L14 Renal Hypertension

Overview

Hypertension is very common, is a major risk factor for both cardiovascular and kidney disease, and the kidney is the key player in both causing and suffering from it. The lecture works through two illustrative cases that separate the two classic renin/aldosterone patterns (renal artery stenosis versus a functioning adrenal adenoma), uses them to revise sodium, potassium and acid handling in the cortical collecting duct, then moves to essential hypertension: dietary salt, the Guyton pressure-natriuresis hypothesis, aldosterone acting on vascular endothelium, and the resulting arterial stiffness. It ends with the consequences for the kidney (arteriolosclerosis, glomerulosclerosis, progression of CKD), the expected fall in GFR when an ACEI or ARB is working, and evidence-based blood pressure targets and therapy.

Hypertension: scale of the problem and first assessment

• Very common in the community; a major risk factor for cardiovascular disease and kidney disease.
• Always look for a cause when hypertension is first seen. Judge the likelihood of a secondary aetiology from age at presentation and the presence of renal, endocrine, obesity or sleep apnoea factors, and from a poor response to drugs (once non-compliance is excluded).
• New Zealand data (2020/21 Ministry of Health New Zealand Health Survey, reported by BPAC January 2023) comparing measured raised blood pressure with medicated high blood pressure gives the percentage untreated: Total 25.8%, Māori 38.1%, Pacific 57.7%, Asian 46.9%, European/Other 18.5%. Treatment gaps are largest for Pacific and Asian peoples.

Confirming and screening:

• 24 hour ambulatory blood pressure monitoring is the gold standard for confirming hypertension. Traces show the systolic/diastolic band across ~24 hours with an overnight dip and a heart-rate trace.
• Consider obesity and cuff size as a source of error.
• Secondary causes to screen for: obstructive sleep apnoea (about 30%); renal, using urinalysis plus urine albumin/creatinine ratio (UACR) and kidney function; endocrine, using renin and aldosterone. Others are rare.
• Renal artery stenosis is rare: reduced renal perfusion gives raised renin, raised aldosterone and ischaemia.

Case 1: hypertension with hypokalaemia and a high renin

• 28 year old woman, BP 160/100 found on a routine check for the oral contraceptive. Not overweight, no symptoms, no risk factors (non-smoker, no family history), but the notes show a progressive rise in BP.
• No end organ damage: no proteinuria, no cardiomegaly.
• Bloods: Na+ 140 mmol/l, K+ 3.1 mmol/l (normal 3.5 to 5.2), creatinine 72 umol/l, urea 4.3 mmol/l.
• The clue is hypokalaemia with hypertension, which points to activation of ENaC by aldosterone. The next question is what has happened to renin, that is whether the renin-angiotensin system is activated or not.
• Results: plasma renin activity (PRA) 4.2 nmol/l/hr (normal 0.8 to 3) and aldosterone 957 pmol/l (normal 150 to 830). Both are elevated, which indicates renal ischaemia rather than autonomous adrenal secretion.
• Magnetic resonance angiography shows a narrowing at the origin of a renal artery. The sequence is reduced renal blood flow, then increased renin, angiotensin II and aldosterone, then increased BP.
• Diagnosis: fibromuscular hyperplasia producing renal artery stenosis. Treated by angioplasty, which was curative: BP 116/76 on no medications, with PRA and aldosterone normal.

The cortical collecting duct

The principal cell (lumen on the left, blood on the right):

• Na+ enters from the lumen through ENaC and K+ exits into the lumen.
• On the blood side the Na+/K+ ATPase moves 3 Na+ out and 2 K+ in.
• Aldosterone acts on the principal cell to increase ENaC activity, increasing Na+ reabsorption and, coupled to it, K+ excretion. This is why aldosterone excess produces hypertension with hypokalaemia.

The intercalated cell:

• H+ is pumped out into the lumen by an ATPase (with K+ moving in), and Cl-/HCO3- exchange occurs on the blood side via AE1, with carbonic anhydrase generating H+ and HCO3- from H2O and CO2.
• Aldosterone also drives H+ secretion here. With excess aldosterone the excretion of acid is inappropriately elevated, and the low luminal Na+ produced by increased ENaC reabsorption in the cortical collecting duct contributes, producing a metabolic alkalosis.

Case 2: hypertension with a suppressed renin

• 32 year old woman, routine check, contemplating pregnancy, not on the oral contraceptive, vegetarian. BP 156/96, attributed by her to a stressful job.
• Bloods: Na 139, K 3.6, urea 5.6, creatinine 82, HCO3- 29 (normal 22 to 28), pH 7.48. No proteinuria, ECG normal.
• PRA 0.32 nmol/l/hr (suppressed), aldosterone 1167 pmol/l (elevated). A low renin with a high aldosterone is autonomous (primary) hyperaldosteronism, in contrast to the high renin of Case 1.
• The teaching point is the combination of hypertension, hyperaldosteronism and metabolic alkalosis without hypokalaemia: the alkalosis is explained by increased acid excretion by the α-intercalated cell and increased Na+ reabsorption through ENaC in the cortical collecting duct, and the K+ here sits at the lower end of normal rather than frankly low.
• Management: control blood pressure with spironolactone, and image the adrenals by CT. CT showed a left adrenal nodule. The question then is whether the adenoma is functional.
• Options: medical treatment with spironolactone, or surgery, which is curative. The resected gland shows a nodular adenoma-like enlargement.

Mechanism of aldosterone-driven hypertension

• Increased aldosterone leads to increased Na+ and water retention, which raises blood pressure.
• Increased aldosterone also directly increases vascular tone.
• The Na+ and water retention is accompanied by increased K+ excretion and reduced renin release.
• Spironolactone blocks the action of aldosterone at the principal cell, removing the drive to ENaC.

Pathophysiology of hypertension and essential hypertension

• $BP=CO\times TPR$, with the rise in hypertension driven by total peripheral resistance.
• The fundamental defect is endothelial dysfunction with an increase in peripheral resistance (vessel stiffness). Proteinuria is itself a marker of endothelial dysfunction, and drug action is aimed at reducing peripheral resistance.

Essential hypertension:

• Accounts for 90% of cases, but there is still a probable underlying renal component and it is polygenic.
• In Western society the incidence increases progressively in the 4th to 5th decade.
• Elevated blood pressure is defined as >130/80.
• Normal systolic pressure is NOT 100 + age.
• The same first-presentation rules apply: always look for a cause, weigh age at presentation and renal, endocrine, obesity and sleep apnoea factors (sleep apnoea about 30%), and note a poor response to drugs.

Salt and the kidney

• “Therefore if large amounts of salt are taken the pulse will stiffen and harden” (Huang Ti Nei Ching Su Wein, 1700 BC, translation Wan Ping AD 762).
• Humans evolved in a low dietary salt, high potassium environment (fruit, cereals), with dietary salt <0.5 g/day. Current intake is 5 to 20 g/day, with New Zealand about 9 g/day. One teaspoon is 4 g of salt.
• Inability to excrete a salt load leads to volume expansion and hypertension, with probable polygenic inheritance related to sodium transporters.
• New Zealanders consume an average of 150 mmol of salt per day (NNS 1997); the WHO recommended intake is 80 mmol per day.
• 75 to 85% of New Zealanders’ salt intake comes from processed foods: bread, hard cheese, processed meats, soups, sauces, gravies, snack foods, frozen meals.

The Guyton hypothesis: pressure-natriuresis

• The pressure-natriuresis relationship links renal sodium handling to dietary sodium intake and is the central mechanism for long term blood pressure control.
• Normal response: an increase in dietary salt produces a transient rise in blood pressure, which elicits an appropriate renal response eliminating the excess salt and restoring normal blood pressure.
• Abnormal response: less than optimal salt excretion in response to the load maintains the elevated blood pressure. The pressure-natriuresis curve is shifted to the right (“escape”, with pressure reset at a new level).
• The loop, as drawn: increased sodium intake leads to increased renal sodium reabsorption, increased extracellular fluid volume, increased cardiac output, increased arterial pressure, and increased total peripheral resistance feeding back on arterial pressure. In parallel: salt intake raises plasma sodium concentration, driving water intake, extracellular fluid volume, cardiac output, blood pressure and peripheral vascular resistance, with the kidneys closing the loop through salt and water excretion.

Aldosterone, ENaC and the vascular endothelium

• Minor changes in aldosterone synthesis amplify salt sensitivity.
• An expanded intravascular volume increases arterial pressure.
• ENaC channels are expressed on vascular endothelial cells and sense vascular pressure (Wilding et al., Eur J Physiol 2009).
• Aldosterone acting via a receptor on the endothelial cell admits Na+ (and Ca2+) through these channels, increasing stiffness, decreasing NO release, and increasing vascular smooth muscle tone and vascular resistance.
• Proposed mechanosensor model (Drummond et al., Physiology 2008): an ENaC/ASIC channel is anchored between the extracellular matrix (via linking proteins) and the intracellular cytoskeleton; vascular wall tension stretches the channel and releases Na+/Ca2+ into the cell.
• A high Na+ / low K+ intake feeds five parallel pathways that all converge on a raised mean arterial pressure and are underpinned by vascular stiffness: impaired renal autoregulation and barotrauma (via WNKs and other pathways) causing sodium retention and volume expansion; endothelial dysfunction increasing systemic vascular resistance and wave reflections; myocardial changes in NOS expression and oxidative stress increasing afterload and causing left ventricular hypertrophy; and cerebral microvascular disease with raised pressure and abnormal shear stress.

Vascular pathology and arterial stiffness

Structural changes in hypertensive vessels:

• Thickened media, reduplication of the elastic lamina, intimal hyperplasia.
• Arteriosclerosis is disease of the media and alters stiffness; atherosclerosis is disease of the intima with plaque and alters the conduit.

Functional changes:

• Reduction in endothelium-mediated vasodilation.
• Changes in smooth muscle function, with smooth muscle cell hypertrophy as an attempt to modify the increased collagen.

Pulse wave analysis:

• Remember the conversion of pulsatile flow to laminar flow.
• Normally there is a forward pressure wave and a wave reflected from branch points which returns in diastole.
• With arteriolar stiffening the reflection arrives in mid systole and augments the peak, producing systolic hypertension and a widened pulse pressure (a stiff artery waveform runs about 90 to 160 mmHg versus 70 to 140 mmHg with the normal double T1/T2 peak).
• Augmentation index is the difference in height of the peaks expressed as a percentage of the pulse pressure, and is used as a marker of arterial stiffness.
• In young arteries the reflected wave returns late and augments diastolic pressure; in old or hypertensive arteries it returns early and augments systolic pressure, raising SBP and lowering DBP, and increasing pressure delivered to heart, brain and kidney (SE Greenwald, J Pathol 2007). Transmitted pressure (Pf forward, Pb backward, Pt transmitted) passes along the aorta and muscular arteries to the resistance vessels, including the renal arterioles.

Impact of vascular stiffness:

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

Hypertension and chronic kidney disease

• Hypertension is present in 80 to 85% of patients with CKD.
• Prevalence rises from 65% to 95% as GFR falls from 85 to 15 ml/min/1.73m2 (CKD grade 2 down to 5).
• Contributing factors: sodium retention, the renin-angiotensin-aldosterone system, sympathetic neural activity, and altered NO (vasodilator) versus endothelin (vasoconstrictor) activity. Inheritance is polygenic.
• Renal histology in hypertension: arteriolosclerosis, interstitial fibrosis, glomerulosclerosis and tubular atrophy, with compensatory glomerular hypertrophy of remaining glomeruli.

Progressive nephropathy:

• In CKD with hypertension the protective vasodilation or vasoconstriction is lost.
• The kidney senses the highs and lows in perfusion pressure, and creatinine rises and falls as perfusion pressure is corrected, in an almost linear relationship.
• Both the pre-glomerular pressure response and the post-glomerular compensation are lost, so rising systemic BP is transmitted directly to the glomerulus. On a plot of intraglomerular pressure against mean arterial pressure (80 to 160 mmHg), the line is steepest for chronic hypertension with chronic renal disease, intermediate for chronic hypertension with normal renal function, and flattest for normal.
• There is a strong relationship between hypertension and progression of renal disease, and between hypertension, end organ damage and survival (Klag 1996). The relationship is positive and continuous over the entire spectrum of blood pressure, and drives both progression of existing renal disease and morbidity and mortality in renal failure.

ACEI or ARB induced changes in GFR

• Scenario: an individual with CKD and hypertension is started on an ACEI or ARB and plasma creatinine rises from 136 umol/l to 188 umol/l. Is this AKI, critical renal artery stenosis, or an adverse drug effect? No: it demonstrates the ACEI or ARB working effectively.
• Mechanism: at normal perfusion pressure the afferent and efferent arteriolar resistances give a normal GFR. With an ACEI or ARB there is slightly increased afferent vasodilation (prostaglandin mediated) and, more importantly, loss of efferent angiotensin II tone giving greater efferent vasodilation, so intraglomerular pressure and therefore GFR fall.
• $SNGFR=K_f\times NFP$, with $K_f$ referring to the glomerulus and resistance highly sensitive to radius ($P\propto 1/r^4$).
• Worked example: BP 160/100 with eGFR 44 ml/min falls to BP 130/80 on an ACEI with eGFR 36 ml/min. The eGFR drop accompanies the intended fall in intraglomerular pressure.
• Long term, the two drug classes give different GFR trajectories (Weir M, Kidney Int 2011): felodipine shows an initial rise in GFR then a decline, whereas an ACEI shows a steady mild decline from a lower starting point.

Blood pressure targets and therapy

• Control BP (level 1 RCT evidence): the goal is a sitting systolic BP less than 120 mmHg if tolerated (SPRINT trial, N Engl J Med 2015). The greater the proteinuria, the lower the target blood pressure.
• SPRINT showed a significant reduction in major cardiovascular events and all-cause mortality with intensive blood pressure control in older individuals at high cardiovascular risk, including patients with CKD and mild proteinuria. Primary outcome (composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardiovascular causes) hazard ratio 0.75 (95% CI 0.64 to 0.89); death from any cause hazard ratio 0.73 (95% CI 0.60 to 0.90). Nephrologists should consider these results when setting BP targets in CKD (Rocco and Cheung, Kidney International 2016).
• Restrict NaCl intake (level 2 evidence generally, level 1 for BP control): goal 80 to 120 mmol/d (2.0 to 3.0 g Na) to optimise the antiproteinuric effect of ACEI, ARB or non-dihydropyridine calcium channel blocker therapy. Consider the role of a diuretic. Lower salt intake controls BP, which may further reduce proteinuria. Dietary advice matters.

Assessment of risk:

• Assess end organ involvement.
• Proteinuria (elevated albumin/creatinine or protein/creatinine ratio) is present in 30 to 40% of hypertensive individuals at diagnosis and is an indication to start an ARB or ACEI as first line treatment. It carries a 10-fold risk of a cardiovascular event.
• Normal blood pressure is less than 130/80, ideally less than 120/70.
• Framingham data (Vasan 2001, NEJM) show cumulative incidence of cardiovascular events over 14 years rises stepwise across BP categories in both women and men: optimal <120 mmHg systolic, normal 120 to 129 mmHg, high normal 130 to 139 mmHg.
• Tonelli et al. (BMJ 2006;332:1426) show that proteinuria and reduced GFR combine: for all cause mortality, new congestive heart failure, coronary death or non-fatal MI, and stroke, outcomes are worst in the group with GFR <60 plus proteinuria, and better in GFR ≥60 without proteinuria.

Proteinuria, hypertension and progression of kidney disease:

• Kidney protection in proteinuric individuals requires a lower target blood pressure: target BP < 120/76 mmHg.
• Preferred agents on meta-analysis are ACEI or ARBs (Palmer et al., Lancet 2015;385:2047-56); candesartan is the most potent anti-proteinuric agent.
• Use maximum recommended doses if tolerated. The goal is proteinuria <0.5 g/d, UACR < 50 mg/mmol.
• The antiproteinuric response and the residual proteinuria are predictive of long term outcome.

Non-pharmacological interventions: exercise, dietary salt reduction, stopping smoking.

Deciding when to start drug therapy (PREVENT-CVD equation, AHA 2025): antihypertensive drug therapy is indicated in stage 2 hypertension (≥140/90); and in stage 1 hypertension (130 to 139 or 80 to 89) where there is existing clinical cardiovascular disease, diabetes or CKD comorbidity, a PREVENT 10-year risk ≥7.5%, or persistent BP ≥130/80 after 3 to 6 months of lifestyle change. The paired lifestyle approach references Life’s Essential 8, stress reduction, and avoiding substances that raise BP (alcohol, over-the-counter pain medicines, herbal products).

Take home points

• The kidney is the key regulator of blood pressure.
• Hypertension is a major contributor to ischaemic heart disease.
• Hypertension is a major component of kidney disease and contributes to progression of CKD.
• Proteinuria and hypertension are major prognostic factors and require more aggressive treatment.
• Patients frequently require three drug therapy: ACEI or ARB first, then consider spironolactone, watching K+.
• Do not forget salt.

Self-test

1. List the secondary causes of hypertension to screen for at first presentation, with the investigation used for each, and state the gold standard test for confirming hypertension.
2. Distinguish the renin and aldosterone pattern of renovascular hypertension from that of primary hyperaldosteronism.
3. Describe, in order, the steps by which renal artery stenosis raises blood pressure.
4. Explain why aldosterone excess produces hypokalaemia, referring to the principal cell of the cortical collecting duct.
5. Explain the mechanism of the metabolic alkalosis seen with excess aldosterone, referring to the α-intercalated cell.
6. Describe the mechanism by which increased aldosterone raises blood pressure, including its effects on renin and potassium.
7. Explain where spironolactone acts and what it blocks.
8. State the equation relating blood pressure to cardiac output and peripheral resistance, and name the fundamental defect in hypertension.
9. State the threshold that defines elevated blood pressure, and explain what is wrong with the rule “normal systolic pressure is 100 + age”.
10. Describe the Guyton pressure-natriuresis hypothesis and predict what happens to blood pressure when the natriuretic response to a salt load is subnormal.
11. Give the average New Zealand salt intake, the WHO recommended intake, and the proportion of intake coming from processed foods.
12. Explain how ENaC on vascular endothelial cells is thought to contribute to hypertension.
13. Describe the structural histological changes of hypertensive vascular disease, and distinguish arteriosclerosis from atherosclerosis.
14. Explain how arterial stiffening alters the arterial pulse waveform, and define the augmentation index.
15. List the consequences of vascular stiffness for the heart, brain and kidney.
16. Give the prevalence of hypertension in CKD and how it changes as GFR falls, and list the contributing factors.
17. Describe the renal histological changes found in hypertensive kidney disease.
18. A patient with CKD and hypertension starts an ACEI; plasma creatinine rises from 136 to 188 umol/l. Explain what is happening at the glomerulus and what you would do.
19. State the SPRINT blood pressure goal, the target in proteinuric kidney disease, and the effect sizes SPRINT reported.
20. State the recommended salt restriction goal in mmol/d and g of sodium, and explain why it is used alongside an ACEI or ARB.
21. What proportion of hypertensive individuals have proteinuria at diagnosis, what does it change about management, and what risk does it carry?
22. Under the PREVENT-CVD based algorithm, in which situations is drug therapy indicated for stage 1 hypertension?
23. Integrative: explain how a single organ, the kidney, links dietary salt, aldosterone and vascular stiffness into a self-sustaining rise in blood pressure that then damages the kidney itself.

Answers

Reveal answers

1. Obstructive sleep apnoea (about 30%); renal causes, screened with urinalysis plus UACR and kidney function; endocrine causes, screened with renin and aldosterone; others are rare. Renal artery stenosis is a rare renal cause. The gold standard for confirming hypertension is 24 hour ambulatory blood pressure monitoring; also consider obesity and cuff size as a source of error.
2. Renovascular hypertension (renal ischaemia) raises BOTH renin and aldosterone, for example PRA 4.2 nmol/l/hr (normal 0.8 to 3) with aldosterone 957 pmol/l (normal 150 to 830). Primary hyperaldosteronism has a suppressed renin with a high aldosterone, for example PRA 0.32 nmol/l/hr with aldosterone 1167 pmol/l.
3. Stenosis reduces renal blood flow, which increases renin, and therefore angiotensin II and aldosterone, which raises blood pressure.
4. Aldosterone acts on the principal cell to increase ENaC activity. Na+ entry from the lumen through ENaC is increased, and K+ exit into the lumen is coupled to it (with the basolateral Na+/K+ ATPase moving 3 Na+ out and 2 K+ in), so increased Na+ reabsorption is obligatorily accompanied by increased K+ excretion, producing hypokalaemia alongside hypertension.
5. In the α-intercalated cell an apical ATPase pumps H+ into the lumen (taking K+ in), while AE1 exchanges Cl- for HCO3- on the peritubular side, with carbonic anhydrase generating H+ and HCO3- from H2O and CO2. Aldosterone drives H+ secretion, so acid excretion is inappropriately elevated; this, together with the low luminal Na+ resulting from increased ENaC-mediated reabsorption in the cortical collecting duct, produces a metabolic alkalosis.
6. Increased aldosterone causes Na+ and water retention, which raises blood pressure, and also directly increases vascular tone. The Na+ and water retention is accompanied by increased K+ excretion and reduced renin release.
7. Spironolactone blocks the action of aldosterone at the principal cell of the cortical collecting duct, removing the aldosterone drive to ENaC.
8. $BP=CO\times TPR$, with the rise in hypertension driven by total peripheral resistance. The fundamental defect is endothelial dysfunction with increased peripheral resistance from vessel stiffness; proteinuria is itself a marker of endothelial dysfunction.
9. Elevated blood pressure is >130/80. The 100 + age rule is wrong: normal systolic pressure is NOT 100 + age, and accepting it would leave most older hypertensive people untreated.
10. The pressure-natriuresis relationship links renal sodium handling to dietary sodium intake and is the central mechanism of long term BP control. Normally a rise in dietary salt causes a transient rise in blood pressure which drives the kidney to excrete the excess salt, restoring normal BP. If excretion of the salt load is less than optimal, the elevated blood pressure is maintained: the curve shifts to the right and pressure is reset at a new level (escape).
11. New Zealanders consume an average of 150 mmol of salt per day (NNS 1997); the WHO recommended intake is 80 mmol per day; 75 to 85% of intake comes from processed foods such as bread, hard cheese, processed meats, soups, sauces, gravies, snack foods and frozen meals.
12. ENaC channels are expressed on vascular endothelial cells and sense vascular pressure. Aldosterone acting via an endothelial receptor admits Na+ (and Ca2+) through these channels, which increases stiffness, decreases NO release, and increases vascular smooth muscle tone and vascular resistance. In the proposed mechanosensor model the ENaC/ASIC channel is anchored between extracellular matrix and cytoskeleton, and wall tension stretches it open, releasing Na+/Ca2+ intracellularly. Minor changes in aldosterone synthesis therefore amplify salt sensitivity.
13. Thickened media, reduplication of the elastic lamina, and intimal hyperplasia. Arteriosclerosis is disease of the media and alters stiffness; atherosclerosis is disease of the intima with plaque formation and alters the conduit. Functionally there is reduced endothelium-mediated vasodilation and altered smooth muscle function, with smooth muscle cell hypertrophy attempting to modify the increased collagen.
14. Normally the forward pressure wave and the wave reflected from branch points return in diastole. With stiffening the reflected wave returns in mid systole and augments the systolic peak, producing systolic hypertension and a widened pulse pressure (for example about 90 to 160 mmHg in a stiff artery versus 70 to 140 mmHg with a normal T1/T2 double peak), with a raised SBP and lowered DBP. The augmentation index is the difference in height of the peaks expressed as a percentage of the pulse pressure, used as a marker of arterial stiffness.
15. Heart: impaired diastolic perfusion, diastolic dysfunction, plus the added impact of coronary calcification. Brain: increased risk of stroke. Kidneys: arteriolosclerosis and glomerulosclerosis, and loss of autoregulation with a greater risk of AKI.
16. Hypertension is present in 80 to 85% of patients with CKD, and prevalence rises from 65% to 95% as GFR falls from 85 to 15 ml/min/1.73m2 (CKD grade 2 to 5). Contributing factors are sodium retention, the renin-angiotensin-aldosterone system, sympathetic neural activity, and altered NO (vasodilator) versus endothelin (vasoconstrictor) activity, on a background of polygenic inheritance.
17. Arteriolosclerosis, interstitial fibrosis, glomerulosclerosis and tubular atrophy, with compensatory hypertrophy of the remaining glomeruli.
18. This is not AKI, critical renal artery stenosis or an adverse effect: it demonstrates the ACEI working effectively. The drug causes slightly increased afferent vasodilation and, more importantly, loss of efferent angiotensin II tone with greater efferent vasodilation, so intraglomerular pressure and therefore GFR fall ($SNGFR=K_f\times NFP$, with resistance highly sensitive to radius, $P\propto 1/r^4$). The illustrative example is BP 160/100 with eGFR 44 ml/min falling to BP 130/80 on ACEI with eGFR 36 ml/min. Continue the drug rather than stopping it.
19. The SPRINT goal is a sitting systolic BP less than 120 mmHg if tolerated. In proteinuric kidney disease the target is < 120/76 mmHg, and the greater the proteinuria the lower the target. SPRINT reported a hazard ratio of 0.75 (95% CI 0.64 to 0.89) for the primary composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death) and 0.73 (95% CI 0.60 to 0.90) for death from any cause, in older people at high cardiovascular risk including those with CKD and mild proteinuria.
20. The goal is 80 to 120 mmol/d, which is 2.0 to 3.0 g of sodium. It optimises the antiproteinuric effect of ACEI, ARB or non-dihydropyridine calcium channel blocker therapy, and lowering salt intake also controls BP, which may further reduce proteinuria. A diuretic and dietary advice both have a role.
21. Proteinuria is present in 30 to 40% of hypertensive individuals at diagnosis. It is an indication to start an ARB or ACEI as first line treatment and to aim at a lower BP target, and it carries a 10-fold risk of a cardiovascular event. Goal proteinuria is <0.5 g/d with UACR < 50 mg/mmol, and both the antiproteinuric response and the residual proteinuria predict long term outcome.
22. In stage 1 hypertension (130 to 139 systolic or 80 to 89 diastolic), drug therapy is indicated where there is existing clinical cardiovascular disease, diabetes or CKD comorbidity, a PREVENT 10-year risk of 7.5% or more, or persistent BP ≥130/80 after 3 to 6 months of lifestyle change. Stage 2 hypertension (≥140/90) is treated with drugs from the outset.
23. An inherited (polygenic) limitation in sodium transport means a modern salt load of 5 to 20 g/day cannot be excreted at normal pressure, so the pressure-natriuresis curve shifts right and pressure resets higher (Guyton). Extracellular volume expansion raises cardiac output and then, through endothelial dysfunction, total peripheral resistance. Aldosterone amplifies this both at the principal cell, by increasing ENaC-mediated Na+ reabsorption, and at the vascular endothelium, where ENaC-mediated Na+ entry stiffens the cell and reduces NO release. The resulting arterial stiffness makes the reflected pulse wave return in systole, raising systolic pressure delivered to the kidney. Because pre-glomerular and post-glomerular autoregulation are lost, that pressure is transmitted directly to the glomerulus, producing arteriolosclerosis and glomerulosclerosis, which further impairs salt excretion and closes the loop. This is why the kidney is called the key player, and why treatment attacks both the salt and the renin-angiotensin-aldosterone arms.