L14 Renal Hypertension

Hypertension 2026

Lecture in one line

The kidney is the central regulator of long-term blood pressure. The lecture moves from a clinical approach (when to suspect a secondary cause), through two paired cases of secondary hypertension (Renal artery stenosis then Primary hyperaldosteronism), into the core pathophysiology of essential hypertension (salt handling, endothelial dysfunction, vascular stiffness), then the bidirectional link with Chronic kidney disease, and finally evidence-based management centred on BP targets, proteinuria, and ACEI/ARB therapy.

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Approach: when to suspect secondary hypertension

• Understand why hypertension matters: very common, and a major risk factor for both cardiovascular disease and kidney disease.
• Be able to state the clues that raise the probability of a secondary (identifiable) cause:
  • Young age at presentation
  • Renal, endocrine, obesity, or sleep apnoea features
  • Poor response to drugs (once non-compliance is excluded)
• Know the categories to screen for: renal, endocrine, obstructive sleep apnoea, others (rare).
• Burden: OSA contributes to ~30% of cases; secondary aetiology overall is estimated around 30%.

Confirming the diagnosis and first-line investigations

• 24-hour ambulatory BP monitoring is the gold standard for confirming hypertension.
• Measurement pitfall: obesity and inappropriate cuff size distort readings.
• Screening workup for a secondary cause:
  • Renal: urinalysis plus UACR and kidney function
  • Endocrine: Renin and Aldosterone
  • Renal artery stenosis (rare): renin to aldosterone to ischaemia axis
• Lecture objectives this builds toward: recognising presentations, pathophysiology, relevant investigations, cardiovascular implications, therapy.

Case 1: Renal artery stenosis (renovascular hypertension)

Presentation

28-year-old woman, progressively rising BP (160/100), no classic risk factors, no end-organ damage, no proteinuria. Key clue: hypokalaemia with hypertension (K+ 3.1, Na+ 140).

• Understand why hypokalaemia plus hypertension points to a mineralocorticoid effect: aldosterone activates ENaC in the cortical collecting duct, driving Na+ reabsorption and K+ loss.
• Understand the cortical collecting duct cell model: the principal cell reabsorbs Na+ via apical ENaC (driven by the basolateral Na+/K+ ATPase) and secretes K+; aldosterone (ALDO) stimulates this. The intercalated cell handles H+ secretion.
• Work through the renin question. Here both PRA (4.2) and Aldosterone (957) are elevated.

Diagnostic pivot

Both renin AND aldosterone elevated indicates renal ischaemia driving renin (and therefore angiotensin II and aldosterone), i.e. a renovascular cause rather than primary adrenal overproduction. This is the key contrast with Case 2.

• Understand the cascade: stenosis lowers renal blood flow, which raises renin / angiotensin II / aldosterone, which raises BP.
• Imaging: magnetic resonance angiography demonstrates the stenosis.
• This case: fibromuscular hyperplasia causing the stenosis; treated with angioplasty; curative, BP normalising to 116/76 off medication with renin and aldosterone normalising.

Case 2: Primary hyperaldosteronism (Conn’s)

Presentation

32-year-old woman, mild hypertension (156/96), contemplating pregnancy. Pattern: hyperaldosteronism (aldosterone 1167) with suppressed renin (PRA 0.32) plus a metabolic alkalosis (HCO3- 29, pH 7.48).

• Key contrast with Case 1: renin is suppressed, indicating autonomous primary aldosterone production rather than renin-driven secondary hyperaldosteronism.

Reasoning point left open by the slide

Hyperaldosteronism with alkalosis, yet the patient is not hypokalaemic. Why? The lecture poses this without answering it; potassium can sit at the low-normal range despite ongoing aldosterone excess.

• Understand the alpha-intercalated cell of the cortical collecting duct: it secretes H+ into the lumen via apical ATPases and exports HCO3- to blood via the AE1 (Cl-/HCO3-) exchanger, with carbonic anhydrase generating H+ and HCO3- from $H_{2}O+C{O}_2$.
• Mechanism of the alkalosis: increased Na+ reabsorption via ENaC lowers luminal Na+ and creates an electrical gradient that inappropriately enhances H+ excretion, generating a metabolic alkalosis.
• Management:
  • Medical: Spironolactone (aldosterone antagonist)
  • Investigation: CT adrenals
  • Functional adenoma: surgery can be curative
• Gross pathology and CT show a unilateral adrenal adenoma; the question to resolve is whether it is functional.

Aldosterone, ENaC, and spironolactone

• Mechanism by which aldosterone raises BP: increases Na+ and water retention and increases vascular tone (raises BP); also increases K+ excretion and suppresses renin release.
• Spironolactone blocks the aldosterone effect on ENaC in the principal cell, reducing Na+ reabsorption and K+ loss.

Pathophysiology of essential hypertension

Governing equation

$BP=CO\times TPR$ The proposed fundamental defect is endothelial dysfunction with increased peripheral resistance (vessel stiffness). Therapy acts to reduce peripheral resistance.

• Link proteinuria to endothelial dysfunction (proteinuria is a marker of it).
• Definition and epidemiology:
  • ~90% of cases; still a probable underlying renal component; polygenic.
  • Western society: incidence rises through the 4th to 5th decade.
  • Elevated BP defined as >130/80.
  • Reject the old rule: normal systolic is NOT "100 + age".

The kidney and salt: the Guyton pressure-natriuresis hypothesis

• Evolutionary framing: humans evolved in a low-salt, high-potassium environment (dietary salt <0.5 g/day); current intake is 5 to 20 g/day (NZ ≈ 9 g/day; 1 tsp ≈ 4 g salt).
• Core mechanism: inability to fully excrete a salt load leads to volume expansion and hypertension; inheritance is probably polygenic and related to sodium transporters.
• Salt-intake figures: NZ averages ~150 mmol/day; WHO recommends ~80 mmol/day; 75 to 85% of intake comes from processed foods (bread, hard cheese, processed meats, soups, sauces, snack foods, frozen meals).

Guyton hypothesis

Renal sodium handling versus dietary sodium intake is the central mechanism for long-term BP control.

• Normal: a rise in dietary salt transiently raises BP, prompting the kidney to excrete the excess and restore normal BP.
• Abnormal: sub-optimal salt excretion keeps BP elevated.
• Escape: the pressure-natriuresis set point is reset to a new, higher level.

• Understand the abnormal pressure-natriuresis curve: in hypertension the curve shifts rightward, so a higher arterial pressure is needed to excrete the same Na load. Cascade: ↑Na intake, ↑renal Na reabsorption, ↑extracellular fluid volume, ↑cardiac output (and ↑TPR), ↑arterial pressure, with the kidney at the centre of the loop.

Salt sensitivity and vascular mechanosensing

• Proposed role of aldosterone and vascular endothelial cells (Wilding et al. 2009): minor changes in aldosterone synthesis amplify salt sensitivity; expanded intravascular volume raises arterial pressure; ENaC channels on vascular endothelial cells sense vascular pressure.
• A proposed mechanosensor model exists in vascular endothelial cells (Drummond et al. 2008).

Vascular stiffness and pulse wave analysis

• Structural changes of hypertensive vessels: thickened media, reduplication of the elastic lamina, intimal hyperplasia.
• Arterial stiffness is both functional and structural:
  • Functional: reduced endothelium-mediated vasodilation, altered smooth muscle function.
  • Structural: smooth muscle cell hypertrophy and increased collagen.
• Pulse wave velocity: stiff arteries shift pulsatile flow toward laminar flow and raise pulse wave velocity (loss of the Windkessel effect).
• Pulse wave analysis:
  • The waveform is a forward pressure wave plus a reflected wave from branch points; normally the reflection returns in diastole.
  • With stiffening, the reflected wave returns earlier (mid-systole), causing augmentation.
  • Result: systolic hypertension and a widened pulse pressure.
  • Augmentation index: the difference in height of the peaks as a percentage of pulse pressure.
• Older, stiffer vessels return the reflected wave early, raising pressure delivered to heart, brain, and kidney.

Impact of vascular stiffness on end organs

• Heart: impaired diastolic perfusion, diastolic dysfunction, additional impact of coronary calcification.
• Brain: increased stroke risk.
• Kidneys: arteriolosclerosis, glomerulosclerosis, loss of autoregulation with greater risk of AKI.

Hypertension and chronic kidney disease

• Epidemiology: hypertension is present in 80 to 85% of CKD patients; prevalence rises from ~65% to ~95% as GFR falls from 85 to 15 mL/min/1.73m² (CKD grade 2 to 5).
• Contributing factors: sodium retention, RAAS activity, sympathetic neural activity, altered nitric oxide (vasodilator) versus endothelin (vasoconstrictor) balance, polygenic inheritance.
• Renal histology of hypertensive damage: arteriolosclerosis, interstitial fibrosis, glomerulosclerosis, tubular atrophy, with compensatory glomerular hypertrophy.
• Progressive nephropathy: the protective ability to vasodilate or vasoconstrict is lost; the kidney is exposed to the highs and lows of perfusion pressure; creatinine rises and falls almost linearly as perfusion is corrected; both pre-glomerular pressure response and post-glomerular compensation are lost.
• Loss of renal autoregulation: normally intraglomerular pressure is held constant across a range of mean arterial pressures. In chronic hypertension with renal disease the autoregulatory plateau shifts and is lost, so rising systemic BP is transmitted directly to the glomerulus.
• Prognostic relationship (Klag 1996): a strong, positive, continuous relationship across the entire BP spectrum between hypertension and progression of renal disease, end-organ damage, and survival.

ACEI/ARB effect on GFR (the expected creatinine rise)

Common trap

Starting an ACEI or ARB in CKD can raise creatinine (e.g. 136 to 188; or eGFR 44 to 36 as BP falls 160/100 to 130/80). A modest rise is NOT AKI, critical renal artery stenosis, or toxicity . It demonstrates the drug working effectively.

• Mechanism: ACEI/ARB cause increased efferent arteriolar vasodilation (and slightly increased afferent vasodilation), lowering intraglomerular pressure. Since $SNGFR=K_f\cdot NFP$ lowering filtration pressure lowers GFR slightly while protecting the glomerulus long term.
• Resistance relationship: $P\propto \frac{1}{r^4}$, so small calibre changes have large effects.

Management: targets, salt, and proteinuria

• BP target (level 1 RCT, SPRINT trial, NEJM 2015): aim for sitting systolic <120 mmHg if tolerated; reduced major cardiovascular events and all-cause mortality, including in CKD with mild proteinuria.
• Proteinuria principle: the greater the proteinuria, the lower the target BP.
• Salt restriction goal: 80 to 120 mmol/day (2.0 to 3.0 g Na) to optimise the antiproteinuric effect of ACEI, ARB, or non-dihydropyridine CCB; lower salt both controls BP and may further reduce proteinuria; diuretics and dietary advice have a role.

Risk assessment and non-pharmacological measures

• Proteinuria as a risk marker: elevated UACR or PCR present in 30 to 40% of hypertensives at diagnosis; ~10x cardiovascular event risk; an indication to start ACEI or ARB first-line.
• BP thresholds: normal <130/80, ideally <120/70.
• Framingham (Vasan 2001): cardiovascular event incidence rises continuously even within “normal” ranges: optimal (<120) < normal (120 to 129) < high normal (130 to 139).
• Proteinuria/kidney-dysfunction outcomes (Tonelli, BMJ 2006): time to clinical outcomes worsens with both proteinuria and kidney dysfunction.
• Proteinuria-specific management (Palmer, Lancet 2015): target <120/76; preferred agents ACEI or ARB; candesartan cited as most potent antiproteinuric agent; use maximum tolerated doses; goal proteinuria <0.5 g/day (UACR <50 mg/mmol); antiproteinuric response and residual proteinuria predict long-term outcome.
• Non-pharmacological: exercise, dietary salt reduction, smoking cessation.
• Risk tool for initiating therapy: PREVENT-CVD equation (AHA 2025).

Take-home points

Summary

• The kidney is the key regulator of blood pressure.
• Hypertension is a major contributor to ischaemic heart disease.
• Hypertension is both a major component and a driver of progression of kidney disease.
• Proteinuria and hypertension are major prognostic factors and require more aggressive treatment.
• Treatment frequently requires three drugs, with an ACEI or ARB first; consider spironolactone but watch K+.
• Do not forget salt.

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Self-test

Can you answer these without looking?

• Clinical clues that should make you suspect secondary hypertension?
• Gold-standard method for confirming hypertension and the first-line secondary screen?
• Why does hypokalaemia with hypertension implicate aldosterone, using the cortical collecting duct?
• How do you distinguish renal artery stenosis from primary hyperaldosteronism using renin and aldosterone?
• How does excess aldosterone produce a metabolic alkalosis via the alpha-intercalated cell?
• Where does spironolactone act and why?
• Write $BP=CO\times TPR$ and state the fundamental defect in essential hypertension.
• Explain the Guyton pressure-natriuresis hypothesis, including “escape”.
• How does the pressure-natriuresis curve shift in hypertension, and the resulting cascade?
• Explain pulse wave analysis, the augmentation index, and why stiffening causes systolic hypertension and widened pulse pressure.
• End-organ consequences of vascular stiffness for heart, brain, kidney?
• How does hypertension damage the kidney histologically, and how is autoregulation lost in CKD?
• Why does creatinine rise modestly after starting an ACEI/ARB, and why is this reassuring?
• SPRINT-based BP target and how proteinuria modifies it?
• Salt restriction goal and the preferred antiproteinuric agents and targets?
• Prognostic significance of proteinuria in a hypertensive patient?