Module 5 Urinary, DM nephropathy Flashcards
Development of Urinary System
- Develop at 3rd-4th week embryonic life
- Germ layer of origin intermediate mesoderm
Kidneys arise from two sources:
- Ureteric bud - ureter pelvis calyces and collecting duct
2. Renal blastema - nephron except collecting duct
Development of renal anlage
Develop along cranio-caudal gradient
Three stages
1. Pronephros - forekidney transitory structure
- develop during 4th wk and atrophies 5th wk
2. Mesonephros - functional for awhile
3. Metanephros - definite kidney
Development
Upper urinary system
- collecting duct, calices, renal pelvis and ureter
- arise from ureter anlage
Lower urinary system
- bladder and urethra
- formed from the endoderm of the posterior intestine
The intermediate mesoderm forms a longitudinal elevation along the dorsal body wall called the __
urogenital ridge
A portion of the urogenital ridge forms the __, which gives rise to the urinary system.
nephrogenic cord
The nephrogenic cord develops into three sets of nephric structures:
- pronephros
- mesonephros
- metanephros.
- develops by the differentiation of mesoderm within the nephrogenic cord to form pronephric tubules and the pronephric duct
- is the cranial-most nephric structure and is a transitory structure that regresses completely by week 5
- is not functional in humans.
pronephros
- develops by the differentiation of mesoderm within the nephrogenic cord to form mesonephric tubules and the mesonephric duct (Wolffian duct)
- is the middle nephric structure and is a partially transitory structure.
- Most of the tubules regress, but the mesonephric duct persists and opens into the urogenital sinus.
- is functional for a short period.
mesonephros
- develops from an outgrowth of the mesonephric duct (called the ureteric bud) and from a condensation of mesoderm within the nephrogenic cord called the
metanephric mesoderm. - is the caudal-most nephric structure
- begins to form at week 5 and is functional in the fetus at about week 10.
- develops into the definitive adult kidney
metanephros
Development of the collecting system
The ureteric bud is an outgrowth of the mesonephric
duct. This outgrowth is regulated by WT-1 (an
anti-oncogene), GDNF (glial cell line–derived
neurotrophic factor), and c-Ret (a tyrosine kinase receptor).
The ureteric bud initially penetrates the metanephric mesoderm and then undergoes repeated branching to form the URETERS, RENAL PELVIS, MAJOR CALYCES, MINOR CALYCES, AND COLLECTING DUCTS.
Development of the nephron
The inductive influence of the collecting ducts causes the
metanephric mesoderm to differentiate into metanephric vesicles, which later give rise to primitive S-shaped renal tubules, which are critical to nephron formation.
The S-shaped renal tubules differentiate into the connecting tubule, distal convoluted tubule, loop of Henle, proximal convoluted tubule, and Bowman’s capsule. Tufts of capillaries called glomeruli protrude into Bowman’s capsule. Nephron formation is complete at birth, but functional maturation of nephrons continues throughout infancy.
The transitional epithelium lining the ureter, pelvis, major calyx, and minor calyx and the simple cuboidal epithelium lining the collecting tubules are derived from __ of the ureteric bud.
mesoderm
The simple cuboidal epithelium lining the connecting tubule and distal convoluted tubule, the simple squamous epithelium lining the loop of Henle, the simple columnar
epithelium lining the proximal convoluted tubule, and the podocytes and simple squamous epithelium lining Bowman’s capsule are derived from __.
metanephric mesoderm
Development of Urinary Bladder
A. The urinary bladder is formed from the upper portion of the urogenital sinus, which is continuous with the allantois.
B. The allantois becomes a fibrous cord called the urachus (or median umbilical ligament in the adult).
C. The lower ends of the mesonephric ducts become incorporated into the posterior wall of the bladder to form the trigone of the bladder.
Development of Urinary Bladder 2
D. The mesonephric ducts eventually open into the urogenital sinus below the bladder.
E. The transitional epithelium lining the urinary bladder is derived from endoderm because of its etiology from the urogenital sinus and gut tube.
The female urethra is formed from the __ of the urogenital sinus.
lower portion
The female urethra develops __ outgrowths into the surrounding mesoderm to form the urethral glands and paraurethral glands of Skene (which are homologous to the
prostate gland in the male).
endodermal
The transitional epithelium and stratified squamous epithelium lining the female urethra are derived from __.
endoderm
- These parts of the urethra are formed from the lower portion of the urogenital sinus. The transitional epithelium and stratified columnar epithelium lining these parts of the urethra are derived from endoderm.
Prostatic urethra, membranous urethra, bulbous urethra, and proximal part of penile urethra
__ is formed from an ingrowth of surface ectoderm called the glandular plate. Ectodermal septa appear lateral to the navicular fossa and become canalized to form the foreskin. The stratified squamous epithelium lining of the distal penile urethra is derived from ectoderm.
Distal part of the penile urethra
The __ joins the proximal penile urethra and becomes canalized to form the navicular fossa.
glandular plate
__ occurs when the ureteric bud fails to develop, thereby eliminating the induction of metanephric vesicles and nephron formation.
Renal agenesis
__ occurs when there is a congenitally small kidney with no pathological evidence
of dysplasia.
Renal hypoplasia
__ occurs when there is a disorganization of renal parenchyma with abnormally developed and immature nephrons
Renal dysplasia
__ occurs when one or both kidneys fail to ascend and therefore remain in the pelvis or lower lumbar area (i.e., pelvic kidney). In some cases, two pelvic kidneys fuse to
form a solid mass, commonly called a pancake kidney.
Renal ectopia
The most common type of __ is the horseshoe kidney. A horseshoe kidney occurs when the inferior poles of the
kidneys fuse across the midline. Normal ascent of the kidneys is arrested because the fused portion gets trapped behind the inferior mesenteric artery. Kidney rotation is also arrested, so that the hilum faces ventrally.
Renal fusion
The __ consists of the paired kidneys and ureters, the bladder, and the urethra. This system’s primary role is to ensure optimal properties of the blood, which the kidneys continuously monitor.
urinary system
This general role of the kidneys involves a complex combination of renal functions:
■ Regulation of the balance between water and electrolytes (inorganic ions) and the acid-base balance
■ Excretion of metabolic wastes along with excess water
and electrolytes in urine
■ Excretion of many bioactive substances, including many
drugs
■ Regulation of arterial blood pressure by secretion of
renin
__ is a protease secreted into the blood that helps regulate blood pressure by cleaving circulating angiotensinogen to angiotensin I.
Renin
Other renal functions include the following:
■ Secretion of erythropoietin, a glycoprotein growth factor that stimulates erythrocyte production in red marrow when the blood O2 level is low;
■ Conversion of the steroid prohormone vitamin D, initially produced in the epidermis, to the active form ( 1,25-dihydroxyvitamin D3 or calcitriol); and
■ Gluconeogenesis during starvation or periods of prolonged fasting, making glucose from amino acids to
supplement this process in the liver
- the excretory product of the kidneys, passes through the ureters to the bladder for temporary storage and is then released to the exterior through the urethra.
Urine
The functional and structural unit of the kidney, the__, consists of a renal corpuscle (including the glomerulus) plus a long, folded renal tubule.
nephron
The kidneys and ureters are found in the __, while the urinary bladder is in the anterior part of the pelvis.
retroperitoneum
Blood is supplied to each kidney by the __, which arise from the aorta. One or more renal veins drains the blood from each kidney to the inferior vena cava. The total blood volume of the body is circulated through the kidneys about 300 times each day.
renal arteries
The __ is a bean-shaped organ lying in the upper
retroperitoneal area and oriented with the concave surface
directed medially.
kidney
The __ is the site of entry and exit of the renal blood vessels and the ureter.
hilum
Within the hilum the __ expands as the renal pelvis and divides into two or three major calyces . Smaller branches, the minor calyces, arise from each major calyx. The area surrounding the renal pelvis and calyces contains adipose tissue.
upper end of the ureter
The kidney has an outer __, a darker region with many
corpuscles and cross sections of tubules, and an inner medulla consisting of straight, aligned structures
cortex
In humans, the __ consists of 8-12 conical structures called renal pyramids, which are separated by extensions from the cortex called renal columns . Each pyramid plus the cortical tissue at its base and along its sides constitutes a renal lobe .
renal medulla
Striations extending from the medulla into the cortex are called __; these plus the attached cortical tissue are considered lobules. The tip of each pyramid, called the renal papilla, projects into a minor calyx that collects urine formed by tubules in the pyramid
medullary rays
Th e major divisions of each nephron are the following:
■ Renal corpuscle - an initial dilated part enclosing a tuft
of capillary loops and the site of blood fi ltration, always
located in the cortex;
■ Proximal tubule - a long convoluted part, located entirely in the cortex, with a shorter straight part that enters the medulla;
■ Loop of Henle (or nephron loop), in the medulla, with a
thin descending and a thin ascending limb;
■ Distal tubule - consisting of a thick straight part ascending
from the loop of Henle back into the cortex and a convoluted part completely in the cortex; and
■ Connecting tubule - a short final part linking the nephron
to collecting ducts.
Connecting tubules from several nephrons merge to form
__ that then merge as larger collecting ducts. These converge in the renal papilla, where they deliver urine to a minor calyx.
collecting tubules
__ are located almost completely in the cortex while juxtamedullary nephrons (about one-seventh of the total) lie close to the medulla and have long loops of Henle.
Cortical nephrons
The kidney is invested by a tough fibrous capsule which is
surrounded by a thick layer of perinephric fat that is in turn
encased in a delicate condensation of connective tissue known as __. The fat around the kidney cushions it against trauma.
Gerota’s fascia
The nephron, the functional unit of the kidney, consists of two major components, __
the renal corpuscle and the renal tubule
The __ is responsible for the filtration of plasma and is a combination of two structures, Bowman’s capsule and the glomerulus.
renal corpuscle
- consists of a single layer of flattened cells resting on a basement membrane;
- it is derived from the distended blind end of the renal tubule.
Bowman’s capsule
The __ is a globular network of anastomosing capillaries which invaginates Bowman’s capsule
glomerulus
the capillary loops of the glomerulus are invested by the visceral layer of Bowman’s capsule, a highly specialised layer of epithelial cells called __
podocytes
The visceral layer is reflected around the vascular stalk of the glomerulus to become continuous with the parietal layer that constitutes __.
Bowman’s capsule proper
The space between the two layers is known as __ and is continuous with the lumen of the renal tubule
Bowman’s space
In the renal corpuscle, water and low molecular weight constituents of plasma are filtered from the glomerular capillaries into Bowman’s space to form the __, which then passes into the renal tubule.
glomerular ultrafiltrate
The filtration barrier between the capillary lumen and Bowman’s space consists of the capillary endothelium, the podocyte layer and their common basement membrane known as the glomerular basement membrane; these three components are sometimes called the __.
glomerular filtration barrier
The __, which supplies the glomerulus
afferent arteriole
__, which drains it, enter and leave the corpuscle at the vascular pole that is usually situated opposite the entrance to the renal tubule, the urinary pole
efferent arteriole
- extends from Bowman’s capsule to its junction with a collecting duct
- is up to 55 mm long in humans and is lined by a single layer of epithelial cells
- primary function: selective reabsorption of water, inorganic ions and other molecules from the glomerular filtrate.
Renal tubule
In humans, glomerular filtrate is produced at a steady rate of approximately __; of this, all but about 1 mL is reabsorbed by the renal tubules, giving a normal rate of urine production of around 1mL/min.
120 mL/min
The renal tubule has a convoluted shape and has four distinct zones, each of which has a different role in tubular function and a corresponding difference in histological appearance.
- The proximal convoluted tubule (PCT)
- The loop of Henle
- The distal convoluted tubule (DCT)
- The collecting tubule
The __ is the most convoluted section of the tubule and is responsible for the reabsorption of approximately 65% of the ions and water of the glomerular filtrate. __ are confined to the renal cortex and make up the greater part of its bulk.
proximal convoluted tubule (PCT)
The __ includes the distal straight part of the proximal tubule, the pars recta, the thin descending and ascending limbs and the thick ascending limb. The difference between these parts is due to differences in the epithelium.
loop of Henle
The__ tend to be located in the superficial and midcortical regions, the loops extending very little beyond the corticomedullary junction.
corpuscles of short-looped nephrons
__ are mainly associated with juxtamedullary corpuscles; a small proportion of long loops almost reach the tips of the renal papillae, but successively greater numbers turn back at higher levels as necessitated by the tapering shape of the medullary pyramids
Long-looped nephrons
The limbs of the loop of Henle are closely associated with parallel wide capillary loops, the __, which arise from the efferent arterioles of glomeruli located near the corticomedullary junction. The vasa recta descend into the medulla then loop back on themselves to drain into veins at the junction of the medulla and cortex
vasa recta
The main function of the loops of Henle is to generate a high osmotic pressure in the extracellular fluid of the renal medulla; the mechanism by which this is achieved is known as the __
counter-current multiplier system
The medulla can be divided into different zones according to the components of the loop of Henle that are present:
- the INNER MEDULLA contains only thin limbs of the loop of Henle
- the INNER STRIPE of the outer medulla contains thick descending limbs as well as thin limbs
- the OUTER STRIPE of the outer medulla contains thick ascending limbs as well as thick
- is a continuation of the thick limb of the loop of Henle after its return to the cortex.
- is responsible for reabsorption of sodium ions, an active
process controlled by the adrenocortical hormone
ALDOSTERONE. - Sodium reabsorption is coupled with the secretion of hydrogen or potassium ions into the DCT, the secretion of hydrogen ions resulting in a net loss of acid from the body.
distal convoluted tubule (DCT)
The __ is the straight terminal portion of the nephron, several collecting tubules converging to form a
collecting duct.
collecting tubule
The collecting ducts descend through the
cortex in parallel bundles called medullary rays, progressively merging in the medulla to form the large __, which open at the tips of the renal papillae to discharge urine into the pelvicalyceal system.
ducts of Bellini
The collecting tubules and ducts are not normally permeable to water. However, in the presence of __ secreted by the posterior pituitary, the collecting tubules and ducts become permeable to water. Thus the high osmotic pressure generated by the counter-current multiplier system into the interstitial tissues of the medulla removes water that is returned to the general circulation via the vasa recta. The loops of Henle and ADH thus provide a mechanism for the production of urine that is hypertonic with respect to plasma.
antidiuretic hormone (ADH)
In most cases, each kidney is supplied by a __ which divides in the hilum into two main branches; in some individuals, however, there are two or even more renal arteries that derive directly from the aorta.
single renal artery
Each of these gives rise to several __ which ascend between the pyramids to the corticomedullary junction. Here they branch to form the ARCUATE ARTERIES, which run in an arc-like course parallel to the capsule of the kidney.
interlobar arteries
The arcuate arteries give rise to numerous interlobular (cortical radial) arteries that radiate towards the capsule, branching to form the __ of the glomeruli.
afferent arterioles
The __ form a continuation of the efferent arterioles of juxtamedullary glomeruli and form the microcirculation of the renal medulla. The efferent arterioles of the rest of the cortex divide to form the plexus of capillaries that surround the tubules of the renal cortex.
vasa recta
The cortical and medullary capillaries drain via cortical radial (interlobular) veins to arcuate veins at the cortico-medullary junction and thence to the __.
renal vein
The __ is easily identified even at low magnification by the presence of renal corpuscles, which are absent in the renal medulla. However, the bulk of the cortex is occupied by the proximal and distal convoluted tubules. The arcuate arteries and veins help to demarcate the cortex from the medulla.
renal cortex
__, which have features resembling smooth muscle cells, are contractile and are thus able to modify the diameter of the glomerular capillaries in response to vasoactive substances, some of which they themselves produce.
Mesangial cells
Functions of the mesangium include the following:
■ Physical support of capillaries within the glomerulus;
■ Adjusted contractions in response to blood pressure
changes, which help maintain an optimal filtration rate;
■ Phagocytosis of protein aggregates adhering to the
glomerular filter, including antibody-antigen complexes
abundant in many pathological conditions; and
■ Secretion of several cytokines, prostaglandins, and other factors important for immune defense and repair in the glomerulus.
the glomerular basement membrane consists of three layers
- a dense central layer, the LAMINA DENSA
- with a thinner electron-lucent layer on either side
of it, the LAMINA RARA INTERNA under the endothelium - and the LAMINA RARA EXTERNA supporting the podocytes
The podocytes have long cytoplasmic extensions called
primary processes that embrace the capillaries, giving rise to short secondary __, which interdigitate with those of other primary processes
foot processes (pedicels)
The gaps between adjacent secondary foot processes, known as filtration slits, are of uniform width (40nm) and are bridged by __
slit diaphragms
The slit diaphragm is composed of a single layer of the
transmembrane protein, __, whose extracellular domains from adjacent foot processes link together rather in the manner of a zip.
nephrin
A glycocalyx rich in negatively charged __ covers the urinary surface of the podocytes, including the slit diaphragms.
podocalyxin
The __, the space between the podocyte foot processes and the podocyte cell bodies, has been recently shown to be a restricted space that comprises a fourth component of the GFB.
- covers approximately 60% of the glomerular capillary surface.
subpodocyte space (SPS)
Ultrafiltrate in this confined space can only leave it via the subpodocyte space exit pore, which leads into the __ between the podocyte cell bodies and finally into Bowman’s space proper
interpodocyte space
The __ is a specialisation of the glomerular afferent arteriole AA and the distal convoluted tubule DCT of the same nephron and is involved in the regulation of systemic blood pressure via the renin-angiotensin aldosterone system (RAAS).
juxtaglomerular apparatus (JGA)
The juxtaglomerular apparatus is made up of three components:
- the MACULA DENSA of the DCT
- renin-secreting JUXTAGLOMERULAR CELLS of the afferent arteriole
- EXTRAGLOMERULAR MESANGIAL CELLS.
- is an area of closely packed, specialised DCT epithelial cells where the DCT abuts the vascular pole of the glomerulus.
- are taller and have larger more prominent nuclei situated towards the luminal surface. Mitochondria
are scattered throughout the cytoplasm, and Na+ pump
activity is absent. The basement membrane between the
macula and underlying cells is extremely thin. - The cells are sensitive to the concentration of sodium ions in the fluid within the DCT; a decrease in systemic blood pressure results in decreased production of glomerular filtrate and hence decreased concentration of sodium ions in the distal tubular fluid.
Macula densa
- are modified smooth muscle cells of the wall of the afferent arteriole, forming a cluster around it just before it enters the glomerulus.
- cytoplasm contains immature and mature membrane-bound granules of the enzyme renin.
Juxtaglomerular cells
- Also called Goormaghtigh cells or lacis cells
- these cells form a conical mass, the apex of which is continuous with the mesangium of the glomerulus; laterally it is bounded by the afferent and efferent arterioles, and its base abuts the macula densa.
- The cells are flat and elongated, with extensive fine
cytoplasmic processes extending from their ends and
surrounded by a network (‘lacis’) of mesangial material.
Extraglomerular mesangial cells
Lacis cells participate in the__ by which changes in Na+ concentration at the macula densa give rise to signals that directly control glomerular blood flow. The extraglomerular mesangial cells are thought to be responsible for transmission of a signal arising in the macula densa to the intraglomerular mesangial cells, which then contract or relax to make the capillary loops narrower or wider.
tubuloglomerular feedback
mechanism
The juxtaglomerular apparatus is believed to act as both a
__, controlling systemic blood pressure by the secretion of renin by the juxtaglomerular cells.
baroreceptor and a chemoreceptor
The __ are suitably placed to monitor
systemic blood pressure, with a fall in blood pressure resulting in renin secretion. Reduction in blood pressure results in reduced glomerular filtration and consequently a lower concentration of sodium ions in the DCT.
juxtaglomerular cells
Acting as chemoreceptors, the cells of the __ in
some way then promote renin secretion. Renin diffuses into the bloodstream, catalysing the conversion of angiotensinogen, an α2-globulin synthesised by the liver, into the decapeptide angiotensin I. In the lungs, angiotensin converting enzyme (ACE) cleaves two amino acids from angiotensin I to form angiotensin II, which is a potent vasoconstrictor.
macula densa
Angiotensin II raises blood pressure in three ways:
- constriction of peripheral blood vessels
- release of aldosterone from the adrenal cortex
- via a direct effect on the renal tubules, where it promotes the reabsorption of sodium ions (and therefore water) from the DCT, thus expanding the plasma volume and increasing blood pressure
The __ consists of closely packed tubules of two
types: the loop of Henle and the collecting tubules and
ducts, as well as the vasa recta.
renal medulla
The __ is a continuation of the proximal convoluted tubule. It dips down into the medulla, where it loops back on itself and returns to the cortex to its own renal corpuscle, becoming the first part of the distal convoluted tubule.
loop of Henle
The loop of Henle is made up of four parts:
- Thick descending limb (pars recta of the PCT)
- Thin descending limb
- Thin ascending limb
- Thick ascending limb (pars recta of the DCT)
The __ is the second, straight part of the proximal tubule that extends down into the outer medulla. There is an abrupt transition to the thin descending limb, which loops down into the medulla for a variable distance.
thick descending limb
The __ extend down to the inner medulla before turning back on themselves, while those in the outer cortex only extend a short way into the medulla. After the hairpin bend, the tubule becomes the thin ascending limb for a short distance before abruptly changing into the thick ascending limb. Thus the thin descending limb is longer than the thin ascending limb.
thin limbs of juxtamedullary nephrons
The __ have a simple squamous epithelium and
may be differentiated from the vasa recta by the absence of erythrocytes and their regular rounded shape in transverse
section. Erythrocytes, stained orange by this staining method, are easily seen in the vasa recta.
thin limbs
The __ are lined by low cuboidal epithelium and are also round in cross-section. Neither thick nor thin limbs of the loop of Henle have a brush border.
thick ascending limbs
__ have a similar epithelial lining to the ascending limbs but are wider and less regular in shape.
Collecting tubules
The __ are easily recognised by their large diameter and pale stained columnar epithelial lining.
collecting ducts
The function of the loop of Henle is to produce an increasing osmotic gradient from the cortex to the tip of the renal papilla by the __
counter-current multiplier mechanism
- is a unique glycoprotein produced only by the epithelium of the thick ascending limb.
- has protective functions, including binding to certain types of Escherichia coli to prevent the bacteria adhering to the renal tubular epithelium and prevention of the formation of renal calculi.
Tamm-Horsfall protein
The __ joins the distal convoluted tubule to the collecting duct. Several collecting tubules merge to form each collecting duct.
collecting or connecting tubule
The collecting tubules and ducts descend in the medullary rays towards the renal medulla where they progressively merge to form the large ducts of Bellini which drain urine from the tip of the renal papilla into the __.
pelvicalyceal system
The simple low columnar epithelium of the collecting ducts
consists of two cell types, __
- principal cells
2. intercalated cells
- have pale cytoplasm with scanty organelles and
short microvilli - cells have prominent infoldings of the basolateral plasma membrane but no lateral interdigitations
- actively reabsorb Na+ and secrete K+, as well as reabsorbing water.
Principal cells
- have darker cytoplasm due to the content of multiple mitochondria, polyribosomes and membrane-bound vesicles.
- These cells secrete H+ and reabsorb bicarbonate and are thus important in acid-base homeostasis.
- The number of cells varies between different parts of the collecting duct and they are virtually absent in the inner
medullary segment.
Intercalated cells
The __ includes the renal pelvis and calyces, the ureters, the urinary bladder and the urethra.
- is specialised for the storage and excretion of urine at a convenient time; no further modification of the urine is possible after it leaves the renal medulla.
lower urinary tract
The __ are muscular tubes that carry urine from the kidneys to the bladder. Urine is transported from the pelvicalyceal system as a bolus, propelled by peristaltic action of the
ureteric wall. The wall contains two layers of smooth muscle, arranged as an inner elongated spiral but traditionally known as the longitudinal layer and an outer tight spiral traditionally described as the circular
layer. Another outer longitudinal layer is present in the lower third.
ureters
The lumen of the ureter is lined by __ which is thrown up into folds in the relaxed state, allowing the ureter to dilate during the passage of a bolus of urine. Beneath the epithelium is a broad collagenous lamina propria. Surrounding the muscular wall is a loose collagenous adventitia containing blood
vessels, lymphatics and nerves.
transitional epithelium (urothelium)
The __ serves as a urine store in which urine can be held until a convenient time and place for its excretion (micturition). The general structure of the bladder wall resembles that of the lower third of the ureters. The wall consists of three loosely arranged layers of smooth muscle and elastic fibres that contract during micturition.
urinary bladder
Note the inner longitudinal, outer circular and outermost longitudinal layers of smooth muscle; together the three layers are called the __.
detrusor muscle
__, also called urothelium, is found only within the conducting passages of the urinary system, for which it is especially adapted. The epithelium is stratified, comprising three to six layers of cells, the number of layers being greatest when the epithelium is least distended at the time of fixation.
Transitional epithelium
The __ are compact and cuboidal in form, while those of the intermediate layers are more columnar, with their nuclei orientated at right angles to the basement membrane.
cells of the basal layer
- The surface cells are called __ and have unique features that allow them to maintain the impermeability of the epithelium to urine, even when at full stretch. This permeability barrier also prevents water from being drawn through the epithelium into hypertonic urine.
- The cells are large and ovoid with round nuclei and
plentiful eosinophilic cytoplasm; some surface cells are
binucleate (not illustrated). The surface outline has a
characteristic scalloped appearance and the superficial
cytoplasm is fuzzy, indistinct and more intensely stained than the rest of the cytoplasm.
umbrella or dome cells
Ultrastructural studies have revealed that much of the
surface plasma membrane consists of thickened inflexible
plaques, often called__, interspersed with narrow zones of normal membrane.
asymmetrical unit membrane
The ability of the tubule to produce concentrated urine is
dependent on the high osmolarity of the renal medulla, which is created by the unique structure of the loops of Henle and vasa recta dipping down into the medulla. This is known as the __
counter-current multiplier mechanism
- Endothelium, glomerular basement membrane and podocytes with foot processes
- Special Features: Glomerular filtration barrier (GFB)
- Functional significance: Allow water, ions and small molecules to pass into subpodocyte space while retaining large protein molecules
Glomerulus
- The most problematic issue in clinical nephrology is the relentless and progressive increase in patients with ESRD.
- The impact of diabetic nephropathy on the increasing population with CKD and ESRD is enormous.
Diabetic Nephropathy
Hormones of the Kidney
Juxta-glomerular (JG) cells:
Lacis cells or extraglomerular mesangial cells:
Also known as polar cushion or polkissens cells. These cells are formed at one angle between the afferent and efferent arteriole at the vascular pole. They may produce Erythropoietin, a hormone that stimulates erythropoiesis in the bone marrow.
- On one side of the wall of the afferent arteriole at the vascular pole becomes transformed into modified smooth muscle cells called juxta-glomerular cells or JG cells, which have a slightly basophilic cytoplasm and their specific granules are clearly demonstrated.
- Electron microscopy of secretory granules of JG cells shows that cells are variable in shape and membrane bounded with an internal crystalline structure.
- cells secrete Renin, which activates Angiotensinogen into Angiotensin I. Angiotensin I is inactive but is converted in the lungs to Angiotensin II, which is a potent vasoconstrictor, increasing blood pressure
Juxta-glomerular (JG) cells
- Also known as polar cushion or polkissens cells.
- These cells are formed at one angle between the afferent and efferent arteriole at the vascular pole.
- They may produce Erythropoietin, a hormone that stimulates erythropoiesis in the bone marrow.
Lacis cells or extraglomerular mesangial cells
Glomerular Filtration Rate
Cockcroft-Gault formula
[140 – age (years) x weight (kg)]/[(72 if male or 85 if female ) x serum creatinine (mg/dl)]
(Albuminuria Categories In CKD)
Category: A1
AER:
Normal to mildly increased
(Albuminuria Categories In CKD)
Category: A2 AER: 30-300 ACR: 3-30 ACR: 30-300 Terms: \_\_
Moderately increased
(Albuminuria Categories In CKD)
Category: A3 AER: >300 ACR: >30 ACR: >300 Terms: \_\_
Severely increased
GFR Categories In CKD (G1-G2)
G1: ≥ 90 - Normal or high
G2: 60 – 89 - Mildly decreased
GFR Categories In CKD (G3a-G3b)
G3a: 45 – 59 - Mildly to moderately decreased
G3b: 30 – 44 - Moderately to severely decreased
GFR Categories In CKD (G4-G5)
G4: 15 – 29 - Severely decreased
G5:
Criteria for CKD
Abnormalities of kidney structure or function, present for >3 months, with implications for health
- Markers of kidney damage (one or more) pathologic abnormalities
- Albuminuria (AER ≥30 mg/24 hours; ACR ≥30 mg/g [≥3 mg/mmol])
- Urine sediment abnormalities
- Electrolyte and other abnormalities due to tubular disorders
- Abnormalities detected by histology
- Structural abnormalities detected by imaging
- History of kidney transplantation - Decreased GFR
- GFR
ESRD vs Kidney Failure
ESRD is a federal government defined term that indicates chronic treatment by dialysis or transplantation
Kidney Failure: GFR
Diabetic nephropathy is well characterized with accumulation of ECM and the progression of diabetic nephropathy consists of three steps:
- Glomerular hypertrophy and hyperfiltration
- Inflammation of glomeruli and tubulointerstitial regions
- Reduction of cell number by apoptosis and accumulation of ECM
The natural history of diabetic nephropathy shows an analogy with the progression of pancreatic beta cell failure in __.
Type 2 diabetes mellitus
__ is a complex disease, since the functional impairment and structural remodelling of the kidney is tightly linked to the changes in specific cell types in the kidneys.
For example, hyperglycemia induced phenotypic changes in mesangial cells expressing the embryonic form of myosion heavy chains (Smemb), which links to the subsequent enhanced production of ECM and glomerulosclerosis.
Diabetic nephropathy
- Hyperglycemia induces cell cycle arrest and cellular hypertrophy of podocytes, and the expression of nephrin is reduced.
- As a result, the permeability of glomerular capillaries is impaired and this induces proteinuria and subsequent focal and global sclerosis.
Diabetic nephropathy
Three major pathways showing abnormality of intracellular metabolism have been identified in the development of diabetic nephropathy:
- The activation of polyol and PKC (protein kinase C) pathways
- The formation of advanced glycation end-products
- Intraglomerular hypertension induced by glomerular hypertension
- is the major driving force of the progression to ESRD from diabetic nephropathy
Hyperglycemia
__ are common pathways for the progression of diabetic nephropathy
Microinflammation and subsequent extracellular matrix expansion
Pathogenesis of Diabetic Nephropathy
- The three major pathways induce glomerular endothelial cell injuries accompanied by expression of adhesion molecules and chemokines, which result in macrophage infiltration into renal tissues.
- Prolonged microinflammation is the common pathway for progression of diabetic nephropathy.
Various molecules related to the inflammation pathways in diabetic nephropathy include:
- Transciption factors
- Pro-inflammatory cytokines
- Chemokines
- Adhesion molecules
- Toll-like receptors
- Adipokines
- Nuclear receptors
Diabetic nephropathy can be divided into 4 phases:
- Microalbuminuria
- Macroalbuminuria or proteinuria (>300 mg/24 h)
- Nephrotic syndrome
- Chronic Renal Failure
- (urinary albumin excretion 30-300 mg/24 h)
- Microalbuminuria is the first clinical sign of diabetic damage to the kidney and is a harbinger of progressive kidney damage.
- Microalbuminuria also reflects a higher risk for cardiovascular disease.
Microalbuminuria
- Once microalbuminuria is present, it progresses over 5-10 years to macroalbuminuria in 22%-50% of patients
- Macroalbuminuria denotes significant diabetic nephropathy and will be followed by a decline in glomerular filtration rate (GFR)
Macroalbuminuria or proteinuria (>300 mg/24 h)
- Once a patient with type 2 diabetes develops macroalbuminuria, further decline in renal function appears to be inevitable; GFR declines at a rate of 4-12 mL/min/year
Nephrotic syndrome
- Some patients develop the nephrotic syndrome, which usually heralds progressive renal insufficiency and end-stage renal disease.
Chronic Renal Failure
Pro-inflammatory macrophages
- M1 macrophages - exacerbate the renal cell damage
2. ANTI-INFLAMMATORY M2 MACROPHAGES which promote epithelial and vascular repair
Several AGE-formation inhibitors, such as __ were tested in animal models of diabetic nephropathy, suggesting that the AGE–RAGE system is a new therapeutic target for the treatment of diabetic nephropathy.
pyridoxamine
The application of __ ameliorated the progression of the diabetic nephropathy of animal models
NADPH oxidase inhibitors
__ is the common pathway for progression of diabetic nephropathy, and antiinflammatory
agents would be beneficial for the amelioration of diabetic nephropathy
Prolonged microinflammation
- is a well-characterized key molecule for the accumulation of ECM glycoproteins, and treatment with monoclonal TGF-β1 antibody prevents renal insufficiency in db/db mice
TGF-β1 (transforming growth factor-β1)
- is the most important in the pathogenesis of diabetic
nephropathy - is activated by a wide variety of stimuli such as cytokines, oxygen radicals, inhaled particles, ultraviolet irradiation and bacterial or viral products
- In diabetic kidney disease, proteinuria itself is the important activator for __ and is an important
pro-inflammatory stimulus for tubular cells - is induced by high glucose and is activated in peripheral blood mononuclear cells and also in kidney biopsy specimens.
- binds to the promoter regions of several genes that play a
pivotal role in the pathogenesis of diabetic nephropathy
NF-κB
- leads to destruction via the ubiquitination pathway, thereby allowing activation of the NF-κB complex.
Phosphorylation of serine residues on IκB proteins
__ are structurally distinct forms of IL-1 and they are synthesized by a variety of cell types, including macrophages, B-cells and fibroblasts, and are potent mediators of inflammation and immunity.
IL-1A and IL-1B
- is another important immunoregulatory cytokine that activates cell surface signalling assembly involving IL-6, IL-6RA (IL-6 receptor α) and the shared signalling receptor gp130 [IL-6ST (IL-6 signalling transducer)].
- IL6 mRNA was first demonstrated in glomeruli and the interstitium in renal biopsy specimens derived from patients with diabetic nephropathy and elevation of IL-6 was demonstrated in serum and urine.
IL-6
- is a multifunctional pro-inflammatory cytokine secreted
predominantly from monocytes and macrophages that is functional in lipid metabolism, coagulation, insulin resistance and endothelial biology.
TNF
- was originally cloned as an IFNγ (interferon γ )-inducing factor that augments natural killer cell activity in spleen
cells. - have been reported in patients with diabetic nephropathy
and they are closely related to the progression of diabetic nephropathy
IL-18
- is a member of the small inducible gene family and plays a role in the recruitment of monocytes to the site of tissue injury and inflammation
CCL2
- also known as stromalcell-derived factor-1) is a homoeostatic chemokine with multiple functions including cell homing, tumour metastasis, angiogenesis and tissue regeneration after acute injuries
- is produced by podocytes, contributing to podocyte loss, and specific inhibitors ameliorated proteinuria and glomerulosclerosis in db/db mi
CXCL (CXC chemokine ligand) 12
- is a ligand for the integrin LFA-1 (lymphocyte function-associated antigen 1) and is induced by the activation of NF-κB and by pro-inflammatory cytokines, such as IL-1, IL-6 and TNF, which promote the adhesion of leucocytes to vascular endothelial cells.
ICAM1
- plays a central role in the signalling pathways that control dorsal–ventral axis formation and the innate non-specific immune response.
Toll transmembrane receptor
- secrete various factors, adipokines, and they are dysregulated in obesity and Type 2 diabetes
Adipocytes
- is a hormone secreted by adipocytes
and has anti-inflammatory effects - suppressed the activation of NF-κB, TNF-induced monocyte adhesion to aortic endothelial cells and the expression of ICAM1, VCAM1 and SELE
- Serum concentrations of __ were significantly
lower in patients with metabolic syndrome, obesity, Type 2
diabetes and coronary artery disease
ADPOQ (adiponectin)
- is a 16-kDa protein that plays a critical role in the regulation of body mass by inhibiting food intake and stimulating energy expenditure.
- Defects in __ production cause severe hereditary obesity in rodents and humans.
Leptin
- is expressed in the proximal tubules and in the medullary thick ascending limb of the loop of Henle
- has an important role in modulating energy utilization in the kidney through the regulation of fatty acid β-oxidation.
- In __ deficient mice with STZ-induced diabetes, albuminuria and glomerulosclerosis were reduced in association with increased levels of serum free fatty acids and TGs.
PPAR (peroxisome-proliferator-activated receptor) α
