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

Microvascular

•Malignant HTN• Hypertensive Nephrosclerosis• Thrombotic microangiopathy• 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

Macrovascularo Large-vessel renal artery occlusive disease can result

from o extrinsic compression of the vessel

o fibromuscular dysplasiaso 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 (18–23%) &/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• 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

HTN

• 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 3–5 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- & institution- dependent

•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

•When HTN is refractory to effective therapy, revascularization offers real benefits.

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 disease &

renal artery stenosis

•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 (60–80%), 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. Statin therapy may improve outcome.

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)

venous circulation if RL shunting occurs (through a patent foramen ovale)

• 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 arteriography

•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 6–12 months "malignant"

•Pathology: “fibroid necrosis” & “onionskin” lesion

•most common in patients w/ treated hypertension that neglect to take meds, or who use vasospastic drugs (cocaine)

• Labs: rising serum creatinine, occ’lly 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

•Kidneys characterized by swelling of the endocapillary cells (endotheliosis), fibrin thrombi, platelet plugs, arterial intimal fibrosis, & membranoproliferative changes

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 infarction) •pathogenic agent: shiga toxin/verotoxin (E.coli &

Shigella dysenteriae)

•STEC strain 0157:H7: most common shiga-toxigenic 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 preformed

IgM results in severe MAHA.

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 autoantibody–positive (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 & surface-bound 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. • Plasma & WB should be avoided contain IgM w/c would

exacerbate the MAHA

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, & HLA-mismatched 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 for clinical trials. A firm diagnosis may be difficult because thrombocytopenia, anemia, and renal insufficiency are common in the posttransplant period.

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

•Tx: Plasma exchange + antiviral therapy

Radiation Nephropathy

•kidney 1 of the most radiosensitive organs• injury can result w/ as little as 4–5 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, & vascular cells

•Tx: No specific therapy is available

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)

• TX: ACE inhibition 1st-line therapy •Goal: reduce systolic BP by 20 mmHg & diastolic by 10

mmHg q24 hours until BP is normal

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 variant of APS

•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 anticoagulationGlucocorticoids may be beneficial in accelerated HTNImmunosuppression & 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; 10–20% 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 • shares many features w/ other forms of MAHA •both aHUS & TTP flares can be triggered by pregnancy•Aps patients have a higher risk for HELLP

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 markersPlasma exchange: considered if hemolysis is refractory

to glucocorticoids &/or delivery (esp if TTP is not ruled out)

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 • Kidney’s 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• (+) Proteinuria (20–30%)

•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 12–20% •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 - Aps, proteins C & S, antithrombin deficiency, factor V Leiden, disseminated malignancy, & OCPs

•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