CKD 👉🏿 a problem of chronic sympathetic activation and parasympathetic suppression: how to avoid it!

docbinah
Jul 7
12 min read

by Robin Rose MD July 7, 2025

Kidney decline and CKD roll off the tongue easily enough - most people think of kidney filtration without seeing the whole horizon of consequences.

In this blog I want to look at how come the nervous system gets dysregulated when kidney declines and offer some readily-available life hacks that each of us can engage to remedy this unpleasant and dangerous situation. Both clinicians and patients need to know this.

Autonomic dysfunction means the autonomic nervous system (ANS)—which controls involuntary functions like heart rate, blood pressure, digestion, and temperature regulation—is not working properly.

This imbalanced autonomic nervous system tone worsens with advancing CKD - but this can show itself as early as stage 2 - it is especially exaggerated in later stage CKD or with uremic neuropathy. Stress, poor sleep, inflammation, and anxiety further feed into this autonomic dysregulation.

Uremic neuropathy is the nerve-damaging consequence of kidney decline and failure —::> when toxic solutes can no longer be adequately filtered they invade and inflame the peripheral nervous system.

While most people associate it with numbness, burning feet, or restless legs, what’s less appreciated is its silent assault on the autonomic nervous system—the nerves that regulate heartbeat, blood pressure, gut motility, and even breathing during sleep.

CKD disarms the body’s natural calming signals and leaves the sympathetic nervous system in overdrive. .

👉🏿FIRST•••> How Does CKD Affect the Autonomic Nervous System?

First is the so what - when there’s excessive sympathetic nervous system stimulation the risk for complications becomes worse.

🍃🪷Increased SNS Activity🪷🍃

CKD causes chronic overactivation of the sympathetic nervous system (SNS).

This leads to:
- High blood pressure (hypertension)
- Increased heart rate (arrhythmias)
- Vascular stiffness, edema, CHF
- Sleep disturbances
- Worsening kidney function (vicious cycle)

👉🏿But why does this happen?

Diseased kidneys send abnormal afferent signals to the brain.
Reduced clearance of toxins like guanidines, uremic toxins, or AGEs will stimulate the SNS.
Inflammation and oxidative stress also activate the central sympathetic centers.

🍃🪷Reduced PSNS Tone🪷🍃

CKD results in decreased vagal tone

Heart rate variability (HRV) studies show reduced vagal (parasympathetic= PSNS) activity in CKD.
This results in decreased ability to recover from stress or regulate digestion and immune response (not trivial)!!

🍃🪷Baroreceptor Dysfunction🪷🍃

The baroreflex controls blood pressure moment to moment.

In CKD, this reflex is blunted, so the body struggles to stabilize blood pressure after standing, eating, or exercising.

🍃🪷Gut–Kidney–Brain Axis🪷🍃

We know how significantly CKD disrupts the gut microbiome (dysbiosis) •••> producing neurotoxic metabolites (including indoxyl sulfate, p-cresol sulfate).

These and many other toxins influence vagal tone and brain inflammation — which worsens the autonomic imbalance.

👉🏿Chronic kidney disease (CKD) doesn’t just affect filtration — it slowly rewires the body’s autonomic nervous system •••>> leading to disturbing dysregulated blood pressure, heart rate, and stress responses.

This can be remediated with intent.

At the core of this dysfunction is a silent biochemical imbalance involving renalase, COMT, and nitric oxide— molecules that normally maintain calm and cardiovascular balance.

🍃🪷 Renalase is a kidney-secreted enzyme flavoprotein which degrades excess circulating catecholamines like norepinephrine and dopamine.

In CKD, renalase production drops, allowing sympathetic overactivation—a key driver of hypertension and cardiovascular stress.

🍃🪷Similarly, COMT (catechol-O-methyltransferase), which breaks down catecholamines centrally and peripherally, can be affected by inflammation, uremic toxins, and genetic polymorphisms, further amplifying autonomic imbalance.

🍃🪷On the vascular side, nitric oxide (NO) bioavailability is impaired in CKD due to oxidative stress, elevated asymmetric dimethylarginine (ADMA), and reduced endothelial NOS activity—leading to stiff vessels, poor baroreceptor signaling, and sympathetic overdrive.

🍃🪷Other players include baroreceptor desensitization, carotid body overactivity, angiotensin II, FGF23, and increased oxidative stress, all converging to erode autonomic control.

This biochemical “storm” doesn’t just cause high blood pressure—it feeds a vicious cycle of left ventricular hypertrophy, arrhythmias, and sudden cardiac death.

🍃CKD Toxins Disrupting ANS 🍃

Indoxyl Sulfate
🪷Origin: Gut-derived (from tryptophan metabolism)
🪷Effect: Promotes oxidative stress, endothelial dysfunction, and vagal suppression
🪷Mechanism: Inhibits nitric oxide production; crosses the blood-brain barrier; increases sympathetic drive
🪷Clinical impact: Contributes to baroreflex impairment, arrhythmias, and vascular stiffness

p-Cresyl Sulfate

🪷Origin: Gut microbiota metabolizing tyrosine/phenylalanine

🪷Effect: Neuroinflammatory, damages endothelial and neural tissue

🪷Mechanism: Triggers inflammatory cascades in glial and autonomic neurons

🪷Clinical impact: Linked to orthostatic intolerance, vagal dysfunction, and depression

Asymmetric Dimethylarginine (ADMA)
🪷Origin: Endogenous; impaired clearance in CKD
🪷Effect: Inhibits nitric oxide synthase (NOS)
🪷Mechanism: Reduces NO bioavailability → baroreceptor dysfunction, hypertension, and sympathetic overactivity
🪷Clinical impact: Elevated SNS tone, sleep apnea, vascular spasm, HRV decline

Advanced Glycation End-products (AGEs)
🪷Origin: Endogenous and dietary; accumulate with low GFR
🪷Effect: Promote oxidative stress and neuroinflammation
🪷Mechanism: RAGE receptor activation on neurons, glia, and endothelium disrupts ANS signaling
🪷Clinical impact: Autonomic neuropathy, delayed gastric emptying, reduced thermoregulation

Urea & Guanidino Compounds (Creatol, Methylguanidine)
🪷Origin: Protein metabolism
🪷Effect: Direct neurotoxicity, particularly to peripheral and autonomic neurons
🪷Mechanism: Impair axonal transport and myelin structure
🪷Clinical impact: Uremic neuropathy, restless legs, impaired sympathetic outflow

Homocysteine
🪷Origin: Methionine metabolism; poorly cleared in CKD
🪷Effect: Endothelial and neuronal injury
🪷Mechanism: Promotes oxidative stress, disrupts autonomic tone via vascular baroreceptor injury
🪷Clinical impact: Hypertension, HRV reduction, cognitive-autonomic impairment

Phosphate
🪷Origin: Dietary and cellular breakdown; accumulates in CKD
🪷Effect: Vascular calcification and baroreceptor rigidity
🪷Mechanism: Stiffens carotid and aortic arch → impairs baroreflex sensitivity
🪷Clinical impact: Increases BP variability, HRV decline, sympathetic dominance

Uremic Toxins from Microbiome Dysbiosis (ie TMAO)
🪷Origin: Gut-derived; worsens with dysbiosis
🪷Effect: Inflammation, neurovascular disruption
🪷Mechanism: Alters vagal tone, contributes to systemic inflammation and endothelial dysfunction
🪷Clinical impact: Sleep dysregulation, fatigue, sympathetic overdrive

Beta-2 Microglobulin
🪷Origin: Cellular turnover; retained in CKD
🪷Effect: Promotes amyloid deposits and neuropathy
🪷Mechanism: Associated with nerve conduction delay and ganglionic injury
🪷Clinical impact: Sensorimotor and autonomic neuropathy in advanced CKD
🪷of note - it is elevated in stage 2 when tubular dysfunction has started - it is a useful laboratory test to determine if tubular proteinuria is happening ( different than glomerular proteinuria- a topic for a future blog )

Aluminum & Heavy Metals (from dialysis water or from the diet and the environment)
🪷Origin: Contaminants; accumulate in renal failure
🪷Effect: Central neurotoxicity, especially brainstem autonomic centers
🪷Mechanism: Disrupts mitochondrial function and neuronal signaling
🪷Clinical impact: ANS dysfunction, tremor, BP instability
🪷 heavy metal damage begins in stage 2 harming tubules - often under the clinical radar until CKD is way more advanced - have a high index of suspicion and test early

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👉🏿Clinical Manifestations of Autonomic Dysfunction in CKD

Long term consequences of decreased kidney function are many. Many — and often lead to severe struggling, suffering, and chronic illness and life compromise.

Once it is understood however, the RENOLOGY mind set becomes activated and what to do to achieve kidney success is the next order of business. Here’s some valuable info for understanding what results from a rattled ANS:

🧬Cardiovascular

Hypertension, arrhythmia, orthostatic hypotension

🧬Gastrointestinal

Gastroparesis, constipation, nausea

🧬Bladder

Urinary retention or urgency

🧬Thermoregulation

Cold intolerance, night sweats

🧬Fatigue

Especially postural or after meals

🧬HRV

Low variability = higher cardiac mortality risk

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🍃🪷NOREPINEPHRINE IN CKD🪷🍃

In healthy physiology, the sympathetic nervous system activates during stress, then subsides.

But in CKD, sympathetic tone becomes chronically elevated •••> and plasma norepinephrine levels reflect this state. This means prolonged and exaggerated response to stressors, toxins, and traumas - out of synch with other people.

Norepinephrine (NE) is both a neurotransmitter and a hormone. When persistently elevated
- It constricts blood vessels, raising blood pressure.
- Increases heart rate and cardiac workload.
- Impairs baroreceptor sensitivity, reducing feedback inhibition on the SNS.
- Suppresses vagal tone, weakening parasympathetic balance (heart rate variability declines).
- Exacerbates sleep disturbances, anxiety, and arrhythmias.

👉🏿 In CKD Specifically:

Reduced renal clearance of NE - kidneys help clear circulating catecholamines. As GFR drops, norepinephrine builds up.
Renal ischemia activates renal afferent nerves:
Hypoxia and tubulointerstitial injury activate renal sensory nerves that feed back to the brainstem—stimulating central SNS outflow and driving systemic NE release. The body’s wisdom is reflected in this communication ability between tissues.
Baroreceptor dysfunction:
A stiffened aorta and blunted carotid baroreceptors (common in CKD) impair buffering of NE surges. The result? Uncontrolled SNS surges and poor autonomic modulation.
( it’s unpleasant )
Uremic toxins and inflammation:
They disrupt central autonomic regulatory centers and increase COMT inhibition, further amplifying NE activity.

👉🏿 Clinical Impact of Elevated NE in CKD:

Hypertension resistant to standard therapy
Left ventricular hypertrophy and fibrosis
Arrhythmias and sudden cardiac death
Impaired renal perfusion, worsening kidney function (a vicious cycle)
Progression of proteinuria via glomerular hemodynamic stress
Fatigue and reduced heart rate variability—markers of poor prognosis

👉🏿 Clinical Marker

Plasma NE > 500 pg/mL is considered elevated.
In CKD, levels can exceed this due to both reduced clearance and increased production.

🧬 Key Insight:

Plasma norepinephrine is not just a biomarker—it’s a driver.

In CKD, the body becomes trapped in a state of persistent “fight or flight,” without the brakes of renalase, baroreflexes, or endothelial nitric oxide.

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🍃🪷 STAGE 2 CKD & the ANS🪷🍃

Stage 2 chronic kidney disease is often dismissed as “mild,” “normal,” or “age-related,” when in reality, it reflects a silent, progressive autonomic unraveling that begins deep within the renal tubules and echoes across every vascular and neurological system in the body.

At Stage 2 [ so very long before dialysis ] the tubulointerstitial matrix is already suffering. There’s hypoxia, fibrosis, loss of peritubular capillary integrity, and oxidative stress—and yet, somehow, this isn’t considered “clinically significant”? [That’s a true medical failure.]

Here’s the truth: the kidney isn’t just a filter. It’s an endocrine-autonomic command center. And when the tubules falter—even slightly—the result is a domino collapse in autonomic regulation:

Renal afferent nerves send distress signals to the brainstem.
The sympathetic nervous system activates reflexively, even in Stage 2.
Norepinephrine levels rise, unchecked by declining renalase.
COMT function falters under uremic and inflammatory pressure, choking the breakdown of catecholamines.
Baroreceptors desensitize, and vagal tone collapses.
Nitric oxide bioavailability plummets, stiffening vessels and further dysregulating blood pressure control.
And yet clinicians are still being taught to “watch and wait”?

No. This is not benign aging. This is an autonomic storm-in-the-making—a biochemical and neurologic crisis emerging from tubular microinjury that’s ignored until Stage 4. By then, the heart is hypertrophied, the arteries calcified, the nerves dulled, and the sleep shattered.

👉🏿Why Is there Urgency?

The same healthcare system that panics at elevated cholesterol shrugs off early CKD, even though:

Autonomic imbalance begins before eGFR drops below 60
HRV declines and nocturnal BP surges occur as early as Stage 2
Subtle tubular stress triggers global sympathetic overdrive

Why aren’t we monitoring renalase, COMT methylation status, HRV, or ADMA levels in Stage 2 CKD? Why are we waiting for irreversible damage?

As Jersey Girl says WHADDYA WAITIN FOR? 🤷🏾‍♀️

The tubules whisper early — but medicine only listens when the glomeruli scream.

👉🏿 Call to Action:

Stage 2 CKD is not mild—it is a neurovascular endocrine crisis incubating quietly.
Tubular injury must be seen as a trigger of systemic autonomic failure.
We can and have to intervene early by harvesting the low hanging fruit from the tree of lifestyle, endothelial support, renalase modulators, and sympathetic tone reduction, botanicals, supplements, peptides - not just ACE inhibitors and false reassurance.

👉🏿 SIDE BAR:

What are Renalase modulators👈🏿

🍃These act through:

STAT3 activation (anti-apoptotic)
Inhibition of NF-κB and MAPK (anti-inflammatory)
Reduction of ROS and mitochondrial dysfunction
NAD⁺ metabolism restoration
Suppression of sympathetic overdrive via catecholamine degradation

🪷🍃Renalase Modulation Benefits🍃🪷

🍃With ↑ Sympathetic tone —>Degrades excess norepinephrine & dopamine

🍃With Tubular hypoxia —>Protects from oxidative/apoptotic damage

🍃With Cardiovascular risk —>Lowers inflammation, improves endothelial function

🍃With Inflammation —>Suppresses cytokine cascades via STAT3

🍃With Fibrosis

Reduces TGF-β signaling & pro-fibrotic gene expression

🪷🍃Some natural renalase modulators🍃🪷

🪷Resveratrol

Activates SIRT1 and AMPK, enhancing renalase expression and mitochondrial protection.

🪷Curcumin

Inhibits NF-kB, reducing cytokine-driven renalase downregulation.

🪷Pterostilbene

Like resveratrol but more bioavailable; may promote renalase via antioxidant pathways.

🪷Berberine

Reduces sympathetic drive, improves endothelial function - with indirect renalase upregulation.

🪷CoQ10 / PQQ

Mitochondrial support may preserve renalase expression under oxidative stress.

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🍃🪷NOW LET’S LOOK AT SOME WAYS TO ENHANCE THE VAGUS AND FEEL BETTER🪷🍃

👉🏿🧬Exercise , qi gung, tai chi and yoga

Enhances vagal tone, reduces SNS, with improved HRV in CKD. Daily. With joy.

👉🏿🧬Omega-3 fatty acids ( diet & supplement)

Anti inflammatory, HRV improvement. Small RCTs have shown benefits.

👉🏿🧬Breathing Practices, meditation & HRV training

Enhances parasympathetic tone - this is a topic that deserves its own blog ••• daily mindfulness with breath has so many benefits in CKD. Watching the breath and the thoughts can assist us to rise into health.

👉🏿🧬Include pre/probiotics

Reduces gut-derived neurotoxins, promising gut–brain–kidney modulation

👉🏿🧬Low protein diet (LPD)

Reduces Sympathetic Over-activation

High urea and nitrogenous waste levels from excess protein stimulate sympathetic nerve activity, particularly via the carotid body and renal afferents.

LPD lowers uremic toxin load, which reduces sympathetic nerve firing, heart rate, and peripheral vasoconstriction.

Improves Baroreflex Sensitivity

Elevated protein breakdown raises phosphate, homocysteine, and ADMA, all of which impair nitric oxide (NO) and stiffen blood vessels, reducing baroreceptor sensitivity. LPD can reduce vascular resistance and restore baroreflex tone, improving heart rate variability (HRV).

Dampens Inflammation and Neuroimmune Crosstalk

Uremic inflammation (TNF-α, IL-6) disrupts central ANS regulation. LPD—especially when combined with plant-based or ketoanalogue support—lowers systemic inflammation, indirectly normalizing hypothalamic-pituitary-autonomic signaling.

Lowers Gut-Derived Neurotoxins

High-protein diets increase production of indoxyl sulfate and p-cresyl sulfate—gut-derived uremic toxins that impair vagal tone, promote neuroinflammation, and stimulate sympathetic outflow. LPD reduces substrate availability for these toxins, enhancing parasympathetic resilience.

Modulates Renal Afferent Signaling

High intratubular solute load increases renal sensory afferent signals that drive central sympathetic tone.

LPD lessens this burden, reducing afferent-driven sympathetic hyperactivity (renal-ANS feedback loop normalization).

👉🏿🧬Peace in the home

Intentional practice to create a sanctuary for healing in life. Make this a priority.

👉🏿🧬 Detox the Toxic People

A challenging practice in an often chaotic world - yet the effect of others’ behavior on our own health can be significant. Not always, but sometimes we are able to achieve this level of purification. Side stepping the stress induced by others takes practice.

👉🏿🧬 Joyful Abiding

Walking in the light of hope, with love, gratitude, forgiveness, and reciprocity can be the path to joy- a mind state that helps overcome the proverbial fear of kidney decline and allows us to embrace the way of joy. Remember joy and happiness are different.

👉🏿🧬Peptides (ie Cortexin, Pinealon)

These offer some reclaim in CKD neuroregulation in CNS/ANS- including pielotax and thymus bioregulators and personalizing each case is the asset and art of rehab by epigenetic repair.

👉🏿🧬 Botanicals and Functional Foods

This also deserves to be its own blog - but always critically important to have lovely fragrant herbs to put in the tea pot and in the cooking.

🪷 Ashwagandha (Withania somnifera) reduces cortisol, calms sympathetic overactivity - GABA-mimetic. May reduce uremic oxidative stress; monitor for potassium shifts.

🪷 Lemon Balm (Melissa officinalis) Calming, mild anxiolytic, supports vagal tone. Gentle on kidneys; useful for sleep and gut motility

🪷 Holy Basil (Ocimum sanctum)— aka Tulsi:

Adaptogenic, anxiolytic, modulates stress-induced sympathetic activity. Lowers catecholamines, supports dopamine-serotonin balance. May reduce uremic inflammation; gentle on the kidneys

🪷Reishi (Ganoderma lucidum) mushroom:

Balances HPA axis and immune-ANS crosstalk. Beta-glucans, triterpenes; modulates inflammatory cytokines and vagal anti-inflammatory pathway.

Renal protective in models; use low-dose to avoid hepatic interaction. Available as a supplement and is an edible functional food

🧬Vagus Nerve Stimulation (VNS) Devices & Tools

VNS enhances parasympathetic tone, regulates inflammatory reflexes, and is emerging as a option in CKD. There are many wearable vagus stimulation devises available commercially.

🍃🍃🪷WHAT ELSE TO DO🪷🍃🍃

Live joyously, with purpose, love, faith, and hope.

Creativity is a portal to GO TO VAGUS

👉🏿 How Creativity Restores ANS Balance

1. Singing and Vocalization

Stimulates the vagus nerve via deep exhalation, humming, chanting, or vocal music.
Promotes coherent heart rate variability (HRV)—a sign of improved parasympathetic tone.
Group singing synchronizes breathing and heart rhythms, enhancing social safety cues and reducing inflammation.
Studies show singing increases oxytocin and reduces cortisol

2. Visual Arts, Crafts, and Drawing

Induces a meditative, flow state, lowering SNS activity and reducing intrusive thoughts.
Increases dopamine and self-agency, vital in people with chronic fatigue or trauma.
Activates sensorimotor integration, helping those with ANS-related dissociation (common in trauma, CKD, and long illness).
Neuroimaging shows reduced amygdala activity and enhanced frontal lobe regulation during art-making

3. Cooking and Sensory Engagement

Involves tactile, olfactory, and visual stimuli, grounding the nervous system in present-moment experience.
Promotes mindful embodiment and slow breathing through scent and rhythm (cutting, stirring, plating).
When shared with others, it activates social parasympathetic pathways—a vital antidote to loneliness-driven dysautonomia.
Cooking can be considered “active mindfulness” a and self love - and supports vagal tone through enjoyment and mastery

4. Writing and Storytelling (reading aloud)

Facilitates emotional processing and reduces sympathetic arousal through narrative formation.
Journaling improves HRV and reduces systemic inflammation.
Enhances coherence and integration of trauma-related fragments in the brain, restoring ANS flexibility.

5. Dance and Expressive Movement

Combines physical activation with emotional expression, releasing stuck sympathetic energy.
Promotes body awareness (interoception), which is often blunted in ANS dysfunction.
Group or rhythm-based movement enhances social synchrony and oxytocin release.

🍃🍃🪷🪷 YOU GOT THIS🪷🪷🍃🍃

This topic really matters in CKD - knowing about this autonomic nervous system issue means we can observe it happening, we can listen to the body messages telling us it’s happening. We can embrace the self love and KidneYogi discipline to include what helps and eliminate what harms. Listen. Honor. Act lovingly. We can achieve kidney success.

YES! Kidney success - just those words sings a tune of good unfoldings. Together we can keep each other buoyant- and alone we can sustain our deepest holy health with intent for calm and the sanctity of wellness.

Aloha Kidney!

References

Converse RL et al. NEJM, 1992 – SNS activation in CKD
Campese VM et al. Hypertension, 2005 – Afferent renal nerve signaling
Rajendran S et al. Kidney Int Rep, 2020 – Autonomic imbalance and CKD
Yang T et al. Hypertension, 2021 – Gut–brain–kidney neural circuits
Karason K et al. Clin Auton Res, 2001 – HRV in dialysis patients
Converse RL et al., NEJM 1992; et al., J Physiol 2016
Vaziri ND et al., Nephrol Dial Transplant 2013;
Evenepoel et al., JASN 2009
Porges SW. Polyvagal Theory (2011)
Fancourt & Perkins, Perspectives in Public Health (2018)
Kaimal G et al. Art Therapy (2016)
Bolwerk A et al. PLoS ONE (2014)
Spence C. The Psychology of Food (2017)
Garfinkel SN et al. Nat Neurosci (2016)
Van der Kolk B. The Body Keeps the Score (2014)
Koch SC et al. Front Psychol (2019)
Chandrasekhar et al. Indian J Psychol Med (2012)
Kennedy et al. Nutrients (2011);m
Shahzadi et al. J Ethnopharmacol (2021)
Mondal S et al. Evid Based Complement Alternat Med (2011)
Wachtel-Galor et al. Herbal Medicine: Biomolecular and Clinical Aspects (2011)