Vascular Injuries

to the Kidneys

 Kidney filtering organ

rich in blood supply
Vascular injury could be
Microvascular
Macrovascular

Macrovascular

Renal Artery Stenosis

Atheroembolic renal
disease
Thromboembolic renal
disease
Renal Vein Thrombosis

Thrombotic microangiopathy
Microvascular
Hemolytic-Uremic Syndrome
(HUS)/ Thrombotic
Thrombocytopenic Purpura
(TTP)
Transplantation-Associated
Thrombotic Microangiopathy
(Ta-Tma)
HIV-Related Tma
Radiation Nephropathy
Scleroderma (Progressive
Systemic Sclerosis)
Antiphospholipid Syndrome
(Aps)
HELLP Syndrome
Sickle Cell Nephropathy

Macrovascular
o Large-vessel renal artery occlusive disease can
result from
o extrinsic compression of the vessel
o fibromuscular dysplasias
o atherosclerotic disease (most common)
o Any disorder that reduces perfusion pressure to
the kidney can activate mechanisms to restore
renal pressures at the expense of developing
systemic hypertension.
o restoration of perfusion pressures can reverse
these pathways

 Renal artery stenosis

considered specifically treatable "secondary" cause of
HTN
Atherosclerotic renal artery stenosis (ARAS)
common (6.8% of a community-based sample >65 yo)
prevalence increases w/ age & w/ other vascular
conditions
coronary artery disease (1823%) &/or
peripheral aortic/lower extremity disease ( >30%)
untreated, it progresses in 50% of cases over a 5-year
period (sometimes to total occlusion)
Intensive treatment of arterial BP & statin therapy
slow these rates & improve clinical outcomes

 Critical levels of stenosis lead to reduced perfusion

pressure
activates renin-angiotensin system
HTN
reduces sodium excretion
activates sympathetic adrenergic pathways
Renovascular HTN treated w/ agents that block the
renin-angiotensin system & other drugs that modify
these pressor pathways
also treated w/ renal blood flow restoration by
endovascular or surgical revascularization
most patients require continued antihypertensive
therapy revascularization alone rarely lowers BP to
normal

 ARAS & systemic HTN: affect both poststenotic &

contralateral kidneys reducing overall GFR in ARAS
Ischemic nephropathy: when kidney function is
threatened by large vessel disease
Unlike FMD, ARAS develops in pts w/ other risk factors
for atherosclerosis & commonly superimposed upon
preexisting small vessel dse in the kidney d/t HTN,
aging, & DM
Nearly 85% of pts considered for renal
revascularization have stage 35 CKD w/ GFR <60
mL/min per 1.73 m2.
The presence of ARAS is a strong predictor of
morbidity- and mortality-related cardiovascular
events, independent of whether renal
revascularization is undertaken.

 Diagnostic approaches to RAS depend on the specific

issues to be addressed.
Noninvasive characterization of the renal vasculature
may be achieved by several techniques (Table 286-1).
Activation of renin-angiotensin system is a key step in
developing renovascular HTN, but it is transient.
Renal artery velocities by Doppler UTZ >200 cm/s
predict hemodynamically important lesions (> 60%
vessel lumen occlusion)
Renal resistive index has predictive value regarding
the viability of the kidney operator- & institutiondependent

 Captopril-enhanced renography has a strong

negative predictive value when entirely
normal.
Magnetic resonance angiography (MRA): less
often used
gadolinium contrast associated w/
nephrogenic systemic fibrosis
Contrast-enhanced CT w/ vascular
reconstruction: excellent vascular images &
functional assessment (small risk of contrast
toxicity)

 FMD pts are younger females w/ otherwise normal

vessels & long life expectancy
TX: respond well to percutaneous renal artery
angioplasty
For ARAS: If BP is controlled to goal levels & kidney
function remains stable medical therapy w/
follow-up for disease progression is equally effective
Medical therapy includes:
blockade of renin-angiotensin system, attainment
of goal BPs, cessation of tobacco, statins, & ASA

 Techniques of renal revascularization are

improving.
Major complications (9%)
renal artery dissection, capsular perforation,
hemorrhage, & occasional atheroembolic
disease
Renal blood flow usually restored by
endovascular stenting
recovery of renal function is limited to 25% of
cases, no change in 50%, some deterioration
in others

Atheroembolic Renal Disease

Arise as a result of cholesterol crystals
breaking free of atherosclerotic vascular
plaque & lodging in downstream
microvessels
Most events follow angiographic procedures
(coronary vessels)
incidence has been increasing w/ more
vascular procedures & longer life spans
suspected in >3% of ESRD, elderly & likely
underdiagnosed
common in males, w/ history of DM, HTN, &
ischemic cardiac disease
strongly associated w/ aortic aneurysmal

 asso w/ precipitating events: angiography,

vascular surgery, anticoagulation w/ heparin,
thrombolytic therapy, or trauma
Clinical manifestations develop b/n 1 & 14 days
after an inciting event
fever, abdominal pain, & weight loss <1/2 of pts
cutaneous manifestations: livedo reticularis &
localized toe gangrene are more common
worsening HTN & deteriorating kidney function
are common
progressive renal failure can occur & require
dialysis

 Laboratory findings
rising creatinine, eosinophilia (6080%),
elevated sedimentation rate, &
hypocomplementemia (15%)
Definitive diagnosis: kidney biopsy
microvessel occlusion w/ cholesterol
crystals that leave a "cleft" in the vessel
Diagnosis of exclusion
Treatment
No effective therapy is available.
Withdrawal of anticoagulation is
recommended.

Thromboembolic Renal Disease

can lead to declining renal function & HTN
difficult to diagnose & often overlooked (esp
in elderly)
Causes:
local vessel abnormalities (local dissection,
trauma, or inflammatory vasculitis)
hypercoagulability conditions (rare)
distant embolic events (from left atrium in
patients w/ AF or fat emboli from
traumatized tissue --- large bone fractures)
Cardiac sources (vegetations from subacute
bacterial endocarditis)

 Acute arterial thrombosis

flank pain, fever, leukocytosis, nausea, & vomiting
If kidney infarction results LDH rise to extreme
levels
both kidneys affected decline in renal function w/ a
drop in urine output
single kidney involved minor renal function changes
HTN related to sudden release of renin from ischemic
tissue can develop rapidly, so long as some viable
tissue in the "peri-infarct" border zone remains.
Diagnosis of renal infarction may be established by
vascular imaging with MR, CT angiography, or

 Options for interventions of newly detected

arterial occlusion:
surgical reconstruction, anticoagulation,
thrombolytic therapy, endovascular
procedures, & supportive care
(antihypertensive therapy)
Depends upon the patient's overall condition,
precipitating factors, magnitude of renal tissue
& function at risk, & likelihood of recurrent
events in the future
Depending upon the precipitating event,
surgical or thrombolytic therapies can
sometimes restore kidney viability.

Malignant HTN
rapidly progressive BP elevations w/ target
organ injury (retinal hemorrhages,
encephalopathy, & declining kidney function)
If untreated, pts w/ target organ injury
(papilledema & declining kidney function)
mortality rates >50% over 612 months
"malignant"
Pathology: fibroid necrosis & onionskin
lesion
most common in patients w/ treated

 Labs: rising serum creatinine, occlly hematuria &

proteinuria, evidence of hemolysis (anemia,
schistocytes, reticulocytosis) & changes associated
w/ kidney failure
African-American males are more likely affected
Genetic polymorphisms (MYH9) predispose to
subtle focal sclerosing glomerular disease
Antihypertensive therapy: mainstay of Tx
effective BP reduction manifestations of
vascular injury including microangiopathic
hemolysis & renal dysfunction can improve over
time

Hypertensive Nephrosclerosis
Term used for a large portion of pts reaching
ESRD w/o a specific etiologic diagnosis
Pathology: afferent arteriolar thickening w/
deposition of homogeneous eosinophilic
material (hyaline arteriolosclerosis) asso w/
narrowing of vascular lumina
Clinical manifestations: retinal vessel
changes asso w/ HTN (arteriolar narrowing,
crossing changes), LVH & elevated BP
Antihypertensive therapy does NOT alter the
course of kidney dysfunction

Thrombotic Microangiopathy (TMA)

refers to injured endothelial cells that are
thickened, swollen, or detached mainly from
arterioles & capillaries
partial or complete occlusion by platelet &
hyaline thrombi integral to the
histopathology
histologic result of microangiopathic hemolytic
anemia (MAHA) consumes platelets & RBCs,
characterized by thrombocytopenia and
schistocytes

Hemolytic-Uremic Syndrome (HUS)

4 variants
D+ HUS
most common variant
associated w/ bacterial gastroenteritis
affects young children (<5 years)
>80% are preceded w/in a week by diarrhea
(bloody)
GI symptoms: abdominal pain, cramping, &
vomiting
Fever is ABSENT.
Neurologic symptoms are common (lethargy,
encephalopathy, seizures, even cerebral

 STEC strain 0157:H7: most common shigatoxigenic E. coli in US & Europe

shiga toxin enters the circulation binds to
PMNs & preferentially localizes in the kidney
damages endothelial cells results in platelet
aggregation initiates microangiopathic
process
Streptococcus pneumoniae
another bacterium associated w/ HUS
produces neuraminidase cleaves N-acetyl
neuraminic acid moieties that cover the
Thomsen-Friedenreich antigen on platelets &
endothelial cells
Exposure of this normally cryptic antigen to

Atypical HUS (aHUS)

caused by congenital complement dysregulation
low C3 levels (characteristic of alternative pathway
activation)
most common cause: deficiency of factor H
Factor H competes with factor B prevent formation of
C3b,Bb & acts as cofactor for factor I degrades C3b
Deficient for CHFR protein and factor H
autoantibodypositive (DEAP) HUS
autoantibody is formed against factor H
deletion of 84-kb fragment of chromosome encoding for
CFHR1 & CFHR3
autoantibody blocks binding of factor H to C3b & surfacebound C3 convertase

Thrombotic Thrombocytopenic Purpura (TTP)

pentad (hemolytic anemia, thrombocytopenia,
neurologic symptoms, fever, & renal failure)
Classic TTP is differentiated from HUS by neurologic
involvement.
absence or marked decreased activity in ADAMTS13
specific for vWF (not universally present)
Even complete absence of ADAMTS13 alone does not
produce TTP.
initiated by additional trigger (infection, surgery,
pancreatitis, or pregnancy)
median age: 40 years
Higher frequency among blacks (incidence >9x higher)
Women: 3x incidence
Untreated TTP mortality rate >90%

Acquired or Idiopathic TTP

Classic form
usually follows an infection, malignancy, or
intense inflammatory reaction (pancreatitis)
occurs w/ ADAMTS13 deficiency or its activity
result of an autoantibody(IgG or IgM) increase
clearance of ADAMTS13 or inhibit its activity
Upshaw-Schulman
hereditary form w/ congenital deficiency of
ADAMTS13
characterized by MAHA & thrombocytopenia
can start in the 1st weeks of life

Drug-induced TTP/TMA
complication of chemotherapeutic agents,
immunosuppressive agents, antiplatelet agents, & quinine
2 mechanisms are responsible for drug-induced TMA
Endothelial damage dose-dependent
chemotherapeutic agents (mitomycin C, gemcitabine,
etc.) & immunosuppressive agents (cyclosporine,
tacrolimus, sirolimus)
Induction of autoantibodies
Ticlopidine Suppress ADAMTS13 activity form
autoantibody
Quinine autoantibodies against granulocytes,
lymphocytes, endothelial cells & platelet glycoprotein
IbB/IX or IIb/IIIa complexes
Common in women

Treatment
Autoantibody-mediated TTP & DEAP HUS: plasma
exchange or plasmapheresis (remove
autoantibodies & replaces ADAMTS13)
Congenital TTP: Plasma infusion
Plasma exchange if larger volumes of plasma
are needed
TTP due to drug-induced autoantibodies responds
well to plasma exchange (drugs that cause
endothelial damage may not)
D+ HUS: supportive measures (Plasma exchange
is not effective)
aHUS: plasma infusion/exchange may be
beneficial
Neuraminidase-associated HUS: Antibiotics &
washed RBCs.

Transplantation-Associated Thrombotic
Microangiopathy (Ta-Tma)
develop after hematopoietic stem cell transplantation
(HSCT) 8.2%
Etiologic factors :conditioning regimens,
immunosuppression, infections, & graft-versus-host
disease
Other risk factors: female sex, age, & HLAmismatched donor grafts
occurs w/in first 100 days after HSCT
high mortality rate (75% in 3 months)
Plasma exchange is beneficial in <50%
Calciuria inhibitors should be discontinued &
substitute w/ daclizumab [antibody to IL-2receptor]
Rituximab & defibrotide may be helpful
. Table 286-3 lists definitions of TA-TMA currently used

HIV-Related Tma
seen in advanced AIDS & low CD4 count
Occasionally the 1st manifestation of
HIV infection
(+) MAHA thrombocytopenia & renal
failure are suggestive
Renal biopsy is required to establish the
diagnosis
median platelet count: 77,000/L (10,000
to 160,000/L)
CMV coinfection may be a risk factor

Radiation Nephropathy
kidney 1 of the most radiosensitive
organs
injury can result w/ as little as 45 Gy
exposure
characterized by renal insufficiency,
proteinuria & HTN
usually presenting >6 months after
radiation
Renal biopsy classic TMA in the kidney
w/ damage to glomerular, tubular, &

Scleroderma (Progressive Systemic Sclerosis)

affects the kidney 52% of subjects on follow-up
[19%= scleroderma renal crisis (SRC)]
SRC
occurs in diffuse systemic sclerosis (12% vs. 2% in
limited systemic sclerosis)
most severe manifestation
characterized by accelerated HTN, rapid decline in
renal function, nephrotic proteinuria, & hematuria
Retinopathy & encephalopathy may accompany HTN
Salt & water retention w/ microvascular injury can
lead to pulmonary edema.
Other manifestations: myocarditis, pericarditis &
arrhythmias poor prognosis.

 Renal lesion in SRC: arcuate artery intimal &

medial proliferation w/ luminal narrowing
onionskinning
Histologically indistinguishable from malignant
HTN
Fibrinoid necrosis & thrombosis: common
Mortality rate: 30% at 3 years
2/3 w/ SRC require dialysis [1/2 will recover renal
function (median time = 1 year)]
Anti-U3-RNP: identify young patients at risk for
SRC
Anticentromere antibody (ACA): (-) predictor of
SRC
Renal biopsy recommended for atypical renal
involvement (esp. if HTN is absent)

Antiphospholipid Syndrome (Aps)

vascular compartment w/in the kidney: main
site of renal involvement
Arteriosclerosis in the arcuate & intralobular
arteries are common
In intralobular arteries (+) fibrous intimal
hyperplasia (intimal thickening sec. to intense
myofibroblastic intimal cellular proliferation w/
extracellular matrix deposition) +
onionskinning
Renal biopsy: (+) TMA but (-) signs of MAHA &
platelet consumption
TMA is especially common in catastrophic

 Can involve large vessels

Renal vein thrombosis can occur (suspected in pts
w/ lupus anticoagulant LA + nephrotic range
proteinuria)
Can progress to ESRD
Hypertension is common
Treatment (APS):
lifelong anticoagulation
Glucocorticoids may be beneficial in accelerated
HTN
Immunosuppression & plasma exchange: helpful
for catastrophic episodes (but do not reduce
recurrent thrombosis

HELLP Syndrome
hemolysis, elevated liver enzymes, low
platelets
dangerous complication of pregnancy (0.5
0.9% of all pregnancies; 1020% w/ severe
preeclampsia)
mortality rate: b/n 7.4 & 34%
3rd trimester, 10% before week 27 & 30%
postpartum
nearly 20% are not preceded by preeclampsia
Renal failure in 1/2 of patients (etiology is not
well understood)
Renal histo findings= TMA w/ endothelial cell
swelling & occlusion of capillary lumens ; (-)
luminal thrombi

Diagnosis
A history of MAHA episodes before
pregnancy is helpful.
Reduced serum levels of ADAMTS13 (30
60%)
Some suggest LDH to AST ratio for diagnosis
Antithrombin III decreased in HELLP but
not in TTP
d-dimer elevated in HELLP but not in TTP
Treatment
Glucocorticoids may decrease
inflammatory markers

Sickle Cell Nephropathy

result from occlusion of vasa recta in the renal
medulla
The low partial pressure of oxygen and high
osmolarity predispose to hemoglobin S
polymerization & RBC sickling.
Sequelae hyposthenuria, hematuria, & papillary
necrosis
Kidneys response: increase blood flow & GFR
mediated by prostaglandins
SCD pts have greater GFR reduction by NSAIDS
(+) enlarged glomeruli
Intracapillary fragmentation and phagocytosis of
sickled erythrocytes responsible for
membranoproliferative glomerulonephritis-like lesion

 ACE inhibitors reduce proteinuria ((data

lacks on prevention of renal failure)
SCD pts are more prone to acute renal
failure
The cause reflects microvascular
occlusion asso w/ nontraumatic
rhabdomyolysis, high fever, infection, &
generalized sickling
(+) Chronic kidney disease in 1220%
HTN is uncommon

Renal Vein Thrombosis (RVT)

May present w/ flank pain, tenderness, hematuria,
rapid decline in renal function, & proteinuria OR it
can be silent
Left renal vein is more common; 2/3 are bilateral
Etiologies divided into 3 broad categories:
endothelial damage
- Homocystinuria, endovascular intervention,
& surgery
venous stasis
- dehydration
- compression & kinking renal veins from
retroperitoneal processes {retroperitoneal
fibrosis & abdominal neoplasms}
hypercoagulable states

 Diagnostic screening: Doppler ultrasound (more

sensitive than UTZ alone)
CT angiography: most sensitive test (nearly 100%
sensitive)
MR angiography: more expensive & requires
sedation in pedia pts.
Treatment
Anticoagulation & tx for the underlying cause
Endovascular thrombolysis: severe cases
Nephrectomy: life-threatening complications
Vena caval filters: prevent migration of the
thrombi