Kidney Failure And Strokes: What's The Connection?

Stroke and kidney failure are closely linked. Research suggests that cerebrovascular diseases can stimulate kidney dysfunction as kidney activity is regulated by the brain through neural pathways. In addition, chronic kidney disease (CKD) is a risk factor for cerebrovascular and cardiovascular disease. CKD patients, especially those on dialysis, tend to have poorer outcomes after a stroke.

Renal dysfunction following an ischemic stroke

Stroke is a leading cause of mortality and morbidity, with long-term debilitating effects. Research suggests a cross-talk between the brain and kidney after a stroke. The brain and kidney act in concert to maintain normal homeostasis of the extracellular fluid by controlling sodium and water balance. Cerebrovascular diseases can stimulate kidney dysfunction as kidney activity is regulated by the brain through neural pathways.

Epidemiology

Chronic kidney disease (CKD) is a frequent problem in post-ischemic stroke patients. In a large-scale multicenter hospital-based study, approximately 35% of first-ever stroke patients exhibited symptoms of CKD such as proteinuria or low eGFR. CKD increases vascular dysfunction, vascular calcification, and arterial stiffness, which increases the risk of stroke. CKD patients are likely to be older, female, and present with comorbidities such as diabetes.

Acute kidney injury (AKI)

AKI is a common complication of acute ischemic stroke, with a pooled prevalence rate of 12.9% of patients developing AKI. AKI is commonly encountered in patients with critical illness and identified by decreased eGFR, albuminuria, acute rise in serum creatinine, increased serum cystatin C, and oliguria. Serum creatinine levels do not accurately reflect acute changes in kidney function and can vary widely with age, gender, etc. making it difficult to determine reference points.

Mechanisms of kidney dysfunction following stroke

The central autonomic network (CAN) is an integral internal regulation system that controls visceral motor and neuroendocrine responses. Lesions of the brain parenchyma affecting CAN or compression around the CAN after brain injury stimulate the superior sympathetic center, the visceral motor pathway, and finally the sympathetic nerve endings which then release norepinephrine. The hypothalamic–pituitary axis and sympathetic pathway, the renin–angiotensin–aldosterone system, the neuroendocrine system, autoregulation, inflammatory and immune responses, and extracellular vesicles and their cargo microRNA all play a role in mediating kidney dysfunction after stroke.

Effects of renal dysfunction on ischemic stroke

There is a significant increase in the risk of stroke and post-stroke mortality in patients with CKD and with end-stage renal disease. Proteinuria is associated with severe neurological deficits and higher in-hospital mortality after stroke. Hemorrhagic stroke is a leading cause of death in patients with CKD. Patients with end-stage renal disease undergoing peritoneal dialysis or hemodialysis have a high risk of stroke, with an increased risk of hemorrhagic stroke among hemodialysis patients.

Effects of age and sex

The prevalence of CKD rises dramatically with age and while 38% of elderly (>65 years) have moderate or severe CKD, only 13% of middle-aged adults (45–64 years) and 7% of young adults (18–44 years) have CKD. CKD is more common in women (15%) compared to men (12%), and the progression of CKD to end-stage renal disease is faster in men than in women; however, women with CKD are at a higher risk of fatal strokes compared to men with CKD.

Cerebrovascular and cardiovascular disease risk factors

Cerebrovascular and cardiovascular diseases are the leading cause of death globally, with an estimated 17.9 million people dying from them in 2019. These diseases include:

• Coronary heart disease
• Cerebrovascular disease
• Peripheral arterial disease
• Rheumatic heart disease
• Congenital heart disease
• Deep vein thrombosis and pulmonary embolism

The most important behavioural risk factors of cerebrovascular and cardiovascular disease are:

• Unhealthy diet
• Physical inactivity
• Tobacco use
• Harmful use of alcohol

Additionally, the following factors are also risk factors:

Age

Age is a risk factor for cerebrovascular and cardiovascular disease, with the risk of stroke doubling every 10 years between the ages of 55 and 85. However, a stroke can occur at any age, even during infancy.

Sex

Men are more likely to experience cerebrovascular and cardiovascular disease than women.

Hypertension

Hypertension is a major risk factor for cerebrovascular and cardiovascular disease. It is also a cause and consequence of kidney dysfunction.

Diabetes

Diabetes is a risk factor for cerebrovascular and cardiovascular disease. People with diabetes are more likely to experience kidney dysfunction.

Hyperlipidemia

Hyperlipidemia is a risk factor for cerebrovascular and cardiovascular disease.

Systolic blood pressure

Increased systolic blood pressure is a risk factor for cerebrovascular and cardiovascular disease, including any stroke, ischemic stroke, and hemorrhagic stroke.

Diastolic blood pressure

There is no significant association between diastolic blood pressure and the risk of ischemic stroke.

Fasting blood glucose

There is no significant association between fasting blood glucose and the risk of ischemic stroke.

Total cholesterol

Increased total cholesterol is a risk factor for ischemic stroke.

Triglycerides

Increased triglycerides are a risk factor for cerebrovascular and cardiovascular disease, but they are associated with a decreased risk of ischemic stroke.

Chronic kidney disease and stroke

Chronic kidney disease (CKD) is an independent risk factor for stroke, including both hemorrhagic and ischemic subtypes. CKD is often diagnosed by measuring creatinine clearance, proteinuria, cystatin C, albuminuria, estimated glomerular filtration rate (eGFR), urinalysis to evaluate for leukocytes and red blood cells, serum electrolytes, serum calcium, and parathyroid hormone levels. Among these parameters, eGFR is the most commonly used by clinicians to identify the stage of CKD.

CKD may be a frequently encountered problem in post-ischemic stroke patients. CKD increases vascular dysfunction, vascular calcification, and arterial stiffness, which increases the risk of stroke as well as exacerbates the pathogenesis of stroke. CKD patients, especially those who are on dialysis, do less well after stroke and have a higher chance of disability and death.

The risk of hemorrhagic stroke has been reported to be higher than ischemic stroke in hemodialysis patients when compared to peritoneal dialysis patients, though this has not been consistently the case, especially in recent studies. Risk factors for stroke include non-modifiable risk factors such as older age, diabetes, male gender, non-Caucasian/Asian ethnicity, and a positive family history. Hypertension continues to be the major modifiable risk factor for both ischemic and hemorrhagic stroke with risk increasing with worsening systolic and diastolic blood pressure control.

The prevalence of CKD rises dramatically with age and while 38% of elderly (>65 years) have moderate or severe CKD, only 13% of middle-aged adults (45–64 years) and 7% of young adults (18–44 years) have CKD. CKD is more common in women (15%) compared to men (12%), and the progression of CKD to end-stage renal disease is faster in men than in women; however, women with CKD are at a higher risk of fatal strokes compared to men with CKD.

Acute kidney injury (AKI) is an abrupt onset of renal dysfunction involving structural damage and functional impairment that develops within a few hours or days. AKI is commonly encountered in patients with critical illness and is identified by decreased eGFR, albuminuria, acute rise in serum creatinine, increased serum cystatin C, and oliguria, i.e. low urine output. AKI is a common complication of acute ischemic stroke, with a pooled prevalence rate of 12.9% of patients developing AKI, and AKI is associated with increased mortality.

In patients with lacunar infarctions, decreased eGFR and proteinuria have been associated with white matter hyper-intensities, cerebral microbleeds, and enlargement of perivascular spaces. Kidney damage indicated by proteinuria and renal insufficiency was found to be differentially dependent on stroke subtype. Patients who suffered a stroke of cardioembolic subtype displayed kidney damage and renal insufficiency, while hemorrhagic stroke (subcortical and subarachnoid) patients primarily exhibited proteinuria. Proteinuria after stroke was found to be an independent risk factor for worse neurological deficits and mortality.

Stroke-induced kidney dysfunction

Stroke is a leading cause of mortality and morbidity, with long-term debilitating effects. Accumulating evidence from experimental studies as well as observational studies in patients suggests a cross talk between the brain and kidney after stroke. Stroke may lead to kidney dysfunction which can adversely impact patient outcome.

Chronic kidney disease (CKD) is a risk factor for stroke, with CKD patients, especially those on dialysis, doing less well after stroke and having a higher chance of disability and death. CKD patients have a higher risk of heart disease and are thought to have an increased risk of stroke. CKD is becoming more common with increases in chronic conditions such as diabetes and an ageing population- these are known to cause CKD. CKD carries an increased risk of heart disease and is thought to increase the risk of stroke. However until now, research has mainly focussed on the relationship between heart and kidney disease, not stroke and kidney disease.

Acute kidney injury(AKI) is more common in CKD and is also on the rise. CKD patients, especially those who are on dialysis, do less well after stroke and have a higher chance of disability and death. Patients with AKI also do poorly but currently we don't know much about stroke patients who develop AKI. To date, there is no information on patients with stroke and kidney dysfunction in the United Kingdom.

In the past, research in patients with kidney disease has been very challenging for several reasons, including exclusion from large clinical trials due to multiple health problems. There is now a huge amount of data stored in electronic health records which offers huge potential for research in kidney patients.

This epidemiological study will determine how well patients with acute stroke and kidney dysfunction (both acute and chronic) do in comparison to stroke patients with no kidney dysfunction. Doctors need to understand the level of risk, disability and mortality in these patients to drive developments in care, including prompt recognition and treatment. Routinely collected data held in separate databases will be linked to provide a very rich dataset, allowing us to look at treatments and outcomes along the whole stroke care pathway in the NHS.

Brain injury's effect on kidney function

The brain and kidney are highly perfused organs with several common physiological characteristics. The brain controls kidney activity through neural pathways, and the two organs are inextricably linked under normal and disease states. Brain injury can lead to kidney dysfunction, which can adversely impact patient outcomes.

Mechanisms of brain-kidney interaction

The central pathway of brain-kidney interaction may be via the central autonomic network (CAN) and sympathetic nervous system. The peripheral signalling pathways of organ cross-talk may be regulated by inflammatory responses, autoregulation, the neuroendocrine system, and extracellular vesicles.

Role of the central autonomic network

The CAN is an integral internal regulation system that controls visceral motor and neuroendocrine responses. Brain injury can stimulate the superior sympathetic centre, the visceral motor pathway, and the sympathetic nerve endings, which then release norepinephrine. Brain damage to the primary and rostromedial motor area may affect renal function.

Neuroendocrine system

The hypothalamic-pituitary-adrenal axis regulates glucocorticoid release from the adrenal glands and can be directly activated following brain injury. Glucocorticoids affect renal function by influencing glomerular and tubular function. Short-term administration of glucocorticoids leads to an increase in the glomerular filtration rate (GFR), but chronic exposure may decrease it. Peripheral sympathetic nerve excitation stimulates the adrenal glands to secrete catecholamines, leading to elevated plasma norepinephrine levels. High-intensity and long-duration sympathetic excitation can cause renal ischemia.

Renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system may play a role in the pathogenesis of glomerular and interstitial fibrosis in the kidney. Angiotensin II is involved in the pathogenesis of stroke and is increased in the plasma of patients with mild stroke. Angiotensin II promotes the secretion of vasopressin or antidiuretic hormone (ADH), which regulates vasoconstriction and water retention in the body.

Autoregulation

Autoregulation of blood flow is a mechanism that maintains constant and continuous perfusion during changes in blood pressure. Cerebral autoregulation can be modulated by sympathetic nervous activity, the vascular renin-angiotensin system, and other factors that alter cerebral blood flow. Cerebral autoregulation is compromised following acute ischemic stroke.

Inflammatory and immune responses

Inflammation and immune responses play a vital role in the pathological progression of stroke. Brain injury increases the expression of inflammatory factors such as C-reactive protein (CRP), interleukin-6 (IL-6), IL-1β, reactive oxygen species (ROS), tumour necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP9), and IL-33 in the brain tissue and blood. Systemic inflammation and immune responses mediated by the spleen likely play a central role in promoting kidney dysfunction after brain injury.

Extracellular vesicles and microRNAs

Extracellular vesicles (EVs) mediate cell-cell communication and affect recipient cell function by carrying and delivering complex cargos of biomolecules. MicroRNAs (miRs) are a class of small noncoding RNAs that regulate gene expression. Upon brain injury, EVs released by endothelial cells, neurons, astrocytes, microglia, and other cells can mediate a "Yin-Yang" effect, such as injury and repair mechanisms in the brain, as well as be transported to distal organs.

Effects of brain injury on kidney function

Renal dysfunction following stroke

Stroke may lead to kidney dysfunction, which can adversely impact patient outcomes. Chronic kidney disease (CKD) increases vascular dysfunction, vascular calcification, and arterial stiffness, which increases the risk of stroke and exacerbates its pathogenesis. CKD is often diagnosed by measuring creatinine clearance, proteinuria, cystatin C, albuminuria, estimated GFR, and other parameters.

Acute kidney injury (AKI) is an abrupt onset of renal dysfunction involving structural damage and functional impairment that develops within a few hours or days. AKI is commonly encountered in patients with critical illness and is identified by decreased GFR, albuminuria, acute rise in serum creatinine, increased serum cystatin C, and oliguria. Serum creatinine levels do not accurately reflect acute changes in kidney function and can vary widely with age, gender, etc., making it difficult to determine reference points.

Haemorrhagic stroke-induced renal dysfunction

Haemorrhagic stroke can lead to a decrease in renal perfusion, nephrotoxicity, or damage to glomeruli, tubules, interstitium, or renal vasculature. Patients with haemorrhagic stroke had lower admission GFR compared to ischemic stroke patients, and a higher proportion of them developed renal impairment.

Effects of renal dysfunction on ischemic stroke

There is a significant increase in the risk of stroke and post-stroke mortality in patients with CKD and end-stage renal disease. Proteinuria is associated with severe neurological deficits and higher in-hospital mortality after stroke. Haemorrhagic stroke is a leading cause of death in patients with CKD. The risk of atherosclerotic cardiovascular diseases, such as myocardial infarction and stroke, is 5–30 times higher in CKD patients. Patients with end-stage renal disease undergoing peritoneal dialysis or haemodialysis have a high risk of stroke, with an increased risk of haemorrhagic stroke among haemodialysis patients.

Effects of age and sex

The prevalence of CKD rises dramatically with age, and it is more common in women than in men. The elderly with low GFR usually present with comorbidities such as arteriosclerosis and hypertension, while healthy ageing adults have a modest decline in GFR. The rate of progression from CKD to end-stage renal disease with patients needing dialysis or kidney replacement increases with advancing age.

Brain injury can lead to kidney dysfunction through various mechanisms, including the activation of the central autonomic network, neuroendocrine system, inflammatory and immune responses, autoregulation, and extracellular vesicles. This kidney dysfunction can adversely impact patient outcomes and increase the risk of stroke and post-stroke mortality.

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