Quotidian Hemodialysis and Inflammation Associated With Chronic Kidney Disease

Inflammation in CKD 

Chronic inflammation is common in CKD. Inflammation is defined as a pathologic process involving cytologic and histologic reactions that occur in blood vessels and tissues in response to injury.10 Inflammation is accompanied by an acute phase response that is beneficial in the healing process and is important to host defense and adaptation. Positive acute-phase proteins, including C-reactive protein (CRP), fibrinogen, haptoglobin, and ferritin, increase in response to cytokines. Albumin and transferrin are negative acute-phase proteins that decrease in response to cytokines. Cytokines are inflammatory molecules produced by monocytes and macrophages. Examples of cytokines include interleukin IL-6, IL-1β, tumor necrosis factor-α (TNF-α), interferon gamma, and transforming growth factor-β.

The acute inflammatory response is not entirely beneficial. Inflammatory cytokines induce many symptoms including fever, anorexia, anemia, and fatigue. There are multiple possible etiologies for this inflammatory process associated with ESRD, including complications with vascular access such as infections and surgery, autoimmune disorders, atherosclerosis, and neoplasm. Patients with kidney failure have abnormal cellular and humoral immunity. Impaired T-cell proliferation and decreased function occurs in CKD. Humoral immunity, including poor antibody response and defective antigen presentation by monocytes, contributes to increased infections and malignancies in dialysis patients. This acute-phase response is associated with acute and chronic inflammation. Other markers of chronic inflammation include serum amyloid A (SAA) and erythrocyte sedimentation rate (ESR).

Increased production and decreased renal clearance of cytokines result in high levels in CKD.11 There is no consensus regarding optimal levels of inflammatory markers in dialysis patients. SAA increases the affinity of high-density lipoprotein (HDL) for macrophages and affects extracellular matrix binding. Normal SAA levels are <10 mg/L and have been found to be >10 mg/L in patients with ESRD.12 The ESR was found to be >25 mm/h in 93% of patients with ESRD. In the same study, 57% of dialysis patients had ESR levels >60 mm/h (normal is <25 mm/h).13 In a study performed by Ortega et al,14 CRP was elevated in advanced CKD. The elevated CRP correlated inversely with serum albumin. The patients in this study with higher CRP levels also tended to be more anemic. High-sensitivity CRP assays are able to detect levels of 0.3 mg/L. Levels of <1 mg/L are considered low for cardiovascular risk, whereas levels >3 mg/L are associated with a high cardiovascular risk. Zimmermann et al15 found that both CRP and albumin were independent predictors of all-cause mortality. Eighty percent of dialysis patients in the top quartile of CRP (levels >11.5 μg/mL [mg/L]) were dead within 28 months in a study conducted by Yeun et al.16 In this same study, the median CRP level was 3.4 mg/L in living dialysis patients at the end of the study.

IL-6 has been found to increase during hemodialysis treatments and is associated with increased CV risk.17, 18 Shlipak et al19 showed an inverse relationship between IL-6 levels and kidney function in a large study of 5,888 subjects. In patients with a creatinine clearance >60 mL/min, mean IL-6 levels were 2.5 pg/mL. The mean serum IL-6 concentration among hemodialysis patients is 7.2 pg/mL.20 Procalcitonin appears to be a more precise marker for inflammation than CRP, serum amyloid, and homocysteine.21 Procalcitonin levels rose from 0.4 ng/mL to 1.56 ng/mL (normal is <0.5 ng/mL) during a 4-hour dialysis treatment. CRP, SAA, and homocysteine levels remained unchanged in this study.21 TNF-α22 and IL-123 are also significantly increased in patients with CKD and dialysis patients. IL-10 appears to be an anti-inflammatory cytokine. Patients undergoing hemodialysis have higher levels of CRP and lower levels of IL-10 than controls.24

Oxidative and carbonyl stress contribute to an increased inflammatory response. Carbonyl stress is characterized as an increase of reactive carbonyl compounds formed from carbohydrates, lipids, and amino acids by oxidative and nonoxidative pathways. Carbonyl compounds are excreted by normal kidneys and accumulate in ESRD.25 Carbonyl compounds can form advanced glycation endproducts (AGEs) and advanced lipoperoxidation endproducts. AGEs are associated with β2-microglobulin amyloidosis in long-term dialysis patients.26 Oxidative stress occurs when free-radical production increases. Low antioxidant levels of vitamin C and vitamin E also increase oxidative stress associated with increased cardiovascular events. In hemodialysis patients, highly permeable dialyzer membranes induce loss of antioxidants. The average loss of vitamin C is 66 mg per session. There is also a decreased intake of vitamin C because of dietary restrictions.27

Primed peripheral polymorphonuclear leukocytes are also implicated as a cause of systemic oxidative stress and low-grade inflammation.28 The extent of polymorphonuclear leukocytes priming correlated with the severity of kidney disease and intensified with hemodialysis. Increased levels of interleukins are potent activators of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Activated NADPH oxidase catalyzes the reduction of oxygen to superoxide anion, which dismutates to form hydrogen peroxide by the catalyst superoxide dismutase.29 Myeloperoxidase (MPO), found in the azurophilic granules of leukocytes, allows hydrogen peroxide to interact with halides to produce hypochlorous acid, which generates reactive oxidizing and chlorinating species. MPO can serve as nitric oxide oxidase and consume nitric oxide. A decrease in nitric oxide is associated with arterial endothelial dysfunction and impaired endothelium-dependent, flow-mediated vasodilation, which is associated with cardiovascular disease.30 MPO is released from neutrophils during hemodialysis. AGEs result from carbonyl stress and initiate inflammation as well.31

Many comorbid conditions are associated with CKD, and many of the illnesses that lead to ESRD are associated with inflammation, including autoimmune disorders, amyloidosis, hypertension, and insulin resistance with type 2 diabetes and obesity. Several nephritic syndromes are associated with a high degree of inflammation, including Wegener’s disease, Goodpasture’s disease, and lupus nephritis. Volume overload is prominent in dialysis patients. Vascular congestion may result in altered permeability of the gastrointestinal tract. Bacterial endotoxins migrate from the gastrointestinal tract into the vasculature and interstitium and may stimulate monocytes and increase cytokine release.32

Quotidian Dialysis 

Kjellstrand et al33 developed the concept of “unphysiology” in the 1970s. “Unphysiology” is the concept that the large oscillatory nature of intermittent hemodialysis is actually harmful and that daily dialysis might be superior. An observational, prospective study compared patients undergoing nocturnal dialysis and short daily dialysis with conventional dialysis 3 times a week. The findings of the study included improved volume and blood pressure control, improved phosphate control, a lower calcium-phosphate product, and regression of left ventricular hypertrophy. Also noted in this study were lower erythropoietin requirements and lower homocysteine levels.34 Controlling inflammation with more frequent dialysis, such as quotidian dialysis, might contribute to improved parameters.

CVD 

Studies have shown a reduction in blood pressure with daily dialysis.35 The need for antihypertensive medications is reduced.36, 37 Elevated levels of CRP, IL-6, and TNF-α are associated with aortic stiffness.38 Aortic (arterial) stiffness is a strong predictor of cardiovascular morbidity in hypertension and ESRD. Daily hemodialysis improves the cytokine profile, which may help with reducing arterial stiffness.

In a small study by Ayus et al,39 significant reductions in median CRP levels and a decrease in left ventricular mass index occurred in patients on SDHD compared with conventional hemodialysis. Initially, improvement is likely associated with volume control; however, Chan et al40 showed improvement in cardiovascular parameters, including improved ejection fraction, when extracellular fluid volume was unchanged. This would suggest that another mediator is involved, possibly inflammation. Increased levels of CRP and fibrinogen are also related to cardiac valve calcification, which may lead to valvular dysfunction resulting in congestive heart failure.41

Endothelial progenitor cells (EPCs) play an important role in angiogenesis and repair of ischemic myocardium. Vascular risk increases with a reduced number of EPCs. Endothelial progenitor cell number and function are reduced in ESRD patients. Patients on DNHD exhibit normal EPC number and function.42 Elevated CRP levels have been shown to reduce EPC number and function.43 Improved CRP levels with quotidian dialysis might help explain the normal EPC number and function. Vascular calcification occurs commonly in hemodialysis patients. Fetuin-A and matrix G1a protein inhibit vascular calcification and are inversely related with inflammatory markers.44 Low levels of fetuin-A in hemodialysis patients may be associated with increased cardiovascular mortality. An elevated calcium phosphorus product is associated with increased vascular calcification. In vitro calcium phosphate crystals activate macrophages, which release TNF-α and IL-1β.45 Quotidian dialysis is superior to dialysis 3 times a week in reducing phosphorus.34 Further studies in patients on quotidian dialysis are needed to assess the affect reduced phosphorous levels have on the proinflammatory association with calcium phosphate crystals. Peripheral vascular disease may also be positively impacted by DHND. In a case report by Chan et al,46 an individual with refractory intermittent claudication secondary to peripheral artery disease had dramatic improvement measured by arterial flow once switched to DNHD. The patient became symptom free with 7.5-hour sessions 5 nights a week. It is not clear whether this was the effect of inflammation modification or directly a reduction of calcium and phosphate levels.

Dyslipidemia is common in CKD. Typically, in kidney failure triglycerides, total cholesterol, and low-density lipoproteins (LDLs) are high. HDLs are usually low. In patients with inflammation, HDL decreases and apolipoprotein A-1 is replaced by serum amyloid A. This attracts macrophages and ultimately leads to vascular injury.47 NDHD showed a significant effect on decreasing triglycerides and increasing HDL in a small study.48 However, the total cholesterol and LDL did not improve. Larger studies are necessary to further evaluate the effect on total cholesterol and LDL.

Anemia 

Inflammation is implicated in resistance to exogenous erythropoietin. IL-6 causes a hypoproliferative anemia by direct inhibition of erythroid progenitor cells.49 In a small cohort of daily nocturnal dialysis patients, erythropoietin requirements were significantly lower than patients on conventional dialysis 3 times a week. Some patients no longer required exogenous erythropoietin administration after switching to DNHD. Plasma IL-6 levels were significantly decreased in the DNHD group.50 This suggests that quotidian dialysis improves anemia control by decreasing inflammatory cytokines rather than an absolute lack of erythropoietin. Hemoglobin levels tended to be higher in the DNHD group.51 Some argue that more frequent dialysis allows for more blood loss because of the increased frequency of dialysis; however, this does not seem to be the case because hemoglobin levels are higher in patients on nocturnal dialysis. Intravenous iron, which is commonly administered to anemic dialysis patients, may also induce a proinflammatory state by releasing free iron that could react with hydrogen peroxide. The amount of intravenous iron required on nocturnal hemodialysis compared with conventional dialysis has not been adequately reported.

Nutrition 

Mortality in ESRD is strongly associated with the malnutrition, inflammation, atherosclerosis syndrome (MIA).7 In a study by Beddhu and colleagues,52 a low serum albumin correlated with coronary artery disease, although in a different study there was no association between a body mass index of <18.5 kg/m2 and acute coronary syndrome.53 An elevated CRP and low serum bicarbonate level have been found to be associated with a low serum albumin level in subjects with all stages of CKD who participated in the Third National Health and Nutrition Examination Survey (NHANES III).54 High TNF-α and IL-6 levels are predictors of low serum albumin levels. TNF-α is an anorectic cytokine.22 Potential effects of TNF-α include impaired myogenesis and muscle synthesis, lipolysis, and vascular calcification. The potential effect by which IL-6 mediates wasting includes inhibition of insulin-like growth factor-1 (IGF-1) and stimulation of adhesion molecules.7 Both TNF-α and IL-6 cause endothelial dysfunction, oxidative stress, insulin resistance, and depressed appetite. Pentosidine is an advanced AGE that accumulates in ESRD and appears to be associated with increased oxidative stress and inflammation.55 Preliminary studies with short daily dialysis showed a reduction in these AGE compounds.56 More frequent dialysis as seen with NDHD decreased cytokines like IL-6, which may improve nutrition.50 Another aspect contributing to malnutrition in ESRD patients is the dietary restrictions they are often prescribed. DNHD allows for a less restrictive diet. Patients are actually encouraged to maintain high-phosphorus and -protein diets (up to 1.3 g/kg/d) on nocturnal dialysis.34 The liberalization of a diet leads to increased consumption of antioxidants (vitamin C and E), thus decreasing oxidative stress. Loss of amino acids is substantial on NDHD (up to 15 g daily)57; however, levels of essential and nonessential serum amino acids increase on nocturnal dialysis.58 Patients on NDHD may become anabolic rather than catabolic. Galland et al59 found that after an initial drop of weight associated with volume excess, post-hemodialysis weight increased at a rate of 0.85 kg per 6 months, indicating an anabolic state. Serum albumin rose by 0.29 g/dL during the first year on daily dialysis treatments. A higher-serum albumin seen with NDHD may be associated with less inflammation and reduced cardiovascular risk. A few studies have shown decreased serum albumin levels with DNHD.60, 61 Further studies are necessary to assess affect of NDHD on malnutrition and inflammation.

Dialyzer Membrane, Dialysate, and Inflammation 

The dialysis procedure itself can increase inflammation. Several factors involving the dialysis technique can contribute to inflammation including retention and/or production of proinflammatory molecules, increased oxidative stress, and stimulation of monocytes via contaminants. NDHD, with its improved middle molecule clearance, may increase the removal of proinflammatory substances.62 Potential contamination of blood from endotoxins in the dialysate is a major concern. Transfer of pyrogenic substances usually occurs during backfiltration, especially with highly permeable membranes.44 Low–molecular-weight substances may also enter by backdiffusion. Cytokines are released by monocytes activated by endotoxin-type compounds in dialysis fluid. Monocytes express endotoxin receptor antigen CD14 and CD16. Stimulation of the antigen-presenting cells contributes to secretion of cytokines. It has been shown that CD14 receptor expression is enhanced during the hemodialysis session.63 However, when looking at different membranes, the CD14+ CD16+ subset decreased at 30 minutes and remained suppressed for the entire dialysis treatment, regardless of membrane type.64

Korevaar et al65 looked at the effect of an increased CRP level on mortality during hemodialysis. After adjusting for comorbidities, they found a 9% increased mortality risk for each rise in CRP level of 1 mg/L during a dialysis session. Very small amounts of endotoxin or lipopolysaccharide trigger production of reactive oxygen species by activating PMN leukocytes. Contamination of the water used to prepare dialysate has proinflammatory potential. Water may contain Cryptosporidium parvum or cyanobacteria. Cyanobacteria (blue-green algae) contain toxins, including microcystins, which led to the death of hemodialysis patients in Brazil.66 Biofilm can form in stagnant areas of the dialysis circuit water system.67 Bacteria, yeast, and fungi may be present in this biofilm, which stimulates the immune system. Use of ultrapure dialysis fluids may reduce IL-6 and CRP levels.68 Based on current Association for the Advancement of Medical Instrumentation guidelines, dialysate must have <200 colony-forming units (CFUs) of bacteria and 2 endotoxin units/mL. These levels are not low enough to stop chronic inflammation. A standard 3-hour treatment can use up to 90 L of dialysate resulting in up to 18 million CFUs of bacteria. With the standard DNHD flow rates at 300 mL/min, an 8-hour treatment would use up to 144 L of dialysate a treatment, resulting in a much higher amount of bacterial exposure. Ultrapure dialysate passes through an ultrafilter, which removes bacteria and endotoxin.69 Ultrapure dialysate has <0.1 CFU/mL, possibly reducing the risk of inflammation.70 Lamas et al,71 however, showed no improvement in the inflammatory status evaluated by darbepoetin requirements in hemodialysis patients treated with ultrapure dialysate. Acetate found in bicarbonate dialysate may have inflammatory effects. Switching to acetate-free biofiltration may improve the inflammatory response.72

Bioincompatibility of the dialysis membrane may also contribute to free oxygen radical production. There is more contact between the patient’s blood and the dialyzer membrane in patients on DNHD. In theory, this could increase the inflammatory response; however, most studies show a decrease in CRP levels with DNHD.50 Quotidian dialysis either improves cytokine clearance or improves clearance of toxins, thus decreasing the inflammatory response. This improved clearance may be more beneficial than the possible increased inflammatory reaction associated with more frequent dialysis. Vascular access is another dialysis-related cause of inflammation. Infected catheters and clotted arteriovenous access (AVF/AVG) cause repeated acute and chronic inflammation.73 There are few studies of vascular access and DNHD. Pierratos58 reported that systemic infections in DNHD patients using catheters occurred 1 per 25 patient months, and catheters actually lasted longer than with traditional dialysis. DNHD patients do not show increased problems with vascular access.74

Summary 

Inflammation plays an important role in many of the physiological processes contributing to the morbidity and mortality of dialysis patients. The actual dialysis procedure can be proinflammatory. Controlling inflammation theoretically should improve outcomes. Multiple small studies have shown a positive effect on the cytokine profile with daily nocturnal hemodialysis, including decreased levels of IL-6, TNF-α, and CRP. Longer, prospective, randomized controlled trials assessing morbidity and mortality with DNHD compared with dialysis 3 times a week are needed. Larger studies looking at the effects on inflammation with nocturnal hemodialysis are necessary as well. The improved quality of life seen in patients on nocturnal hemodialysis, and the current literature makes quotidian dialysis quite appealing.