (transitional) cell carcinoma – Squamous cell carcinoma 129 43