Renal Vascular Disease Pathology

Large Vessel Disease (Renal Artery Stenosis)

• Atherosclerotic mechanism: Plaques develop in renal artery ostia (ostial disease in 90% of cases) due to traditional atherosclerotic risk factors. Progressive luminal narrowing reduces perfusion pressure distal to the stenosis, triggering juxtaglomerular apparatus (JGA) activation and renin release. This initiates the RAAS cascade: renin cleaves angiotensinogen → angiotensin I → angiotensin II (via ACE). Angiotensin II causes afferent arteriole constriction, maintaining glomerular filtration pressure (GFP) despite reduced renal artery pressure. When stenosis exceeds 70-80% diameter narrowing, autoregulation fails, GFP drops precipitously, and ischemic acute tubular necrosis (ATN) and glomerular ischemia ensue. Chronic ischemia triggers tubulointerstitial fibrosis and glomerulosclerosis.

• Fibromuscular dysplasia (FMD) pathology: Characterized by disrupted arterial architecture with medial fibroplasia (most common; 60% of cases) showing alternating rings of smooth muscle cell hyperplasia and fibrous tissue loss, creating a "string of beads" appearance. Less common variants include intimal fibroplasia, medial hyperplasia, and adventitial fibroplasia. The etiology remains unclear but involves possible embryologic maldevelopment or dysregulation of smooth muscle growth factors (TGF-β, PDGF).

Small Vessel Disease

• Acute tubular necrosis (ATN) from hypoperfusion: Reduced perfusion pressure causes ATP depletion in proximal tubule epithelial cells, loss of Na-K-ATPase function, cellular edema, loss of brush border, and eventual epithelial cell necrosis. Morphologically, tubules appear dilated with flattened epithelium and cellular debris in lumens. If perfusion is restored quickly, the tubular basement membrane remains intact, permitting regeneration.

• Ischemic glomerulosclerosis: Chronic ischemia causes solidification of glomerular tuft with collapse and wrinkling of basement membrane, hyalinosis of afferent arterioles (homogeneous eosinophilic material in arteriolar walls), and eventual glomerular obsolescence. Tubular atrophy accompanies glomerular loss.

• Acute cortical necrosis: In massive renal artery occlusion, the cortex undergoes full-thickness necrosis with coagulative necrosis pattern (nuclei lost, cytoplasm hypereosinophilic) and inflammatory infiltrate. This is irreversible and leads to ESRD.

Arterial Fibrinoid Necrosis (Malignant Hypertension/ANCA Vasculitis)

• Fibrinoid necrosis occurs when acute severe hypertension (typically >180/120 mmHg) overwhelms endothelial autoregulation. Arterioles necrose acutely with deposition of fibrin-like material (antigen-antibody immune complexes, fibrin strands, platelets) within vessel walls. Endothelial injury allows plasma proteins to leak into the media. Light microscopy shows bright pink, homogeneous, proteinaceous material replacing normal architecture. This triggers acute tubular necrosis and acute cortical necrosis if severe.

• ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis) involves segmental necrotizing vasculitis of small arteries and arterioles. Antineutrophil cytoplasmic antibodies (ANCA) bind to neutrophil proteinase-3 (c-ANCA/PR3) or myeloperoxidase (p-ANCA/MPO), causing neutrophil activation, degranulation, and direct endothelial injury. Histology shows fibrinoid necrosis with crescent formation in glomeruli (see Glomerulonephritis entry for details).

Thrombotic Microangiopathy (TMA)

• Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) involve endothelial injury and platelet microthrombi within arterioles and glomerular capillaries. Shiga toxin (in HUS) or ADAMTS13 deficiency (in TTP) triggers endothelial activation. Microthrombi obstruct capillaries, causing mechanical hemolytic anemia (schistocytes on smear from RBC fragmentation), thrombocytopenia, and acute kidney injury (AKI) from capillary obstruction and ischemia. Histology shows platelet thrombi within glomerular and peritubular capillaries without significant inflammation.

Atheroemboli (Cholesterol Emboli)

• Plaque rupture from atherosclerotic aorta or renal artery releases needle-shaped cholesterol crystals (appear as clefts in formalin-fixed tissue due to cholesterol dissolution), fibrin, and platelet material into distal arterioles. Crystals lodge in small arteries and arterioles, triggering foreign-body giant cell reactions and inflammation. Downstream ischemia and inflammatory response cause acute tubular necrosis and can trigger vasculitis.

Atherosclerotic Renal Artery Stenosis (90% of RAS)

• Age >50 years, male sex, smoking, hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, previous coronary or peripheral artery disease
• Risk of progression: 5-15% per year; 50% develop hemodynamically significant stenosis within 5 years

Fibromuscular Dysplasia (10% of RAS)

• Young to middle-aged women (70% of cases), possible estrogen dependency (controversial)
• No clear genetic inheritance but occasionally familial
• Bilateral in 60% of cases, may involve other vessels (carotid, cerebral, coronary, mesenteric)

Acute Cortical Necrosis

• Acute massive renal ischemia from renal artery dissection, embolism, or severe thrombosis
• Obstetric causes (placental abruption, amniotic fluid embolism, septic shock)
• Severe pancreatitis, transfusion reactions, burns

Malignant Hypertension

• Uncontrolled or untreated hypertension, often from secondary causes (pheochromocytoma, renal artery stenosis, oral contraceptives)
• African American ethnicity (higher risk)

ANCA-Associated Vasculitis

• Genetic predisposition (HLA associations vary by subtype)
• Environmental triggers (infections, drug exposures) possibly implicated

Thrombotic Microangiopathy

• HUS: Shiga toxin-producing E. coli infection (especially O157:H7), preceding bloody diarrhea
• TTP: ADAMTS13 deficiency (congenital or acquired from antibodies)
• Atypical HUS: Complement dysregulation (factor H, factor I, membrane cofactor protein mutations)
• Drugs: Gemcitabine, mitomycin C, calcineurin inhibitors (tacrolimus, cyclosporine)
• Malignancy-associated TMA, pregnancy-related (preeclampsia/eclampsia)

Atheroemboli

• Aortic atherosclerotic disease, aortic aneurysm
• Iatrogenic: Aortic instrumentation (cardiac catheterization, aortic surgery, angiography)
• Anticoagulation or thrombolysis paradoxically increasing embolic burden

Other Vascular Causes

• Renal artery dissection (spontaneous or after trauma)
• Renal artery thrombosis (hypercoagulable states, antiphospholipid syndrome, nephrotic syndrome)
• Renal vein thrombosis (nephrotic syndrome, malignancy, prothrombotic states)

Acute Presentation (Acute Kidney Injury/Acute Arterial Occlusion)

• Sudden flank pain and hematuria (from cortical infarction with hemorrhage)
• Rapid rise in serum creatinine (doubling within days)
• Nausea, vomiting, abdominal discomfort
• Elevated LDH (from tissue necrosis) and elevated transaminases (hepatic infarction if massive occlusion)
• Mild proteinuria (<1 g/day) from ischemic tubular injury
• Absence of systemic features helps distinguish from vasculitis or TMA

Chronic Renal Artery Stenosis

• Refractory or accelerated hypertension (resistant to 3+ antihypertensive agents)
• Hypertension of sudden onset in older patients (atherosclerotic RAS) or young women (FMD)
• Recurrent hypertensive episodes or hypertensive urgency/emergency
• Gradual progressive renal insufficiency (GFR decline of >10 mL/min/year suggests hemodynamically significant RAS)
• Flash pulmonary edema (from hypertensive crisis and volume overload due to poor renal perfusion)
• Asymmetric renal atrophy on imaging (smaller kidney supplied by stenotic artery)
• Azotemia disproportionate to proteinuria (ischemic pattern, <1 g/day)

ACE Inhibitor or ARB Induced Worsening Renal Function

• Acute rise in creatinine >30% within 1-2 weeks of ACE inhibitor or ARB initiation is classic for bilateral RAS or RAS in solitary kidney
• This occurs because RAAS activation is compensatory for reduced renal perfusion pressure; blocking angiotensin II removes this compensation, dropping GFP acutely

Malignant Hypertension

• Severe hypertension (>180/120 mmHg) with acute end-organ damage
• Headache, altered mental status, seizures (hypertensive encephalopathy from cerebral edema)
• Dyspnea, orthopnea (acute pulmonary edema)
• Chest or back pain (aortic dissection)
• Acute kidney injury with hemolytic anemia (microangiopathic hemolytic anemia; MAHA)
• Retinopathy findings: Papilledema, flame hemorrhages, cotton-wool spots, Roth spots
• Urinalysis: Hematuria, proteinuria, RBC casts

ANCA-Associated Vasculitis

• See Vasculitis entry; pulmonary-renal syndrome common
• Hemoptysis, dyspnea, upper respiratory tract involvement (GPA)
• Acute glomerulonephritis presentation with dysmorphic RBCs, RBC casts, mild-to-moderate proteinuria

Thrombotic Microangiopathy (HUS/TTP)

• Classic triad of HUS: Microangiopathic hemolytic anemia, acute kidney injury, thrombocytopenia
• Diarrhea preceding HUS by 5-10 days (often bloody with O157:H7)
• Neurological symptoms in TTP: Fluctuating confusion, stroke, seizures
• Schistocytes on peripheral blood smear (fragmented RBCs)
• Elevated creatinine, elevated BUN, often severe AKI requiring dialysis
• Low platelets (often <30,000 in TTP)
• Elevated LDH, low haptoglobin (hemolysis markers)
• Normal coagulation studies (PT, PTT, fibrinogen) differentiate from DIC
• Negative Coombs test (RBC destruction is mechanical, not immune)

Atheroemboli

• Subacute kidney injury (days to weeks after aortic instrumentation)
• Lower extremity manifestations: Purple toe syndrome (livedo reticularis of feet), gangrene, pain
• Constitutional symptoms: Fever, malaise, weight loss (mimics vasculitis or infection)
• Eosinophilia (variable, sometimes prominent)
• Elevated ESR, possible low complement (C3, C4 may be borderline low from consumption)
• Rash: Palpable purpura on lower extremities and buttocks
• Can mimic ANCA vasculitis but ANCA and ANA typically negative

Renal Vein Thrombosis

• Acute presentation: Flank pain, hematuria, sudden increase in proteinuria
• Chronic presentation: Asymptomatic proteinuria detected incidentally
• Nephrotic syndrome if acute thrombosis (from infarction causing protein leak)
• Unilateral leg swelling if IVC involved

Imaging: Gold Standard for RAS

• Doppler ultrasound: First-line, operator-dependent; peak systolic velocity >200 cm/s or renal-aortic ratio >3.5 suggests >60% stenosis. Sensitivity 85%, specificity 92% in experienced centers. Non-invasive, no radiation or contrast.

• CT angiography (CTA): Sensitivity 94%, specificity 90% for detecting RAS; excellent for detecting "string of beads" appearance of FMD. Requires iodinated contrast (risk in renal insufficiency). Rapid acquisition useful for unstable patients.

• MR angiography (MRA): Sensitivity 90%, specificity 95%; avoids iodinated contrast but gadolinium is contraindicated in advanced renal disease (risk of nephrogenic systemic fibrosis, though rare with newer agents). "Stacked" appearance on source images is characteristic FMD finding.

• Captopril renography (radionuclide): Historically used; renovascular hypertension causes differential renal perfusion and delayed glomerular filtration on affected side. Low sensitivity (70%), rarely used now.

• Renal artery Duplex ultrasound: Noninvasive, no contrast; useful for follow-up. Peak systolic velocity and resistive index measured.

• Diagnostic renal artery angiography: Gold standard for diagnosis but reserved for cases where intervention (stent) is planned or diagnosis uncertain. Shows exact stenosis percentage, morphology (ostial vs. non-ostial; concentric vs. eccentric). Small risk of contrast-induced nephropathy, atheroemboli, and artery dissection. Pressure wire assessment can determine if stenosis is hemodynamically significant (fractional flow reserve <0.8 predicts benefit from revascularization).

Laboratory Findings

• Elevated creatinine (rise >0.5 mg/dL acutely) with acute rise in BUN; BUN-to-creatinine ratio often >20:1 (prerenal pattern from hypoperfusion)
• Elevated LDH (tissue necrosis)
• Elevated transaminases (hepatic infarction if severe)
• Mild proteinuria (<1 g/day)
• Microscopic hematuria (from cortical necrosis)

• Stable renal function until stenosis becomes hemodynamically significant, then progressive AKI
• Proteinuria <1 g/day (ischemic pattern; heavy proteinuria suggests intrinsic glomerular disease)

Immediate stabilisation

• Hypertensive emergency (malignant nephrosclerosis): admit to ICU for a titratable IV agent — a direct vasodilator such as nicardipine or clevidipine, or labetalol. The 2017 ACC/AHA hypertension guideline advises lowering mean arterial pressure by no more than ~25% in the first hour, then gradually over 24–48 hours; overly rapid correction infarcts the autoregulated kidney and brain. Sodium nitroprusside risks cyanide/thiocyanate accumulation in renal failure.
• Suspected TTP: emergent therapeutic plasma exchange plus glucocorticoids before ADAMTS13 results return; the ISTH guideline adds caplacizumab (anti-VWF nanobody) and rituximab for immune TTP. Delay is lethal.
• Acute renal artery thrombosis/dissection: anticoagulation and consideration of catheter-directed intervention within the window of viability.

First-line therapy for atherosclerotic RAS

• RAAS blockade: an ACE inhibitor (lisinopril) or ARB, plus high-intensity statin (atorvastatin), antiplatelet therapy, smoking cessation, and glycemic control — the medical arm shown non-inferior to stenting in CORAL and ASTRAL. The ACC/AHA hypertension guideline and KDIGO BP guidance favor this optimal medical therapy first.
• Monitor creatinine and potassium 1–2 weeks after initiation; a modest, stable creatinine rise is acceptable, a steep rise suggests bilateral disease.

Escalation / definitive management

• Percutaneous revascularization with stenting is reserved for failure of medical therapy: refractory or accelerating hypertension, recurrent flash pulmonary edema ("Pickering syndrome"), or rapidly deteriorating renal function.
• Fibromuscular dysplasia: balloon angioplasty without stenting is preferred (AHA scientific statement on FMD) and is often curative in young patients.
• Surgical bypass/autotransplant: for complex ostial disease, aneurysm, or failed endovascular repair.

Disease-specific

• ANCA vasculitis: glucocorticoids plus rituximab or cyclophosphamide, with avacopan as a steroid-sparing C5a receptor antagonist (ACR/VF and KDIGO glomerular disease guidance).
• Atypical HUS: terminal complement inhibition (eculizumab) after meningococcal vaccination.
• STEC-HUS: supportive care and volume repletion only.

Contraindicated

• ACE inhibitors/ARBs in bilateral RAS or stenosis of a solitary kidney, and all ACE inhibitors — captopril included — in pregnancy.
• Antibiotics and antimotility agents in Shiga toxin HUS (may increase toxin release).
• Routine platelet transfusion in TTP unless life-threatening hemorrhage.

Complications of the disease

• Progressive ischemic nephropathy and ESRD: chronic hypoperfusion drives tubulointerstitial fibrosis and global glomerulosclerosis. Signalled by progressive GFR decline with bland urine, low-grade proteinuria, and asymmetric kidney size on ultrasound.
• Flash pulmonary edema: impaired sodium excretion plus angiotensin II–driven afterload in bilateral RAS produces abrupt alveolar flooding without LV systolic failure. Recurrent unexplained pulmonary edema in a hypertensive azotemic patient is a revascularization trigger — an emergency.
• Hypertensive emergency with encephalopathy or MAHA: fibrinoid necrosis and hyperplastic onion-skin arteriolosclerosis breach the blood–brain barrier and shear red cells. Look for papilledema, schistocytes with a negative Coombs test, and normal PT/PTT. Emergency.
• Acute cortical necrosis: irreversible full-thickness coagulative necrosis after massive ischemia (obstetric catastrophe, severe TMA); anuria with cortical rim enhancement on CT predicts dialysis dependence.
• Renal infarction: acute flank pain with markedly elevated LDH and a wedge-shaped perfusion defect. Emergency.
• Extrarenal thrombosis in TMA: stroke, myocardial injury, and bowel ischemia from platelet microthrombi — emergency.

Complications of treatment

• Functional AKI after RAAS blockade: loss of angiotensin II–mediated efferent tone collapses filtration pressure. Signalled by a sharp creatinine rise with hyperkalemia within 1–2 weeks; reversible on withdrawal.
• Contrast-associated AKI and atheroembolic disease after angiography: cholesterol crystal showers produce subacute creatinine rise, purple toes, livedo reticularis, eosinophilia, and hypocomplementemia days to weeks post-procedure; often irreversible.
• Procedural: renal artery dissection, perforation, stent thrombosis, and in-stent restenosis (recurrent hypertension after initial improvement).
• Overly rapid BP lowering: watershed cerebral and renal infarction because chronic hypertension shifts the autoregulatory curve rightward.
• Immunosuppression: cyclophosphamide — hemorrhagic cystitis, infertility, urothelial cancer; rituximab — hypogammaglobulinemia, hepatitis B reactivation; eculizumab — meningococcal sepsis, an emergency mandating vaccination and often prophylactic penicillin; caplacizumab — mucocutaneous bleeding.

• Two arteriolar lesions, two settings: hyaline arteriolosclerosis (pink, glassy protein deposition) belongs to benign hypertension and diabetes; hyperplastic "onion-skin" arteriolosclerosis with fibrinoid necrosis belongs to malignant hypertension. Examiners pair onion-skinning with papilledema and schistocytes.
• Young woman, resistant hypertension, "string of beads" on angiography = fibromuscular dysplasia, medial fibroplasia subtype. Best treatment is balloon angioplasty without a stent, not medical therapy alone and not a stent.
• Creatinine jumps >30% within days of starting an ACE inhibitor or ARB = bilateral renal artery stenosis (or stenosis in a solitary kidney) until proven otherwise. Single best next step: stop the drug and image the renal arteries with duplex ultrasound or CTA.
• Recurrent flash pulmonary edema with preserved ejection fraction plus azotemia should prompt evaluation for bilateral RAS — the classic stem for revascularization despite CORAL/ASTRAL showing no benefit of routine stenting.
• Schistocytes + thrombocytopenia + normal PT/PTT/fibrinogen distinguishes thrombotic microangiopathy from DIC; negative direct Coombs excludes autoimmune hemolysis. ADAMTS13 activity below ~10% with an inhibitor defines immune TTP — start plasma exchange before the assay returns.
• Bloody diarrhea in a child followed by AKI = Shiga toxin HUS; the tested distractor is giving antibiotics or antimotility drugs, which may worsen toxin release. Management is supportive.
• Days-to-weeks after cardiac catheterization: rising creatinine, livedo reticularis, blue toes with intact pulses, eosinophilia, low complement = cholesterol atheroembolism. Biopsy shows biconvex needle-shaped cholesterol clefts. It mimics ANCA vasculitis, but ANCA is negative — do not start cyclophosphamide.
• Pregnancy trap: every ACE inhibitor is contraindicated in pregnancy. Captopril's short half-life makes it handy for rapid titration and historically for captopril renography, never for a pregnant patient.