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
