Hypertensive Nephropathy and Renovascular Disease

Pressure-mediated (hypertensive nephrosclerosis)

• Benign nephrosclerosis: decades of moderately elevated pressure drive myointimal thickening and subendothelial hyaline deposition in the afferent arteriole (hyaline arteriolosclerosis), producing downstream ischemic glomerular obsolescence.
• Malignant nephrosclerosis: severe, rapidly rising pressure overwhelms autoregulation, causing fibrinoid necrosis and concentric onion-skin hyperplastic arteriolitis with a thrombotic microangiopathic picture.
• Loss of autoregulatory reserve: a reduced nephron mass (low birth weight, prior AKI, unilateral nephrectomy) transmits systemic pressure directly to the glomerular tuft, accelerating sclerosis.

Occlusive/renovascular

• Atherosclerotic renal artery stenosis: ostial or proximal plaque, essentially aortic disease extending into the renal ostium; the marker of an at-risk patient is atherosclerosis elsewhere (CAD, PAD, carotid disease).
• Fibromuscular dysplasia: non-inflammatory, non-atherosclerotic medial fibroplasia of the mid-to-distal artery in young women.
• Other vascular causes examiners use as distractors: Takayasu arteritis (young Asian woman, absent pulses), neurofibromatosis type 1 and mid-aortic syndrome in children, spontaneous renal artery dissection, radiation arteritis, and atheroembolic (cholesterol crystal) disease after aortic instrumentation.

Non-modifiable risk factors

• Genetic: APOL1 G1/G2 high-risk genotypes in patients of West African ancestry markedly increase risk of hypertension-attributed ESKD — the single best explanation for the racial disparity examiners plant in stems.
• Age, male sex, family history of ESKD, and low nephron endowment.

Modifiable risk factors

• Duration and severity of uncontrolled blood pressure — the dominant driver; the ACC/AHA 2017 Hypertension Guideline and KDIGO CKD guidance both frame CKD progression as pressure-dose dependent.
• Smoking (accelerates both atherosclerotic RAS and FMD), dyslipidemia, diabetes, obesity, high dietary sodium.
• Nephrotoxin exposure: NSAIDs, calcineurin inhibitors, cocaine and sympathomimetics (which can precipitate malignant hypertension).

Hypertensive Nephropathy

• Chronic hypertension-induced endothelial dysfunction: Elevated blood pressure causes mechanical injury to the glomerular endothelium and podocytes, initiating a cascade of inflammatory and fibrotic changes; sustained hypertension leads to medial hypertrophy of afferent and efferent arterioles
• Glomerulosclerosis and tubular atrophy: Ischemic injury from vascular narrowing causes segmental sclerosis of glomeruli, particularly in the juxtaglomerular nephrons; progressive replacement of functional renal parenchyma with fibrotic tissue reduces GFR
• Activation of renin-angiotensin-aldosterone system (RAAS): Hypertension-induced renal ischemia triggers renin release, perpetuating the cycle through angiotensin II-mediated vasoconstriction, glomerular capillary hypertension, and proteinuria
• Proteinuria as driver of progression: Filtered proteins (particularly albumin) undergo reabsorption and catabolism in proximal tubules, releasing inflammatory cytokines and growth factors (TGF-β) that promote tubulointerstitial fibrosis

Renovascular Disease

• Atherosclerotic RAS (85% of cases): Atherosclerotic plaques develop in the proximal renal artery, typically in patients >60 years with generalized atherosclerosis; stenosis >60% causes significant flow limitation and activates RAAS
• Fibromuscular dysplasia (15% of cases): Medial fibroplasia causes alternating segments of stenosis and dilatation ("string of beads" appearance); more common in young women and associated with better prognosis than atherosclerotic disease
• Post-stenotic hemodynamics: Pressure gradient across the stenotic lesion causes ipsilateral renal hypoperfusion, triggering renin secretion and systemic hypertension; the contralateral kidney experiences hypertensive injury from the elevated blood pressure
• Ischemic nephropathy: Severe bilateral RAS (>90% stenosis) or unilateral RAS with solitary kidney causes global renal hypoperfusion, progressive chronic kidney disease, and risk of acute kidney injury with ACE inhibitor/ARB use

Hypertensive Nephropathy

• Asymptomatic progressive renal dysfunction: Most patients present with incidentally discovered elevated creatinine and proteinuria; hypertensive nephropathy develops silently over years to decades with no urinary symptoms
• Proteinuria (usually <2 g/day): Non-nephrotic range proteinuria is characteristic; nephrotic syndrome is uncommon and should prompt consideration of alternative diagnoses (diabetic nephropathy, superimposed glomerulonephritis)
• Hypertension with target organ damage: Patients present with longstanding, often poorly controlled hypertension accompanied by left ventricular hypertrophy, retinopathy, or previous stroke; presence of hypertensive retinopathy supports the diagnosis
• Acute kidney injury on CKD: Deterioration in renal function with initiation of ACE inhibitors/ARBs or NSAIDs (indicating functional dependence on angiotensin II or prostaglandins for renal perfusion pressure)

Renovascular Disease

• Secondary hypertension with atypical features: Abrupt-onset hypertension in patients <30 years (fibromuscular dysplasia) or >60 years (atherosclerotic), hypertension refractory to ≥3 antihypertensive agents, or sudden worsening of previously well-controlled blood pressure
• Acute kidney injury precipitated by ACE inhibitor/ARB initiation: Classic presentation is acute rise in creatinine within days of starting RAAS inhibitor in patient with bilateral RAS or RAS to solitary kidney; creatinine typically stabilizes or improves after drug discontinuation
• Recurrent acute decompensated heart failure: Bilateral RAS with flash pulmonary edema; hypertension-induced LV dysfunction from increased afterload
• Abdominal or flank bruit on physical examination: Systolic bruit heard over upper abdomen or flank suggests turbulent flow through stenotic renal artery; present in only 25-50% of cases but highly specific when present
• Ischemic nephropathy with progressive CKD: Gradual decline in renal function despite antihypertensive therapy, often with small kidneys on imaging (<9 cm length)

Hypertensive Nephropathy

• Clinical diagnosis of exclusion: Diagnosed when chronic hypertension is associated with chronic kidney disease, proteinuria typically <2 g/day, and alternative causes of kidney disease are excluded (no hematuria, normal complement levels, negative ANA)
• Urinalysis findings: Absent or minimal hematuria (not dysmorphic); presence of >10 RBCs/hpf or RBC casts should trigger investigation for glomerulonephritis or other processes
• Renal biopsy (diagnostic confirmation): Shows benign nephrosclerosis with hyaline arteriolosclerosis affecting afferent and efferent arterioles, glomerulosclerosis, and tubulointerstitial fibrosis; rarely performed except to exclude superimposed processes or when diagnosis is uncertain
• Renal imaging: Ultrasound shows bilateral shrunken kidneys (typically asymmetric) with maintained corticomedullary differentiation; distinguish from other causes of CKD by bilateral involvement and lack of hydronephrosis

Renovascular Disease

• Doppler ultrasound: First-line imaging test; sensitivity 85%, specificity 92% for detecting RAS >60% when performed by experienced sonographer; limited by operator dependence and patient factors (obesity, bowel gas); excellent for surveillance in high-risk patients
• CT angiography (CTA) or MR angiography (MRA): Sensitivity and specificity >90% for RAS >60%; CTA is rapid and widely available but exposes patient to radiation and iodinated contrast (risk in CKD); MRA avoids radiation but contraindicated in severe renal insufficiency due to gadolinium-associated nephrogenic systemic fibrosis (avoid if GFR <30 mL/min/1.73m²)
• Captopril renography: Older radionuclide test with limited availability; detects asymmetric renal perfusion after ACE inhibitor challenge; largely replaced by CTA/MRA but useful in centers with expertise
• Renal artery stenosis on angiography: Gold standard diagnostic test; typically performed therapeutically during consideration of revascularization; demonstrates exact morphology and allows pressure gradient measurement across lesion (>20 mmHg systolic gradient suggests hemodynamically significant stenosis)
• Captopril challenge test: ACE inhibitor causes greater blood pressure reduction and greater increase in plasma renin in RAS patients; sensitivity and specificity both ~90%, but rarely used clinically due to superior imaging modalities
• Plasma renin activity: Elevated renin activity in unilateral RAS (renal vein renin ratio >1.5:1 favors hemodynamically significant stenosis); test rarely used given availability of imaging
• Important diagnostic consideration: Absence of RAS on imaging does not exclude "ischemic nephropathy" in patients with severely increased risk (advanced age, diffuse atherosclerosis, progressive CKD); hemodynamically insignificant lesions may still contribute to renal dysfunction through atherosclerotic disease burden

Hypertensive Nephropathy

• Aggressive blood pressure control: Target BP <130/80 mmHg (more stringent than general population) based on SPRINT trial; each 10 mmHg reduction in systolic BP is associated with slowing of GFR decline
• **AC

Complications of the disease

• Progression to ESKD: nephron dropout with glomerulosclerosis and tubulointerstitial fibrosis; signaled by a steady creatinine rise with bland urine sediment and shrinking kidneys.
• Malignant hypertension with thrombotic microangiopathy — emergency: fibrinoid necrosis shears erythrocytes, producing schistocytes, thrombocytopenia, elevated LDH, and oliguric AKI; look for grade III–IV retinopathy (flame hemorrhages, papilledema). Requires ICU-level intravenous therapy per the ACC/AHA 2017 Hypertension Guideline, with controlled pressure reduction to avoid ischemic organ injury.
• **Flash pulmonary edema (Pickering syndrome)** — emergency: bilateral RAS impairs pressure natriuresis, so volume cannot be offloaded; recurrent unexplained acute pulmonary edema in a hypertensive patient with normal or near-normal ejection fraction is the clue, and it is one of the few accepted indications for revascularization.
• Cardiovascular target-organ damage: LVH, HFpEF, atrial fibrillation, stroke, aortic dissection.
• Acute renal artery occlusion/dissection: sudden flank pain, hematuria, LDH spike, and abrupt hypertension — emergency.
• In FMD: extrarenal involvement with cervical/carotid dissection and intracranial aneurysm — screen the cerebrovascular bed.

Complications of treatment

• RAAS-inhibitor AKI: angiotensin II maintains efferent tone behind a stenosis; blocking it drops filtration pressure. Signaled by a creatinine rise within days of ACE inhibitor/ARB initiation, reversible on withdrawal.
• Hyperkalemia: from ACE inhibitor/ARB plus MRA in low-GFR patients — emergency when ECG changes appear.
• Contrast-associated AKI and atheroembolic disease after angiography/stenting: cholesterol crystal emboli cause livedo reticularis, blue toe syndrome, eosinophilia, hypocomplementemia, and subacute renal decline.
• Procedural: renal artery dissection, perforation, in-stent restenosis; gadolinium and nephrogenic systemic fibrosis at very low GFR.
• Overly rapid BP lowering: ischemic AKI, watershed stroke.

• **"*String of beads*" in a young woman: fibromuscular dysplasia, medial fibroplasia of the mid-to-distal renal artery. Per AHA guidance on FMD, treatment is percutaneous balloon angioplasty without** stenting, and hypertension often improves or resolves. Atherosclerotic RAS is ostial/proximal in an older patient with diffuse atherosclerosis — the location distinguishes them on the image.
• Stenting does not beat medical therapy in atherosclerotic RAS: CORAL and ASTRAL found no benefit of revascularization added to optimal medical therapy for BP, renal function, or events. The ACC/AHA 2017 Hypertension Guideline therefore favors medical management; reserve intervention for refractory hypertension, progressive renal failure, or recurrent flash pulmonary edema.
• A creatinine rise up to about 30% after starting an ACE inhibitor/ARB is expected and acceptable — continue the drug and recheck. A larger or progressive rise suggests bilateral RAS (or RAS to a solitary kidney). Common distractor: reflexively stopping the ACE inhibitor for any creatinine bump, or ordering angiography before duplex ultrasound.
• Best first test for suspected renovascular disease is noninvasive imaging — renal duplex ultrasound, or CTA/MRA — not catheter angiography, which is reserved for when intervention is planned.
• Unilateral RAS does not contraindicate RAAS blockade; the contralateral kidney maintains GFR. Bilateral disease is the setting of hemodynamic AKI.
• Biopsy vocabulary: benign nephrosclerosis = hyaline arteriolosclerosis; malignant hypertension = fibrinoid necrosis plus onion-skin hyperplastic arteriolitis with MAHA.
• Proteinuria is subnephrotic in hypertensive nephrosclerosis. Nephrotic-range protein, hematuria with RBC casts, or low complements mean a different diagnosis — look for glomerulonephritis or diabetic nephropathy.
• The association examiners test: APOL1 risk variants in patients of West African ancestry with hypertension-attributed ESKD.