Review ArticleRenal-Cerebral Pathophysiology: The Interplay Between Chronic Kidney Disease and Cerebrovascular Disease
Introduction
The role of the kidneys in maintaining chemical homeostasis is a crucial one, and yet it is only one facet of kidney function. The kidneys are involved in continual hormonal communication regulating blood pressure via the renin angiotensin aldosterone system. Other roles include regulation of erythropoiesis, bone mineral composition/calcium homeostasis, sensing of oxygen delivery, and increasingly the kidneys are recognized to be an important center of endothelial signaling.1
The brain, like the kidneys is the recipient of a large percentage of cardiac output, and is one of the most sensitive organs, requiring tight specifications to maintain optimal function.2 The delicate neurons are sensitive to perturbations in sodium flux, calcium flux, blood pressure changes, oxygen delivery, and overall cleanliness of the blood from urea associated nitrogenous wastes.3
Hence, it is reasonable that the health of the delicate cerebral organ, and the plethora of electrically interconnected and fragile neurons would depend heavily on appropriate renal function.1 The traditional risk factors of neurological disease associated with the kidneys include acute hypertensive emergencies leading to cerebrovascular hemorrhage, thrombosis from vascular disease leading to infarction, and cardiac disease leading to embolism.4 Uremic neuropathies, vascular calcification, hyponatremia are also less recognize renal risk factors for neurological disease. Renal failure also contributes to cerebral pathology via increased bleeding risk, phosphatonin level changes, and derangements in calcium and vitamin D homeostasis.1,5
All these factors could represent nontraditional risk factors for cerebral disease directly stemming from Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD).1,5 In this review, presentation of “basic renal definitions” of hypertension, CKD GFR staging, proteinuria staging, role of AKI, proteinuria staging, urinary markers of injury, CKD epidemiology, electrolyte management, and management of CKD comorbidities are also reviewed. The classic risk factors for cerebrovascular disease in CKD are also reviewed, followed by “nontraditional causes of cerebral disease in CKD.” It is hoped that closer neurological and nephrological collaboration will yield fruitful discoveries to understand the excess risk of neurological dysfunction in CKD patients.
Section snippets
Nephrology for neurologists
Hypertension staging at this point is guided by the agreed upon Joint National Comission-8 (JNC-8) on Hypertension control. Normal blood pressure is defined as <120/80 mmHg. Prehypertension is 120-139 mmHg/80-89mmHg. Stage I Hypertension is 140-159 mmHg/90-99 mmHg. Stage II is defined as >160-180/100-110 mmHg of blood pressure. Stage III is defined as >180mmHg/110 mmHg. Isolated systolic hypertension is defined as >140 mmHg systolic reading with a normal diastolic reading. Resistant
CKD epidemiology
Proteinuria is a major predictor of CKD progression, and most of the patients who progress to ESRD have conditions associated with significant proteinuria.22 Importantly it is associated with severe vascular inflammation and a prothrombotic state.23 Macro-angiopathies are frequently seen in proteinuric diabetics, and include coronary artery disease (CAD), peripheral vascular disease (PVD), and cerebrovascular disease (CVD).24 Micro-angiopathies associated with proteinuria and particular due to
Pertinent electrolytes in neurological care
For the purposes of neurological care, sodium levels are defined in the normal range as >135 meq/L, with an absolute maximum correction of 10 meq/L/day.49 Sodium control remains extremely relevant in neurology given the risk of seizures, cognitive difficulties, gait difficulties, and decreased levels of mentation that are associated with both hyponatremia and hypernatremia.49 The main risk of acute hyponatremia is due to the development of cerebral edema due to the imbalance of central nervous
Management of CKD comorbid disorders
The classic comorbidities of CKD include anemia of CKD, infection risk, electrolyte derangement, metabolic acidosis, bone mineral disease, hypertension, decreased medication clearance.56 Another crucial possible complication is malnutrition due to protein energy wasting (PEW) in advanced CKD.42 Many of these effects become more pronounced after CKD stage IIIb (eGFR <45 mL/min), as this in particular is when phosphorous levels rise and phosphatonin secretion (FGF-23) increases sharply.56
Anemia
Traditional mediators of cerebrovascular disease in CKD patients
Traditional mediators refer to well-known mediators of hemorrhagic and atherosclerotic cerebrovascular disease. These include hypertension and atherosclerosis related to hypercholesterolemia respectively. Cerebral changes can also occur because of microbleeds, microinfarcts, white matter lobal atrophy, arteriosclerosis.1 Given the delicate nature of neural circuits the accumulation of white matter, neuronal, and vascular disease explains the cerebral changes seen in CKD/ESRD patients.1 Since
Nontraditional mediators of cerebrovascular disease in CKD patients
Nontraditional risk factors for cerebrovascular injury include small vessel disease, hyperphosphatemia, vascular calcifications, elastinolysis, chronic inflammation, blood pressure variations, and platelet dysfunction are other nontraditional mediators of cerebrovascular disease.1,5,60,61 These humoral and chemical factors seem to exert their malign influence on cerebral function via endothelial dysfunction, the effect of uremic solutes, and chronic inflammation. SVD is particularly affected by
Small vessel disease (SVD)
Subclinical SVD has been hypothesized to produce cognitive decline, and the syndromic features of cognitive impairment in CKD suggest an organized process.1 It generally affects executive function and decreased speed in information processing. SVD can also produce lipohylanosis of the subcortical penetrating arteries, which is also linked to defective cerebral circulation autoregulation discussed below.1 A common feature of SVD is the presence of low grade ischemia sustained over long periods
Arteriosclerosis
Arteriosclerosis in a volume overloaded patient with defective RAAS signaling is expected, and in CKD, decreased autoregulation and blood pressure spikes and drops likely contribute to chronic cerebral damage in CKD.5 The anatomy of the cerebral microcirculation is sensitive to these fluctuations, like the kidney. The arteriosclerosis can result in cerebral blood flow diminution leading to a risk of ischemia.5 The hardening of the renal vasculature as well likely results in impaired control of
Hyperphosphatemia
Hyperphosphatemia is a crucial pathophysiological event, and its worsening sets off many deleterious cascades in the patient with CKD. Parathyroid hormone dysregulation, phosphatonin hypersecretion, medial intimal calcification, bone mineral disease, surreptitious inflammation leading to protein energy wasting.62, 63, 64, 65 All these processes are hallmarks of the physiologic effects of high serum phosphorous.
Vascular calcification
It is noted that most cardiac lesions in the large number of CKD patients with cardiac lesions are heavily calcified. A similar pattern is seen in patients with cerebrovascular disease and CKD. The process of medial intimal calcification, calciphylaxis on a macroscopic scale, occurs in the vasculature on a microscopic level.63 This is due to the induction of osteogenic factors like SM22 alpha actin in vascular smooth muscle cells (VSMC). These changes involve type II sodium phosphate co
Elastinolysis
Another factor affected by CKD is the loss of elastin in the walls of arterioles, caused by the same osteogenic gene activation that leads to medial intimal calcification. This is also caused by another mechanism the increase in elastolytic enzymes in high uremic toxin environments. The degraded elastin not only damages the vasculature structurally, but can attract the deposition of hydroxyapatite.1
The vascular inflammation resulting from CKD has also been implicated in causing intestinal
Blood pressure variations
Like the renal vascular circuit, the cerebral vascular circuit is a low-pressure circulation and depends on autoregulation to prevent high glomerular pressures.1,5,60,70,71 It is also notable that advanced cellular architecture guard the compartmentalization of both cerebral and renal cells.1 The neuronal-capillary interface (or the blood brain barrier), has a homologous function to the glomerular kidney membrane/slit diaphragm/podocyte filter layer (the blood – urine barrier). As well as the
Platelet dysfunction
Cerebral microbleeds are a commonly seen complication in the CKD population that is complex because it can be present in the general population with HTN.5 In CKD patients are reported to be more common in patients with SVD, and are independently predicted by a decreased eGFR.5 This event may present a proverbial “canary in a coal mine” as the presence of a microbleed augurs a clinically significant hemorrhagic stroke 5 years later.5 In diabetic patients as well (and many of CKD patients have
Conclusions
The complex interplay between CKD and cerebrovascular disease is primarily caused by the fact that both the kidney and the brain have strong similarities in vascular organization.72 The kidneys and the brain are highly vascular organs and any vascular inflammation is highly likely to have end organ effects in both systems (1, 5, 60). In summary comorbid conditions like hypertension, hyperlipidemia, and diabetes contribute to cerebrovascular and renal disease. Sodium fluctuations and blood
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This research work does not contain human subject research material. Ethical permission / consent for publication: Not applicable.
Availability of data and materials
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Funding
KKZ is supported by the National Institutes of Health-National Institute of Diabetes, Digestive and Kidney Disease (NIH-NIDDK) grant K24-DK091419 as well as philanthropist grants from Mr. Harold Simmons, Mr. Louis Chang, Dr. Joseph Lee and AVEO.
CMR is supported by research grants from the National Institutes of Health/National Institutes of Diabetes and Digestive and Kidney Diseases R03-DK114642, and R01-DK122767; and philanthropist grants from Dr. Joseph Lee (C.M.R.).
Sponsorship: this work was
Declaration of Competing Interest
None.
Acknowledgments
None.
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