Renal Pathology Part 6 Flashcards
Thrombotic Microangiopathies
- thrombotic thrombocytopenic purport and hemolytic-uremic syndrome
- caused by diverse insults that lead to the excessive activator of platelets, which deposit as thrombi in capillaries and arterioles in various tissue beds, including those of the kidney
- widespread consumption of platelets leads to thrombocytopenia, and resulting thrombi create flow abnormalities that shear red cells, producing a microangiopathic hemolytic anemia
- thrombi produce microvascular occlusions that cause tissue ischemia and organ dysfunction
Typical HUS
-most frequently associated with consumption of food contaminated by bacteria producing Shiga-like toxins
Atypical HUS associated with
- inherited mutations of complement-regulatory proteins
- diverse acquired causes of endothelial injury, including antiphospholipid antibodies; complications of pregnancy and oral contraceptives; vascular renal diseases such as scleroderma and hypertension; chemotherapeutic and immunosuppressive drugs; and radiation
TTP
-often associated with inherited for acquired deficiencies of ADAMTS13, a plasma metalloprotease that regulates the function of vWF
Within the thrombotic microangiopathies, 2 pathogenetic triggers dominate
- endothelial injury
- excessive platelet activation and aggregation
Endothelial appear to be
the primary cause of HUS
Platelet activation may be
inciting event in TTP
Endothelial injury in typical HUS
- the trigger for endothelial injury and activation is usually a Shiga-like toxin
- endothelial injury appears to cause platelet activation and thrombosis within microvascular beds
- evidence that reduced endothelial production of prostaglandin I2 and NO contribute to thrombosis
For inherited forms of atypical HUS, the cause of endothelial injury appears to be
excessive, inappropriate activation of complement
In TTP, the initiating event
appears to be platelet aggregation induced by very large multimers of vWF, which accumulate due to a deficiency of ADAMTS13, a plasma protease that cleaves vWF multimers into smaller sizes
-very large vWF multimers can bind platelet surface glycoproteins and activated platelets spontaneously
Typical hemolytic uremic syndrome
- best-characterized form of HUS
- most cases occur following intestinal infection with strains of E. coli that produce Shiga-like toxins
- Most cases caused by E. coli are sporadic
- less commonly, infections by other agents can give rise to a similar clinical picture
- can occur at any age, but children and older adults are at higher risk
Typical HUS symptoms
- following prodrome of influenza-like or diarrheal symptoms, there is sudden onset of bleeding manifestations, severe oliguria, and hematuria, associated with microangiopathic hemolytic anemia, thrombocytopenia, and in some patients prominent neurologic changes
- hypertension is present in half of patients
- in presence of cytokines such as TNF, Shiga-like toxin may cause endothelial apoptosis
- These alterations lead to platelet activation and induce vasoconstriction, resulting in the characteristic microangiopathy
In typical HUS, if the renal failure is managed properly with dialysis,
most patients recover normal renal function in a matter of weeks
-however, due to underlying renal damage, the long-term outlook is more guarded.
Atypical hemolytic uremic syndrome occurs
- mainly in adults in a number of different settings
- more than half of those affected have an inherited deficiency of complement-regulatory proteins, most commonly Factor H,w which breaks down the alternative pathway C3 convertase and protects cells from damage by uncontrolled compliment activation
- small number of patients have mutations in 2 other proteins that regulate complement, complement Factor I and CD46
- Roughly half of affected individuals have a course marked by multiple relapses and progression to ESRD
- some patients have neurologic symptoms
Thrombotic thrombocytopenia Purpura (TTP)
- classically manifested by the pentad of fever, neurologic symptoms, microangiopathic hemolytic anemia, thrombocytopenia, and renal failure
- most patients present as adults at ages younger than 40
- neurologic involvement is the dominant feature, whereas renal involvement is seen in about 50% of patients
in acute active thrombotic microangiopathies,
-the kidney may show patchy or diffuse cortical necrosis and sub scapular petechiae
Thrombotic microangiopathy microscopic exam
- the glomerular capillaries are occluded by thrombi composed of aggregated platelets and to a lesser extent fibrin
- capillary walls are thickened due to endothelial cell swelling and sub endothelial deposits of cell debris and fibrin
- disruption of the mesangial matrix and damage to mesangial cells often results in mesangiolysis, interlobular arteries and arterioles often show fibrinoid necrosis of the wall and occlusive thrombi
Chronic thrombotic microangiopathy
- confined to patients with atypical HUS or TTP, and has features that stem from continued injury and attempts at healing
- renal cortex reveals various degrees of scarring
Thrombotic microangiopathy light microscopy
- the glomeruli are mildly hypercellular and have marked thickening of the capillary walls associated with splitting or reduplication of the basement membrane
- walls of arteries and arterioles often exhibit increase layers of cells and connective tissue (onion-skinning) that narrow the vessel lumens
- these changes lead to persistent hypo perfusion and ischemic atrophy of the parenchyma, which manifests clinically as renal failure and hypertension
Atherosclerotic Ischemic Renal Disease
- bilateral renal artery disease, usually diagnosed by arteriography, is fairly common cause of chronic ischemia with renal insufficiency in older individuals, sometimes in the absence of hypertension
- importance of recognizing this condition is that surgical revascularization can prevent further decline in renal function
Atheroembolic Renal Disease
- embolization of fragments of atheromatous plaques from the aorta or renal artery into internal vessels occur in older adults with severe atherosclerosis, especially after surgery on the abdominal aorta, aortography, or inartistic canalization
- these emboli can be recognized in the lumens of arcuate and interlobular arteries by their content of cholesterol crystals, which appear as rhomboid clefts
- clinical consequences vary according to number of emboli and preexisting state of renal function
- acute renal injury or failure may develop in older adults in home renal function is already compromised
Sickle-cell nephropathy
- most common abnormalities include hematuria and diminished concentrating ability (hyposthenuria)
- thought to be due to accelerated sickling in hypertonic hypoxic milieu of renal medulla
- patchy papillary necrosis may occur in both homozygotes and heterozygotes
- usually mild to moderate but can have nephrotic syndrome, associated with sclerosing glomerular lesions
Diffuse Cortical Necrosis
- uncommon; occurs most frequently after an obstetric emergency, such as abruption placentae (premature separation of placenta), septic shock, or extensive surgery
- cortical destruction has features of ischemic necrosis
- glomerular and arteriolar micro thrombi often found and contribute to necrosis and renal damage
- sharply limited to cortex
- histologic appearance of acute ischemic infarction
- lesion may be patchy, with areas of coagulative necrosis
- intravascular and intraglomerular thrombosis may be prominent but usually focal
- hemorrhages occur into the glomeruli
- grave signficance, since it gives rise to sudden anuria, terminating rapidly in uremic death
kidneys are common site for development of infarcts due to
-extensive blood flow to kidneys (1/4 cardiac output), but probably more important is limited collateral circulation from external sites (small blood vessels penetrating from renal capsule supply only the very outer rim of cortex)
Most renal infarcts due to
embolism
- major source is mural thrombosis in the left atrium and ventricle as a result of MI
- vegetative endocarditis, aortic aneurysms, and aortic atherosclerosis are less frequent sources
Most renal infarcts are of the
white anemic variety because of the lack of a collateral blood supply
- within 24 hours infarcts become sharply demarcated, pale, yellow-white areas that may contain small irregular foci of hemorrhagic discoloration
- usually ringed by a zone of intense hyperemia
- infarcts are wedge-shaped, with base against the cortical surface and apex pointing toward medulla
- in time areas of ischemic necrosis undergo progressive fibrous scarring, giving rise to depressed, pale, gray-white scars that assume a V-shape on section
Histologic changes in renal infarcts are
those of ischemic coagulative necrosis
Signs of Renal infarcts
- most are clinical silent
- sometimes, pain with tenderness localized to the costovertebral angle occurs, associated with showers of red cells in the urine
- large infarcts of one kidney are probably associated with narrowing of the renal artery or one of its major branches, which in turn may cause hypertension
Account for 20% of chronic kidney disease in children
-renal dysplasias and hypoplasias
Congenital renal disease can be
hereditary but most often results from an acquired development defect during gestations
Defects in genes involved in normal renal development,
- including Wilms tumor-associated genes, cause urogenital anomalies
- as a rule, the resulting developmental abnormalities involve structural components of both the kidney and urinary tract
Bilateral agenesis of the kidney
- incompatible with life
- typically associated with other congenital disorders
Unilateral agenesis of the kidney
- uncommon; compatible with normal life if no other abnormalities exist
- solitary kidney enlarges as a result of compensatory hypertrophy
- some patients eventually develop progressive glomerular sclerosis in the remaining kidney as a result of the adaptive change in hypertrophied nephrons, and in time, chronic kidney disease ensues
Renal Hypoplasia
- failure of kidneys to develop to a normal size
- may occur bilaterally, resulting in renal failure in early childhood, but it is more commonly encountered as a unilateral defect
- observed in low birth weight infants and may contribute to increased lifetime risk of chronic kidney disease
Ectopic Kidneys
- lie either just above the pelvic brim or sometimes within the pelvis
- usually normal or slightly small in size but otherwise not remarkable
- kinking and tortuosity of the ureters may cause obstruction to urinary flow, which predisposes to bacterial infections
Horseshoe kidneys
-fusion of the upper (10%) or lower poles (90%) of the kidneys produces horseshoe-shaped structure that is continuous across the midline anterior to the great vessels.
Cystic disease of the kidney
- heterogeneous, comprising hereditary, developmental, and acquired disorders
- important because they are reasonably common and often represent diagnostic problems for clinicians, radiologists, and pathologists; some forms, such as adult polycystic kidney disease, are major causes of chronic kidney disease, and they can occasionally be confused with malignant tumors
Autosomal Dominant (adult) polycystic kidney disease
- hereditary disorder characterized by multiple expanding cysts of both kidneys that ultimately destroy the renal parenchyma and cause renal failure
- both alleles have to be nonfunctional–one is inherited and one is mutated
- disease is bilateral!
- cysts initially involve minority of nephrons, so renal function is retained until 40-50 years old
- mutations in PKD1 and PKD2
Polycystin-1 is expressed in
tubular epithelial cells, particularly those of the distal nephron
Polycystin-2
- an integral membrane protein that is expressed in all segments of the renal tubules and in many external tissues
- functions as a Ca2+ permeable cation channel
Tubular epithelial cells of the kidney
- contain a single nonmotile primary cilium
- cilium is made up of microtubules, and arises from and is attached to a basal body derived from the centriole
- cilia are part of a system of organelles and cellular structures that sense mechanical signals
Apical cilia function in the kidney tubule as a
mechanosensor to monitor forces between cells and focal adhesions sense attachment to extracellular matrices
In response to external signals, these sensors
regulate ion flux and cellular behavior, including cell polarity and proliferation
The idea that defects in mechanosensing, Ca2+ flux, and signal transduction underlie cyst formation is supported by several observations
- both polycystin-1 and 2 are localized to the primary cilium
- other genes that are mutated in cystic diseases encode proteins that are also localized to cilia and.or basal bodies
- knockout of the PKD1 gene in one model organisms results in ciliary abnormalities sad cyst formation
- tubular cells obtain from mice with a deletion of PKD1 gene retain normal architecture of cilia but lack the flow-induced Ca2+ flux that occurs in normal tubular cells
Polycystin 1 and 2 appear to form
a protein complex or formation of an aberrant complex
Disruption of normal polycystic activity results in
- alterations of intracellular Ca2+ which regulates many downstream signaling events, including pathways that directly or indirectly impact cellular proliferation, apoptosis, and secretory functions
- the increase in calcium is thought to stimulate proliferation and secretion from epithelial cells lining the cysts, which together result in progressive cyst formation and enlargement
Adult polycystic kidney disease gross appearance
- kidneys are bilaterally enlarged and may achieve enormous sizes
- external surface appears to be composed solely of a mass of cysts with no intervening parenchyma
Adult polycystic kidney disease microscopic appearance
- functioning nephrons dispersed between cysts
- cyst say be filled with a clear, serous fluid or with turbid, red to brown, sometimes hemorrhagic fluid
- as cysts enlarge, may encroach on calyces and pelvis to produce pressure defects
Adult Polycystic Kidney Disease clinical features
- many remain asymptomatic until renal insufficiency
- in others, hemorrhage or progressive dilation of cysts may produce pain
- excretion of blood clots causes renal colic
- enlarged kidneys may induce a dragging sensation
Adult polycystic kidney disease occasionally begins with
insidious onset of hematuria, followed by other features of progressive chronic kidney disease, such as proteinuria, polyuria, and hypertension
Adult polycystic kidney disease progression is accelerated in
-blacks, in males, and in the presence of hypertension
Individuals with polycystic kidney disease also tend to have external congenital anomalies
- 40% have polycystic liver disease
- some have intracranial berry aneurysms that may rupture to cause subarachnoid hemorrhage
- some have mitral valve prolapse and other cardiac valvular anomalies
Childhood polycystic kidney disease
- in perinatal and neonatal forms, serious manifestations are present at birth and infant might succumb rapidly to renal failure
- mostly caused by mutations in PKHD1 gene which encodes fibrocystin
- most cases are compound heterozygotes
- patients who survive infancy (infantile and juvenile forms) may develop hepatic injury characterized by bland periportal fibrosis and proliferation of well-differentiated biliary ductules (congenital hepatic fibrosis)
- hepatic disease predominant concern in older children
Childhood polycystic kidney disease morphology
- kidneys are enlarged and have smooth external appearance
- on cut section, numerous small cysts in cortex and medulla give kidney a sponge-like appearance
- dilated elongated channels present at right angles to cortical surface
Childhood polycystic kidney disease microscopic exam
- cylindrical, or less commonly, saccular dilation of all collecting tubules
- cysts have a uniform lining of cuboidal cells, reflected their origin from the collecting ducts.
- in almost all cases the liver has cysts associated with portal fibrosis and proliferation of partial bile ducts
Medullary sponge kidney
- multiple cystic dilations of the collecting ducts in medulla
- occurs in adults and is usually discovered radiographically
- renal function usually normal
- papillary ducts in medulla are dilated, and small cysts may be present
- cysts lined by cuboidal epithelium or occasionally by transitional epithelium
Nephrophthisis
- group of renal disorders characterized by variable number of cysts in the medulla, usually concentrated at the corticomedullar junction
- initial injury probably involves the distal tubules with tubular basement membrane disruption, followed by chronic and progressive tubular atrophy involving both medulla and cortex and interstitial fibrosis
- cortical tubulointerstitial damage is caused of eventual renal insufficiency
3 variants of nephronophthisis disease complex
- sporadic, nonfamilial
- familial juvenile nephronophthisis (most common)
- renal-retinal dysplasia
- familial forms are inherited autosomal recessive
Children affected with nephronophthisis present first with
polyuria and polydipsia, which reflect a marked defect in the concentration ability of renal tubules
- sodium wasting and tubular acidosis are also prominent
- 16 responsible gene loci
Adult-onset medullary cystic disease
- autosomal dominant pattern
- mutations in MCKD1 and MCKD2
- progression to end-stage kidney disease in adult life
Nephrophthisis Morphology
- kidneys small, have contracted granular surfaces, and show cysts in the medulla, most prominently at the corticomedullary junction
- small cysts are also seen in cortex
- cysts are lined by flattened or cuboidal epithelium and usually surrounded by either inflammatory cells or fibrous tissues
- widespare atrophy and thickening of tubular basement membranes with interstitial fibrosis in the cortex
- glomerular structure generally preserved
Multicystic Renal Dysplasia
- dysplasia is sporadic and can be unilateral or bilateral and almost always cystic
- kidney is enlarged, extremely irregular, and multi cystic
- cysts vary in size from several mms to cms in diameter
- cysts lined by flattened epithelium
- normal nephrons but immature collecting ducts
- presence of islands of undifferentiated mesenchyme, often with cartilage, and immature collecting ducts
- most cases associated with ureteropelvic obstruction, ureteral agenesis or atresia, and other anomalies of the lower urinary tract
Acquired (Dialysis-Associated) Cystic Disease
- patients with ESRD who have undergone prolonged dialysis sometimes show numerous cortical and medullary renal cysts
- cysts contain clear fluid, are lined by either hyper plastic or flattened tubular epithelium, and often contain calcium oxalate crystals
- probably form as a result of obstruction of tubules by interstitial fibrosis or by oxalate crystals
- sometimes cysts bleed, but mostly asymptomatic
- increased risk of renal cell carcinoma
Simple Cysts
- may be single or multiple and usually involve the cortex
- translucent, lined by a gray, glistening, smooth membrane and filled with clear fluid
- on microscopic exam the membranes composed of a single layer of cuboidal or flattened cuboidal epithelium, which can be atrophic
- on occasion, hemorrhage into them may cause sudden distention and pain, and calcification of the hemorrhage may give rise to bizarre radiographic shadows
