The autonomic nervous system and renal physiology

Figures & data

Table 1 Brief history of the physiology of the autonomic nervous system

Dissection	Century	Relevant to physiology of organ systems
		Neuro	Cardiovascular	Renal	Hepatic
Total
Willis^Citation4	17th	+
Macro
Cannon^Citation5	20th		+		+
Smithwick^Citation47	20th		+	+
Parmley^Citation35	20th	+	+
Mini
Von Euler^Citation2	20th	+
Micro
DiBona^Citation6	21st		+	+
Esler^Citation1	21st		+	+

Table 2 Impact of autonomic nerve innervation on renal physiology

Norepinephrine constricts glomerular efferent arteriole

Decreased renal blood flow stimulates renin-angiotensin-aldosterone

Retains sodium in distal tubule

Activates sodium/potassium adenine triphosphatase in thick ascending limb of proximal tubule (loop of Henle) to increase interstitial osmolality promoting antidiuresis at collecting duct

Epinephrine increases expression of renin

Erythropoietin secreted by peritubular interstitial cells derive from a neural cell line that respond to hypoxia^Citation53

Table 3 Mechanisms of resistant hypertension

Secondary forms of hypertension

Renal artery stenosis

Adrenal adenoma/hyperplasia

Pheochromocytoma

Primary = essential hypertension = hyperactivity of the sympathetic nervous system

Inherited

Hyperactivity of the sympathetic system without a decrease in the parasympathetic system

Salt-sensitivity in African-Americans susceptible to focal glomerulosclerosis

Acquired

Sympathetic hyperactivity with a decrease in parasympathetic function in diabetic nephropathy

Excess white adipose tissue associated with sleep apnea-induced hypoxia

Activation of inflammation + oxidative stress = >stimulation of sympathetic system

Activation of cortical pathways to basal ganglia and brainstem by repeated episodes of hypoglycemia in type 1 diabetes

Acute/chronic glomerular or tubulointerstitial renal disease

Table 4 Resistant hypertension occurs in association with a number of factors

Resistant hypertension occurs in association with:

Acute/chronic glomerular or tubulointerstitial renal disease

Salt sensitivity, particularly if inherited with focal glomerulosclerosis

Individuals with a body mass index >30 kg/m^2, particularly if:

Over the age of 40 years

Leading sedentary lives

Demonstrating insulin resistance

Susceptible to sleep apnea-induced hypoxia

Excreting increased levels of urine albumin/creatinine

Type 1 diabetic patients with Body Mass Index <20 kg/m^2

Susceptible to repeated attacks of hypoglycemia

Demonstrating loss of parasympathetic function

Chronic inflammation/oxidative stress, including repeated use of:

Cigarettes

Cocaine

Pseudoephedrine, dextroamphetamine

Ma huang herbal preparation

Licorice root (Glycyrrhiza glabra) ⇨ aldosterone-like effect

Table 5 Classification of hypertension control

From office setting

Greater than 130/80, but less than 140/90 on a diuretic, plus a number of antihypertensive medications

One (mild)

Two (moderate)

Three (severe)

Greater than 140/90 on a diuretic plus three antihypertensive agents

Without papilledema or rapid loss of renal function ⇨ resistant hypertension

With papilledema or rapid loss of renal function ⇨ malignant hypertension

Greater than 140/90 on no antihypertensive, but less than 140/90

If taken outside of the office setting ⇨ white coat hypertension

Less than 140/90 on no antihypertensive, but greater than 140/90

If taken outside of the office setting ⇨ masked hypertension

From 24-hour ambulatory recording on diuretic, plus three antihypertensives

Greater than 140/90 both day and night ⇨ resistant hypertension

Greater than 140/90 during day, less at night ⇨ pseudoresistant hypertension

Less than 140/90 during day, greater at night ⇨ persistent hypertension

Table 6 Consequences of being labeled with the diagnosis of chronic resistant hypertension and reclassification by the use of ambulatory blood pressure monitoring observed in a high-risk group (chronic renal disease)

	Elevated office blood pressure	Controlled office blood pressure
Elevated ambulatory blood pressure	True resistant	Sustained
	25%	40%
	CV events: +++	CV events: ++
	Renal events: ++++	Renal events: +++
	Consider discontinuation of ineffective medications, change medications, enroll in a trial	Increase in appropriate therapy to reduce risk
Controlled ambulatory blood pressure	Pseudoresistant	Controlled
	10%	25%
	CV events: ++	CV events: ++
	Renal event: +	Renal events: +
	Consider whether any problems result from overtreatment

Abbreviation: CV, cardiovascular; +, number of events.

Table 7 Renal artery sympathetic radiofrequency ablation for resistant hypertension

Study inclusion criteria

• Blood pressure greater than 140/90 both day and night while complying with three or more antihypertensive medications of which one is a diuretic

• Between the ages of 18 and 80 years

• Appropriate renal artery anatomy (single renal artery greater than 4 mm diameter, >20 mm length to each kidney)^Citation75,Citation76

Study exclusion criteria

Anatomic

• Renal arterial anatomic exclusions (prior renal arterial intervention or evidence for renal artery stenosis, vessel smaller than 4 mm diameter, or <20 mm length)

Related to systemic disease

• Primary pulmonary hypertension

• Chronic oxygen support or mechanical ventilation

• Type 1 diabetes mellitus

• Chronic kidney disease with eGFR <45 mL/min or active focal sclerosis

• MI, angina, CVA within 6 months

• Prior history of autonomic dysfunction

Related to hypertension

• Secondary forms of hypertension

• Requirement for, or use of, medication or recreational substance known to raise blood pressure

Other

• Pregnancy or plan for pregnancy

• Prior keloid formation

• ICD or pacemaker, or any other metallic implant not compatible with MRI

Abbreviations: eGFR, estimated glomerular filtration rate; MI, myocardial infarction; CVA, cerebrovascular accident; ICD, implantable cardioverter-defibrillator; MRI, magnetic resonance imaging.

Table 8 Pros and cons of radiofrequency ablation of renal artery sympathetic nerve endings

Pros

• Decrease in problems of compliance and drug side effects

• Long-term medication cost lower

• Potential for reducing hard outcomes (suggested by degree of blood pressure lowering in short trials)

• Potentially safe for chronic renal disease patients with ≥45 mL/min in whom antihypertensives are not working (Stage 3A or better)^Citation79

Cons

Absence of:

• Accurate cardiovascular outcome data

• Placebo or sham controlled studies

• Experience with patient groups listed under exclusions in Table 7

• Consensus on trial of ganglionic blocking agents prior to ablation

• Data on comparative cost of medications versus high-tech equipment (catheters, MRI, procedure)

Risks related to:

• Radiation and contrast exposure

• Potential for renovascular complications (perforation, dissection, atheroembolism, keloid, necrosis)^Citation74,Citation75

• Possibility of orthostatic symptoms

• Potential for sympathetic renal dystrophy

Abbreviation: MRI, magnetic resonance imaging.

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