INTRODUCTION — Acute and chronic inflammatory processes are common in individuals with chronic kidney disease (CKD) and especially end-stage kidney disease (ESKD). This is due to many underlying factors, including the uremic milieu, elevated levels of circulating proinflammatory cytokines, oxidative stress, carbonyl stress, protein-energy wasting (PEW), enhanced incidence of infections (especially dialysis access related), and others. Although the definition of inflammation is unclear in this setting, CKD-associated chronic inflammation, as indicated by increased C-reactive protein (CRP) levels above 5 mg/L over at least three months, has been reported in 30 to 60 percent of North American and European dialysis patients, with dialysis patients in Asian countries possibly having a lower prevalence [1-7].
The acute-phase response is a major pathophysiologic phenomenon that accompanies inflammation. With this reaction, normal homeostatic mechanisms are replaced by new set points that presumably contribute to defensive or adaptive capabilities.
Acute-phase proteins are defined as those proteins whose plasma concentrations increase (positive acute-phase proteins), such as CRP, or decrease (negative acute-phase proteins), such as albumin, during inflammatory states. Measurement of the levels of these proteins is frequently utilized to define the presence and/or degree of inflammation in a given patient. A number of inflammatory markers have been studied in patients with CKD (table 1). (See "Acute phase reactants".)
Despite its name, the "acute"-phase response can persist over months to years and become chronic. In such states of chronic inflammation, positive acute-phase proteins including CRP (normal range <1 mg/L) may be slightly but persistently increased, which can predispose to an increased risk of atherosclerotic cardiovascular disease (CVD; CRP 1 to 3 mg/L) [8]. However, in many patients with CKD, especially in maintenance dialysis patients, serum CRP levels are persistently between 5 and 50 mg/L, although they may fluctuate widely [8]. During acute and fulminant infections, such as acute osteomyelitis, serum CRP is not uncommonly above 50 mg/L (table 2).
Among patients with CKD, the presence of an inflammatory state may also be closely related to accelerated atherogenesis, protein-energy wasting (PEW), and anemia [9-11]:
●Kidney function impairment alone is reported to be a risk factor for atherosclerosis and CVD. This may be due in part to the frequent concurrence of inflammation. (See "Chronic kidney disease and coronary heart disease".)
●Increasing attention has focused upon inflammation as a possible cause of the wasting syndrome in ESKD as well as anemia refractory to therapy with erythropoiesis-stimulating agents (ESAs).
The pathogenesis and consequences of inflammatory processes among patients with kidney dysfunction will be discussed in this topic review.
INFLAMMATION AND KIDNEY DISEASE — A generalized increase in the inflammatory response in patients with decreased kidney function may occur via the following mechanisms:
●Decreased renal clearance of proinflammatory cytokines
●Volume overload with endotoxemia
●Oxidative and carbonyl stress
●Decreased levels of antioxidants
●Increased presence of comorbid conditions
Decreased clearance of proinflammatory cytokines — The kidneys are responsible for clearing proinflammatory cytokines and bacterial antigens from circulation [12]. Deteriorating kidney function may enhance overall inflammatory responses because of the decreased renal clearance of factors that are directly or indirectly involved in inflammation. As an example, the serum half-lives of proinflammatory cytokines, tumor necrosis factor alpha (TNF-alpha), and interleukin (IL) 1 are greater in animals without kidney function than those with kidney function [13,14].
In humans, declining kidney function may also affect the levels of additional inflammatory molecules as serum C-reactive protein (CRP), IL-6, and hyaluronan levels are inversely correlated with creatinine clearance [15,16], although inflammation may have a bidirectional relationship with kidney function, being not only a consequence but also a cause for loss of glomerular filtration rate (GFR) [17,18]. In addition, among patients with end-stage kidney disease (ESKD) who have residual kidney function, higher serum CRP concentrations are observed among those with relatively less native kidney function [19,20]. Increased production of cytokines may also be observed. Furthermore, the loss of function in various tissues due to enhanced proinflammatory cytokines can in turn result in release of endogenous damage-associated molecular patterns (DAMPs), such as mitochondrial DNA, which can further drive systemic inflammation in ESKD [21]. (See 'Oxidative and carbonyl stress' below and "Uremic toxins".)
Volume overload with endotoxemia — Vascular congestion due to fluid overload in patients with kidney function impairment may result in altered permeability of the gastrointestinal tract, thereby allowing the translocation of gut-derived toxic products such as endotoxins and bacterial DNA fragments into the systemic circulation [22]. These processes may in turn stimulate immune cells and the increased release of proinflammatory cytokines [23-26].
Oxidative and carbonyl stress — Increased production of cytokines due to oxidative stress is also observed among patients with kidney failure [27,28]. Oxidative stress, which occurs when there is excessive free-radical production or low antioxidant levels, could be an important condition for the development of endothelial dysfunction, inflammation, and atherogenesis [28-30] (see "Coronary endothelial dysfunction: Clinical aspects"). Lower plasmalogen levels, an indicator of such stress, have been reported in malnourished and inflamed patients with chronic kidney disease (CKD) [31].
With kidney failure, molecules that are not cytokines may also accumulate and provoke an inflammatory response. As an example, advanced glycosylated end products (AGEs), which result from carbonyl stress, can clearly initiate inflammation in patients with kidney failure [32,33]. Other uremic toxins, such as indoxyl sulphate, can also evoke inflammatory pathways either directly or through reactive oxygen species (ROS)-mediated activation of nuclear factor kappa B (NF-kB) signaling [28,34]. (See "Uremic toxins".)
Decreased antioxidants — The oral intake or the circulating levels of some antioxidants are lower than normal in patients with CKD and ESKD [35]. An acute-phase response is also associated with decreased plasma levels of several antioxidants, such as serum vitamin C concentrations [27,36]. Low serum vitamin C levels are in turn associated with increased cardiovascular morbidity and mortality [37]. Nuclear factor erythroid 2–related factor 2 (Nrf2) is a transcription factor that plays a key role in adaptive stress response mechanisms against oxidative stress and inflammation [38-42]. The reduced antioxidant activity of Nrf2 coupled with an upregulation of NF-kB is typically seen in the uremic milieu, which can further drive inflammation [43,44].
Comorbid conditions — The frequent occurrence of comorbid illnesses in patients with kidney disease enhances the hypercatabolic state and the development of inflammation [45]. An example is periodontal disease [46]. Even in the absence of overt clinical illness, an inflammatory process may be ongoing and associated with an acute-phase response in this setting [47]. In addition, an increased susceptibility to infections has been described in patients with CKD and ESKD, which may be partly due to impaired immunity, uremia, old age, and comorbid conditions [48-50].
Changes in gut microbiota and diet — Changes in diet composition and in gut microbiota have also been linked to alterations in intestinal permeability and production of uremic toxins, leading to inflammation [51]. This raises the possibility that gastrointestinal alterations, such as constipation or pathologic alterations in the composition of intestinal milieu, may have an effect on kidney function and on cardiovascular outcomes [52-54]. Changes in gut microbiota composition may also be related to protein-energy wasting (PEW) in patients with ESKD [55].
Other factors — A systemic autoimmune condition (which may have caused the kidney disease), clonal hematopoiesis, epigenetic (eg, microRNA and DNA methylation) and genetic factors, premature cellular aging, an unrecognized persistent infection, periodontal diseases, and atherosclerosis may also underlie inflammation among patients with decreased kidney function or ESKD [56-65].
End-stage kidney disease
Hemodialysis — In addition to the previously mentioned causes that may underlie and/or enhance ongoing inflammation in patients with CKD, the following conditions may chronically aggravate inflammatory processes in those undergoing maintenance hemodialysis:
●Exposure to dialysis tubing and dialysis membranes, particularly less biocompatible membranes (eg, cuprophane membranes) [66,67]. (See "Clinical consequences of hemodialysis membrane biocompatibility".)
●Poor quality of dialysis water and back-filtration or back-diffusion of contaminants, resulting in possible exposure to endotoxins. (See "Contaminants in water used for hemodialysis".)
●The presence of foreign bodies (such as polytetrafluoroethylene [PTFE] chronic access grafts) or an intravenous catheter, which may harbor chronic or recurrent latent infection via the formation of a biofilm [68-73].
●A clotted arteriovenous (AV) graft that is not excised.
Peritoneal dialysis — Factors unique to patients on peritoneal dialysis may also enhance chronic inflammation [74,75]:
●Episodes of overt or latent peritonitis or peritoneal dialysis catheter-related infections [6,74,76].
●Constant exposure to peritoneal dialysis solution, which may include bioincompatible substances or endotoxins [74,76].
●Loss of residual kidney function and fluid overload [74]. However, inflammation could be also be a cause of the loss of residual kidney function [77].
Presence of a failed kidney transplant — A chronic inflammatory state has been noted in patients who return to dialysis after a failed kidney transplant but in whom a transplant nephrectomy has not been performed [78,79]. Symptoms and signs of inflammation may abate with kidney removal. (See "Kidney transplantation in adults: Management of the patient with a failed kidney transplant".)
GENERAL MARKERS OF INFLAMMATION — There is no consensus approach to assess the degree of severity of inflammation in individuals with kidney disease (see "Acute phase reactants"). Routine monitoring of inflammatory markers in all patients with end-stage kidney disease (ESKD) or chronic kidney disease (CKD) is not recommended by most guidelines, although it may improve patient management. Periodic measurement of C-reactive protein (CRP) or interleukin (IL) 6 to assess severity and frequency of inflammation is reasonable in select patients as part of an individualized work-up prompted by specific clinical characteristics, such as protein-energy wasting (PEW).
Several measures of general inflammation are used in patients with CKD or ESKD as well as in others [80-90]. These include the following proteins:
●Serum levels of positive acute-phase reactants, such as serum CRP, ferritin, or fibrinogen, are commonly elevated during an acute episode of inflammation. There is increasing literature on elevated serum CRP and increased cardiovascular risk, a relationship that is independent of other coronary risk factors. (See "C-reactive protein in cardiovascular disease".)
●Serum levels of negative acute-phase reactants, such as albumin or transferrin, decrease during an inflammatory process [81,82]. Many negative acute-phase reactants are also traditionally utilized as nutritional markers since their serum levels are decreased with a decline in nutritional status.
Since episodes of occult or overt inflammation may be chronic or recurrent, they have occasionally been referred to as representing a "chronic" acute-phase response [83,84]. Such chronic inflammatory responses are associated with an elevation of serum acute-phase proteins including CRP, erythrocyte sedimentation rate, serum amyloid A, and some proinflammatory cytokines including a variety of ILs. Among the proinflammatory cytokines, IL-6 may have a central role in the pathophysiology of inflammation in patients with kidney disease [85].
No consensus exists as to what threshold levels of inflammatory markers optimally distinguish noninflamed from inflamed patients with ESKD, as well as what exact markers should be measured. Based upon mean values and/or possible correlation with outcomes, several investigators have proposed different serum levels of various markers [1,80,91-96]:
●In a survival study of 91 patients on hemodialysis, a serum CRP level >5 mg/L (>0.5 mg/dL, as measured by end-point nephelometry) was proposed as a sign of inflammation [1]. This was derived from the observation that the mean CRP values among patients who were alive or had died at study end were originally 3.4 and 10.1 mg/L, respectively.
●In a prospective report of 240 patients on peritoneal dialysis with an initial median serum CRP level of 7 mg/L, the CRP level was significantly higher among the 84 patients who experienced a cardiovascular event during the subsequent 41 months (27 mg/L) [91].
●In a third series, the mean serum IL-6 concentrations among patients on hemodialysis or peritoneal dialysis were 7.2 and 5.6 pg/mL, respectively [92]. When levels were categorized by quartiles, the group with the highest initial level had the highest mortality, a finding observed in both patients on hemodialysis and those on peritoneal dialysis.
●In a review of 230 hemodialysis patients and 28 nondialytic controls, serum concentrations of IL-1, 2, 4, 5, 6, 12, and 13 as well as tumor necrosis factor alpha (TNF-alpha) were significantly increased in the dialysis group [80].
There are some patients with ESKD in whom the measurement of such inflammatory markers may help guide clinical decision making. The measurement of serum CRP and IL-6, for example, may help distinguish the relative contributions of inflammation and malnutrition to the development of hypoalbuminemia [11,97].
In addition, the serum measurement of inflammatory markers may help determine whether the presence of hyperferritinemia in patients on dialysis is due to iron overload or inflammation; this may be particularly helpful when the serum ferritin level is >800 ng/mL but the serum transferrin saturation is within the normal range (<50 percent) [98]. The association between increased mortality and serum ferritin levels >800 ng/mL appears to be primarily due to the confounding effect of inflammation [99]. (See "Diagnosis of iron deficiency in chronic kidney disease" and "Treatment of iron deficiency in patients with nondialysis chronic kidney disease (CKD)" and "Treatment of iron deficiency in patients on dialysis".)
DOES INFLAMMATION LEAD TO PROTEIN-ENERGY WASTING? — Protein-energy wasting (PEW) [100], which is present in a large proportion of patients with end-stage kidney disease (ESKD), is a strong risk factor for increased hospitalization and mortality in patients undergoing maintenance hemodialysis or peritoneal dialysis [11,83,101]. The impact of PEW on dialysis outcome may lead to a paradoxical risk factor reversal or reverse epidemiology of risk factors [102,103]. Among patients on dialysis, for example, a low (and not a high) body mass index (BMI) or a low (and not a high) serum cholesterol concentration is associated with increased mortality [11,102,104]. (See "Pathogenesis and treatment of malnutrition in patients on maintenance hemodialysis" and "Patient survival and maintenance dialysis".)
Several investigators suggest that PEW is largely a consequence of chronic inflammatory processes in patients with ESKD [9,10,84]. Although proinflammatory cytokines may be a common link between malnutrition and inflammation, additional factors such as oxidative stress, carbonyl stress, uremic toxins, and others may also play roles [29,30]. Thus, the degree to which there is a link between PEW and inflammation and the independent effect of each upon adverse outcomes in patients with kidney diseases are unclear.
The following two sections provide an overview of the data for and against a relationship between inflammation and malnutrition.
Positive observations — The hypothesis that PEW is a consequence of chronic inflammatory processes in patients with ESKD is supported by the following [9,10,84]:
●Inflammation is associated with a rise in plasma and probably tissue levels of catabolic cytokines; plasma elevations of inflammatory proteins and catabolic cytokines are commonly observed in nondialyzed patients with advanced chronic kidney function impairment and in patients on dialysis. One such cytokine, tumor necrosis factor alpha (TNF-alpha), promotes catabolic processes (engendering both protein degradation and suppression of protein synthesis) and also induces anorexia [11,105].
●Some patients on dialysis with chronic inflammation develop weight loss and a negative protein balance, despite an intact appetite. In this setting, there may be a shift in protein synthesis from muscle to acute-phase proteins, as well as an overall decrease in protein synthesis and increase in protein degradation, as kidney function declines. Such patients also appear to lose more body weight during dialysis when compared with those without discernible inflammatory processes [106].
●Albumin synthesis is suppressed when serum C-reactive protein (CRP) is elevated [10,84]. In patients with chronic kidney disease (CKD), serum albumin decreases and proinflammatory cytokines accumulate as kidney function deteriorates [15,16,19,107,108]. Among well-dialyzed patients, activation of the acute-phase response also correlates with lower serum albumin levels due to decreased albumin synthesis [109].
●Inflammation may lead to hypocholesterolemia, a strong mortality risk factor in patients on dialysis and a marker of poor nutritional status [104,110]. This was best shown in a prospective study of 823 patients who were categorized by either the presence or absence of inflammation/malnutrition, which was defined by a low serum albumin concentration or elevated levels of CRP or interleukin (IL) 6 [104]. Among all patients, as well as those with inflammation, lower cholesterol levels were associated with higher mortality. By comparison, higher cholesterol levels in those without markers of inflammation/malnutrition were associated with higher mortality.
Thus, chronic inflammation may be a principal factor that causally links PEW to increased morbidity and mortality among patients on dialysis. The term "malnutrition-inflammation-complex syndrome" (MICS) suggests the purported close association between PEW and inflammation in patients on dialysis [11,111,112]. Alternatively, "malnutrition-inflammation-atherosclerosis" (MIA) has been used to emphasize the importance of atherosclerotic diseases as a major consequence of the syndrome [113].
Several scoring systems have been proposed to assess the degree of MICS or MIA in dialysis patients, such as the "malnutrition-inflammation score" (MIS) [111]. This correlates strongly with both measures of nutritional status and inflammation and anemia. Similar associations of MIS with lower kidney function and with nutritional status have been described in patients with nondialysis-dependent CKD and kidney transplant recipients [114].
The MIS is also significantly associated with hospitalization rates and mortality in hemodialysis patients [111] since it is essentially a modified version of the Subjective Global Assessment of Nutrition (SGA) [83]; the SGA is recommended in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines to be used routinely to assess the nutritional status of dialysis patients. The SGA also helps measure the degree of inflammation and illness severity [83,111,115].
Negative observations — There is also evidence that does not support inflammation as the principal cause of PEW:
●Serum albumin and prealbumin levels and other indicators of protein-energy nutritional status obviously correlate with protein intake and are independent of inflammatory status [116]. The serum albumin decreases, although only modestly, among normal individuals with PEW induced by reducing their nutrient intake or in malnourished hemodialysis patients fed low-protein diets, suggesting that serum albumin is a direct reflection of protein intake [108,117,118].
●In dialysis patients, the association of serum albumin and CRP is hardly precise, with the reported correlation coefficients usually less than 0.5 [108,117].
●Unlike serum CRP levels, serum albumin concentrations usually do not fluctuate on a month-to-month basis [84].
●In some studies, the provision of adequate nutrition without management of inflammation improves hypoalbuminemia and clinical outcome [119,120].
These considerations, although not conclusive, indicate that factors other than the catabolic consequences of inflammation also affect serum albumin and other nutritional measures. Nutrient intake is obviously one such factor.
Malnutrition may lead to inflammation — There are also some data suggesting that malnutrition can lead to inflammation:
●Malnourished patients on dialysis may be deficient of antioxidants such as vitamin C or carotenoids [35], which may lead to increased oxidative stress and inflammation.
●PEW may decrease host resistance and predispose to infection, which is clearly an inflammatory disorder. Certain nutrients, such as arginine and glutamine, may enhance the immune response [121]. Moreover, preliminary data suggest that levocarnitine may protect against endotoxins and also suppress elaboration of TNF-alpha from monocytes [122].
●Hypocholesterolemia, as a reflection of general hypolipoproteinemia in malnourished patients on dialysis, may mitigate the ability to remove circulating endotoxins. Based upon the lipoprotein-endotoxin hypothesis, there is an optimum serum lipoprotein concentration below which lipid reduction is detrimental because of the decreased ability of lipoproteins to bind lipopolysaccharide; this, in turn, may prevent lipoproteins from decreasing the detrimental effects of endotoxin [123].
Summary — PEW may be associated with a poor outcome in patients on dialysis because of inflammation. However, existing data are consistent with the possibility that nutrient intake may also independently affect outcome.
CHRONIC INFLAMMATION AND OUTCOMES — Increased levels of markers of inflammation and malnutrition predict a poor outcome in patients with end-stage kidney disease (ESKD) and chronic kidney disease (CKD). Despite this, neither infection, which usually leads to an overt inflammatory response, or malnutrition are common causes of death. Rather, most individuals with CKD die of cardiovascular diseases (CVD). Thus, the purported link from underlying inflammation to decreased survival among patients with kidney disease, if it exists, should be most strongly observed for inflammation and atherosclerosis, rather than for inflammation and infection or malnutrition.
Perhaps the best evidence supporting the importance of inflammation in the pathogenesis of atherosclerosis comes from the observation among patients without kidney disease that markers of increased or decreased systemic inflammation are directly associated with an enhanced risk of atherosclerosis.
Although the evidence is less clear, patients with ESKD with coronary heart disease and enhanced cardiovascular risk and mortality frequently have similar elevated levels of acute-phase reactants [3]:
●Increased serum C-reactive protein (CRP) levels in patients with ESKD are as strongly associated with cardiovascular and all-cause mortality as decreased serum albumin levels [1,2,124,125].
●Increased serum levels of interleukin (IL) 6 are associated with increased dialysis mortality [110], and progression of carotid atherosclerosis during dialysis may be related to increased IL-6 levels [126].
Increasing clinical evidence also suggests that inflammation and oxidation stress are associated with adverse outcomes among predialysis patients [127-132]. This was perhaps best shown in a prospective study of 80 nondiabetic predialysis patients in whom the effect of different conventional and nonconventional risk factors on cardiovascular events was examined [130]. At follow-up at a median period of seven years, 21 patients developed adverse outcomes due to coronary, cerebral, or peripheral artery occlusion. Upon multivariate analysis, an adverse cardiovascular outcome was independently associated with increased age and elevated CRP, fibrinogen, and advanced oxidation protein product levels. Elevated plasma levels of fibrinogen and TNF-alpha have also been linked to rapid loss of kidney function in patients with CKD [133].
One study described the role of chemokines (which are 8 to 14 kDa proteins that regulate leukocyte trafficking during inflammatory reactions) in the all-cause and cardiovascular mortality associated with elevated CRP levels in patients with ESKD [134,135]. In this Mendelian randomization study of Dutch and Swedish dialysis patients, there was a statistical interaction between the presence of a nonfunctioning allele of the chemokine receptor 5 (CCR5) and all-cause and cardiovascular mortality associated with elevated CRP level. Patients with the allele appeared unaffected by the higher cardiovascular mortality seen in association with elevated CRP, interpreted as a potential protective effect by the nonfunctioning gene. Noncardiovascular mortality appeared increased in patients with higher CRP levels irrespective of their CCR5 polymorphism, consistent with the hypothesis that CCR5 is involved in the process of atherosclerosis but also suggesting that the effects of inflammation may reach beyond the process of atherosclerosis and affect noncardiovascular mortality as well as cardiovascular mortality in ESKD [135].
In addition to atherosclerosis, inflammation may cause other adverse outcomes in kidney disease such as refractory anemia, laboratory signs of iron overload, or a poor quality of life [136,137]. Inflamed dialysis patients frequently display increased serum ferritin, which is a positive acute-phase reactant and an indicator of increased iron burden [138,139]. Serum ferritin levels correlate with hospitalization rates, and a recent increase in serum ferritin concentration in hemodialysis patients may be associated with an enhanced risk of death [138]. (See "Treatment of anemia in nondialysis chronic kidney disease" and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)
Some studies, however, have not found an association between malnutrition/inflammation and an increased risk of atherosclerosis among patients on dialysis [140,141]. Among over 50,000 incident Medicare patients on dialysis, for example, there was no association between body mass indices (BMIs) suggestive of poor nutritional status and adverse cardiovascular outcomes [140]. These findings suggest that markers other than BMI, such as a subjective global assessment (SGA), may be preferable when assessing a poor nutritional state in patients on dialysis [141].
MANAGEMENT ISSUES
Overview — Inflammation directly resulting from a specific identified source, such as an ongoing chronic infection, should be aggressively treated with targeted therapy. By comparison, the indications for the use of nonspecific measures to possibly help reduce chronic inflammatory processes are less clear.
Although epidemiologic evidence links inflammation to poor outcome in individuals with kidney function impairment, there are no randomized clinical trials to suggest that outcomes are improved by nonspecific inflammation-reducing modalities. There is therefore no consensus upon a uniform or standardized strategy for the treatment of chronic inflammation in patients with kidney function impairment.
Despite this, the 2005 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines suggest that the assessment of C-reactive protein (CRP) levels to help assess the presence of underlying inflammation would be beneficial [142]. The presence of increased levels, usually defined as a serum level greater than 5 to 10 mg/L, may help predict cardiovascular risk.
General interventions — The following interventions are beneficial among patients with chronic kidney disease (CKD) or end-stage kidney disease (ESKD) with inflammation:
●Evaluate and treat occult infection
●Assess for and treat periodontal disease and poor dental hygiene
●Screen for tuberculosis
●Evaluate and treat urinary tract infections
●Routinely assess for pericarditis
●Evaluate and treat diabetic foot ulcers
●Remove old, nonfunctioning arteriovenous grafts
●Remove failed kidney allografts
●Replace standard dialysate fluid with ultrapure dialysate
●Treat rheumatologic conditions (ie, vasculitis, de novo or recurrent lupus flares)
Targeted pharmacologic therapies — If utilized, treatment modalities may target inflammation directly or ameliorate oxidative stress or endothelial dysfunction. The following agents have been evaluated [143,144]:
●Statins – Statins decrease CRP levels independent of their effects on lipids [145-147]. A randomized, placebo-controlled trial of 34 dialysis patients reported that atorvastatin (10 mg/day), after six months, significantly lowered serum CRP (9 and 5 mg/L) and cholesterol concentrations (175 and 156 mg/dL) and increased serum albumin levels (3.69 and 3.99 g/dL) [145]. A meta-analysis of nine clinical trials examining the effect of statin therapy on inflammatory and nutritional markers reported a significant decrease in CRP and high-sensitivity CRP levels but no effect on serum albumin levels [148]. Early data suggested that the use of statins have been associated with decreased mortality [149], but two subsequent, large clinical trials have failed to show a benefit of treatment with atorvastatin [150] and rosuvastatin [151] on clinical endpoints in chronic hemodialysis patients. This was in spite of an 11.5 percent decrease in high-sensitivity CRP levels in patients treated with rosuvastatin in the AURORA study [151], raising doubts about the significance of CRP in cardiovascular morbidity and mortality in this patient population. A third study (SHARP) [152] examined the effects of simvastatin and ezetimibe on clinical endpoints in patients with various stages of CKD (dialysis and nondialysis dependent) and found a significant decrease in a composite cardiovascular event rate in patients treated with simvastatin and ezetimibe [153]. Interestingly, while patients with higher baseline levels of CRP were at increased risk of future cardiovascular and noncardiovascular events in SHARP, the intervention with simvastatin and ezetimibe reduced cardiovascular events independent of CRP level, suggesting that their cardiovascular benefits were not mediated through control of inflammation [154]. (See "Secondary prevention of cardiovascular disease in end-stage kidney disease (dialysis)", section on 'SHARP trial'.)
●Renin-angiotensin-aldosterone system blockers – Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists are used as antihypertensive agents and in the treatment of heart failure, but some of their benefits in patients with CKD and heart failure may be related to effects that are independent from their blood pressure-lowering mechanism. One such mechanism is an antiinflammatory effect [155]. Although the data are inconsistent, ACE inhibitors may have antiinflammatory properties in both the general population and in those with CKD [156,157]. Their utility to treat inflammation has not been formally studied in patients with CKD. Finerenone, a nonsteroidal selective mineralocorticoid receptor antagonist, has proven kidney and cardiac benefits [158,159]. The putative mechanisms of action of finerenone are complex and involve effects on inflammation, oxidative stress, and fibrosis [160]. Nevertheless, the impact of finerenone therapy on systemic inflammation in CKD is unclear.
●Sodium-glucose cotransporter 2 inhibitors – Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antihyperglycemic agents that lower blood sugar through glycosuric actions [161]. SGLT2 inhibitors have been found to improve kidney and cardiovascular outcomes in diverse patient populations including patients with CKD [162-169]. These benefits appear to be mediated by complex metabolic affects, which include the suppression of inflammation [170-173].
●Apabetalone – Apabetalone is a selective modulator of the bromodomain and extraterminal domain transcription system. As an epigenetic modulator, apabetalone has complex mechanisms of action that include (among others) a downregulation of inflammatory responses. Apabetalone has been proposed as a potential therapy for cardiovascular disease in CKD [174]; however, the clinical utility of this agent is uncertain [175,176]. [175,176]
●Antioxidants – Since oxidative stress contributes to inflammation in CKD, antioxidants may lower the incidence of cardiovascular events in patients on hemodialysis:
•High-dose vitamin E was found to lower the risk of cardiovascular events in a small clinical trial in patients on dialysis [177]. A systematic review and meta-analysis concluded that dialyzers coated with vitamin E can reduce oxidative stress and inflammation [178], although a subsequent randomized, controlled clinical trial found no effect on CRP from vitamin E-coated dialyzer membranes compared with non-vitamin E-coated membranes [179]. The use of vitamin C infusion and of vitamin E-coated dialyzers in hemodialysis patients was also shown to reduce oxidative stress [180].
•One small study in dialysis patients showed that treatment with acetylcysteine lowered the incidence of cardiac events [181]. Another small clinical trial in patients on hemodialysis showed a reduction in CRP and interleukin (IL) 6 after a three-month intervention with acetylcysteine [182]. Most studies indicating an antiinflammatory and antioxidant effect of acetylcysteine in patients with CKD or ESKD are experimental, with very few and small clinical trials among them [183].
•Dietary supplementation with Brazil nut, a food source rich in selenium, resulted in a significant decrease in oxidative stress and inflammation in small clinical trials of patients with ESKD [184,185]. Other nutraceuticals with antiinflammatory and antioxidant properties in experimental studies and in small clinical trials in patients with CKD or ESKD include dark chocolate, propolis, curcumin, resistant starch, beetroot, and cinnamon. Further examination of these in larger clinical trials will be needed to assess their effects on inflammation and clinical outcomes [186-192].
•A meta-analysis of clinical trials that examined the effects of various antioxidant therapies on mortality, cardiovascular, and kidney events failed to detect significant effect on mortality and cardiovascular events overall, but there seemed to be benefits in reducing cardiovascular events in patients on dialysis [193]. The small sample size of most studies and the heterogeneity of the studies included in this meta-analysis make it difficult to generalize its results. It is also unclear to what extent the beneficial effects associated with the use of these antioxidants is related to their antiinflammatory effect. The feasibility and safety of these agents await testing in larger studies.
●Sevelamer hydrochloride – Sevelamer hydrochloride is a cationic polymer that is used in patients with ESKD as an intestinal phosphate binder. This agent also possesses "pleiotropic" effects that are unrelated to phosphate binding; one such effect may be the amelioration of inflammation. Sevelamer lowered CRP and other markers of inflammation in some [194-196], but not all [197], studies. A systematic review and meta-analysis that examined the pleiotropic effects of sevelamer found that sevelamer lowered glycated hemoglobin and improved lipid profiles but had no significant effect on inflammatory biomarkers [198].
●Heparin – Heparin is a glycosaminoglycan used as an anticoagulant and has been recognized for its antiinflammatory properties; this appears to be distinct from its anticoagulant activity [199]. It was proposed that new agents could be developed that retain the antiinflammatory properties of heparin but without the anticoagulant effects [199,200]. In our opinion, the practical impact of a heparin-related antiinflammatory effect in the ESKD population is questionable given that heparin is already routinely applied as an anticoagulant with hemodialysis, yet chronic inflammation is still very common in these patients.
●Megestrol acetate – Megestrol acetate is a synthetic derivate of progesterone used as an appetite stimulant. This agent also inhibits the activity of IL-1, IL-6, and tumor necrosis factor alpha (TNF-alpha) [201-205]. The beneficial effects of megestrol acetate in patients with ESKD are related to its appetite-stimulant effects and include improved appetite, increased energy and protein intake, and increased dry weight and quality of life [206-208]. The following side effects limit its usefulness: headaches, dizziness, confusion, diarrhea, hyperglycemia, thromboembolic phenomena, breakthrough uterine bleeding, peripheral edema, hypertension, adrenal suppression, and adrenal insufficiency [201]. A small clinical trial of 12 patients on dialysis receiving megestrol acetate described a beneficial effect on appetite and on nutritional markers but no effect on inflammatory markers [209].
●Bardoxolone methyl – Bardoxolone methyl (RTA 402) is an antioxidant inflammation modulator (AIM) in clinical development for various inflammation and cancer-related indications. It inhibits immune-mediated inflammation by restoring redox homeostasis in inflamed tissues through the induction of the cytoprotective transcription factor Nrf2 and suppresses the activities of the pro-oxidant and proinflammatory transcription factors nuclear factor kappa B (NF-kB) and the signal transducers and activators of transcription (STATs). In vivo, bardoxolone has shown significant antiinflammatory activity in various animal models of inflammation such as kidney damage in the cisplatin model and ischemia-reperfusion model of acute kidney injury. In a phase II clinical trial, bardoxolone methyl therapy led to a significant increase in estimated glomerular filtration rate (eGFR) levels in patients with advanced diabetic kidney disease [210]. A phase III clinical trial designed to test the hypothesis that bardoxolone methyl decreases the incidence of ESKD was terminated for safety reasons due to volume retention among the participants [211]. In a subsequent trial in which 157 patients with Alport syndrome were randomly assigned to bardoxolone methyl or placebo, eGFR was higher in the bardoxolone methyl group at two prespecified time points [212]. However, treatment with bardoxolone methyl was associated with an increase in urinary albumin excretion and with liver enzyme elevations. In addition, bardoxolone methyl had no effect on progression to kidney failure. Based on these data, the US Food and Drug Administration did not approve bardoxolone methyl for treatment of Alport syndrome.
●Omega-3 fatty acids – Omega-3 fatty acids have antiinflammatory effects, and higher dietary intake of omega-3 fatty acids has been associated with less inflammation [213]. However, a 2018 meta-analysis of 12 placebo-controlled trials, including 487 patients with CKD, concluded that omega-3 fatty acid supplementation did not lower levels of the inflammatory markers CRP, IL-6, or TNF-alpha [214]. Another meta-analysis has yielded similar results [215]. However, a 2023 meta-analysis of seven eligible trials found that omega-3 fatty acid therapy was as beneficial as a nonsurgical treatment of periodontal disease [216]. Since periodontal disease may be an important contributor to the inflammation seen in patients with kidney disease, it is possible that omega-3 fatty acids may alleviate inflammation in selected patients with CKD.
●Vitamin D – Vitamin D has multiple effects that have been invoked as potential explanations for its association with improved survival in patients with CKD and ESKD [217]. One such effect is modulation of the inflammatory reaction. In a small proof-of-concept clinical trial, the administration of the selective vitamin D receptor activator, paricalcitol, resulted in significant reduction in CRP, IL-6, and TNF-alpha levels in patients with advanced nondialysis-dependent CKD [218]. However, in a double-blind, randomized, placebo-controlled clinical trial including 46 patients with early CKD, high-dose cholecalciferol supplementation did not result in a significant change in most measured markers of inflammation [219]. Furthermore, in a double-blind, randomized, placebo-controlled clinical trial of ergocalciferol supplementation in 276 patients with ESKD on hemodialysis, ergocalciferol supplementation for six months resulted in no significant change in CRP levels (among other outcomes) [220]. A 2022 meta-analysis that included 18 trials with 1834 patients found that vitamin D supplementation did not lower levels of CRP, IL-6, or TNF-alpha in patients with CKD [221].
●L-carnitine – L-carnitine deficiency is common in patients on dialysis. A systematic meta-analysis of clinical trials examining the effects of L-carnitine supplementation in hemodialysis patients indicated that this therapy resulted in a significant reduction in CRP levels [222]. A more recent, small randomized trial of L-carnitine supplementation in 24 children on hemodialysis showed a significant reduction in IL-6 levels and a nonsignificant reduction in high-sensitivity CRP levels in patients treated with L-carnitine [223].
●Probiotic therapy – The intestinal microbiome is significantly altered among patients with CKD and is emerging as an important risk factor in the development and progression of kidney and heart disease [224,225]. Probiotics have emerged as a potential therapy with broad benefits in patients with CKD and ESKD [226,227].A 2018 meta-analysis of randomized trials (423 patients) including patients with CKD concluded that treatment with probiotic therapy reduced formation of the uremic solute p-cresol, which has been implicated in oxidative stress and systemic inflammation in the setting of CKD [228]. A subsequent meta-analysis of randomized trials involving patients on dialysis (178 patients) found that treatment with probiotics lowered CRP levels, but not TNF-alpha and albumin levels [229]. Broader dietary interventions such as plant-based diets and others remain promising alternatives to positively affect the intestinal microbiome and to alleviate the negative consequences of the uremic milieu [230-234]. The efficacy and safety of these will need to be tested in clinical trials.
In addition to the above agents and interventions with complex mechanisms of action, there are multiple "designer" drugs that target a specific aspect of the inflammatory cascade. These drugs have applications mainly in rheumatoid arthritis, and most of them will likely not be utilized in patients with CKD. However, some agents are considered for patients with CKD:
●Etanercept – Etanercept is an anti-TNF agent that is effective in the treatment of various forms of inflammatory arthritis, such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In a pilot study involving 10 patients on chronic hemodialysis, the administration of etanercept over 44 weeks appeared safe but resulted only in small improvement in prealbumin concentration [235]. A phase II, randomized, double-blind, placebo-controlled clinical trial examining the effectiveness of etanercept in improving serum albumin and CRP levels of patients on hemodialysis was terminated due to insufficient patient enrollment [236].
●Pentoxifylline – Pentoxifylline is a nonspecific phosphodiesterase inhibitor that inhibits TNF transcription [237]. Pentoxifylline has been tested in patients with ESKD in a randomized, double-blinded, placebo-controlled clinical trial [238]. The Anti-Inflammatory and Anti-Oxidative Nutrition in Dialysis Patients (AIONID) study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and examined the effect of oral nutritional supplements with antiinflammatory and antioxidant properties along with pentoxifylline therapy in a factorial design on malnutrition and inflammation in 100 patients receiving maintenance hemodialysis. Daily intake of a high-protein nutritional supplement with antiinflammatory and antioxidative ingredients resulted in a slight but significant increase in serum albumin levels.
Other studies that tested the efficacy of pentoxifylline were less successful in alleviating inflammation. In a small clinical trial of 71 adult patients with elevated CRP, the administration of 400 mg of pentoxifylline thrice weekly did not result in significant changes in serum hepcidin level compared with placebo [239]. This study did not test the effects of pentoxifylline on markers of inflammation such as CRP. Early-phase clinical trials are examining the pentoxifylline derivative CTP-499 as a treatment in diabetic kidney disease [240,241].
●IL-1 antagonists – Anakinra is a human recombinant IL-1 receptor antagonist that is used in rheumatoid arthritis. It also shows some promise in the treatment of inflammation in patients with CKD. A single study examined the pharmacokinetics of this drug in patients with impaired kidney function, showing that the main route of elimination for anakinra is renal clearance and that hemodialysis has a very small effect on clearance [242]. The results of this study indicate that thrice-weekly dosing of anakinra may be possible. The safety and efficacy of anakinra in chronic hemodialysis patients was examined in a randomized, controlled trial. This study reported significant beneficial effects of anakinra on serum CRP and IL-6 levels but no effects on serum albumin, prealbumin, and lean body mass levels [243]. Similarly, another trial that randomly assigned 42 patients with stage 3 and 4 CKD to receive rilonacept (another IL-1 receptor antagonist) or placebo found lower high-sensitivity CRP levels in patients receiving rilonacept [244]. Canakinumab is an IL-1-beta antagonist that lowered IL-6 and high-sensitivity CRP levels in CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), which enrolled 10,061 patients with diabetes and systemic inflammation (high-sensitivity CRP >2 mg/mL) [245]. In a post-hoc analysis of CANTOS, patients with early-stage CKD (eGFR <60 mL/min/1.73m2) treated with canakinumab (versus placebo) showed a significant reduction in major adverse cardiovascular events. This effect was largest in patients who showed a robust antiinflammatory effect after the first dose of canakinumab [246].
●IL-6 antagonists – Ziltivekimab is a novel anti-IL-6 ligand antibody that reduced CRP levels in a clinical trial of 264 patients with moderate to severe CKD and high-sensitivity CRP >2 mg/L [247]. Similar dose-dependent reductions were seen for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab also reduced inflammatory biomarker levels and erythropoiesis-stimulating agent (ESA) requirements in a phase I/II clinical trial conducted in patients on hemodialysis with inflammation and ESA hyporesponsiveness [248]. Another small trial in Japan randomly assigned 36 patients on chronic hemodialysis to two different doses of ziltivekimab or placebo [249]. Compared with patients treated with placebo, patients treated with ziltivekimab showed significant reductions in inflammatory biomarkers after 12 weeks of therapy. Larger clinical trials are needed to test the efficacy and safety of this agent and its impact on clinical outcomes.
●Rituximab – Rituximab is a B-cell-depleting monoclonal anti-CD20 antibody [250]. B-cell depletion affects the levels of autoantibodies that play important roles in the pathophysiology of diseases such as rheumatoid factor in rheumatoid arthritis [251,252], systemic lupus erythematosus [253], and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [254-256]. Rituximab also has been examined for the treatment of various glomerular diseases [257-261]. It is unclear if this agent will be employed for the treatment of chronic inflammation in CKD since the autoantibody depletion resultant after B-cell depletion may be more specific to certain types of diseases.
●Chemokine inhibitors – Several agents targeting chemokine pathways have been evaluated for the treatment of diabetic nephropathy, such as C-C chemokine receptor type 2 (CCR2) inhibitors [262], the C-C motif-ligand 2 (CCL2) (ie, monocyte chemotactic protein 1) inhibitor emapticap pegol [263], or the Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor baricitinib [264]. (See "Treatment of diabetic kidney disease".)
●Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs) – This class of agents is used for the treatment of anemia in ESKD. HIF PHIs may be more effective in treating anemia associated with inflammation, which is typically resistant to traditional anemia therapies [265,266]. Preclinical studies suggest that HIF PHIs may also directly decrease inflammation [267].
Optimization of dialysis treatment may also improve inflammatory status in patients on dialysis, with the type of dialysis membrane and dialysis method (online hemodiafiltration versus standard hemodialysis) possibly having an impact upon mortality [268,269]. As an example, the use of biocompatible membranes decreases serum levels of CRP, although such interventions may not completely normalize its serum concentration [66,67]. (See "Clinical consequences of hemodialysis membrane biocompatibility".)
However, a major clinical trial, known as the HEMO study, failed to show a major improvement in clinical outcomes with the use of high-flux membranes. Nevertheless, this finding does not necessarily refute a role of dialysis membranes in the development of chronic inflammation in patients with ESKD, since the membrane effect on survival may have been small compared with that of other variables.
There is no consensus as to which medication or combination of drugs should be used under different clinical conditions. In general, ACE inhibitors are commonly used in patients with CKD or ESKD with hypertension and/or heart failure, statins are used in those with hyperlipidemia, and vitamin E in patients with refractory muscle cramps. Clinical trials have not been performed to determine whether the use of these medications is warranted for the treatment of inflammation in patients with kidney dysfunction but without an indicated concurrent comorbid condition.
NOVEL APPROACHES — Novel treatment strategies are needed to help manage inflammation among patients with kidney disease:
●Additional clinical trials of antiinflammatory and anticytokine agents should be conducted in patients with CKD and ESKD [174].
●Clinical trials are needed to compare the effect of antiinflammatory agents with that of nutritional support in patients suffering from the malnutrition-inflammation complex syndrome (MICS) [112,143].
●Limited evidence suggests that resistance training may help reduce MICS and improve cardiometabolic profiles in patients with CKD and ESKD [270-274].
SUMMARY AND RECOMMENDATIONS
●Inflammation and kidney disease – Chronic inflammatory processes are common in individuals with chronic kidney disease (CKD), including those with early-stage CKD and especially end-stage kidney disease (ESKD). This is due to many underlying factors, including the uremic milieu, elevated levels of circulating proinflammatory cytokines, oxidative stress, carbonyl stress, protein-energy wasting (PEW), enhanced incidence of infections (especially dialysis access related), and others. (See 'Introduction' above and 'Inflammation and kidney disease' above.)
●General markers of inflammation – Routine monitoring of inflammatory markers in all patients with ESKD or CKD is not recommended by most guidelines, although it may improve patient management, for example, by providing evidence of an unrecognized infection or other treatable inflammatory conditions. Periodic measurement of C-reactive protein (CRP) or interleukin (IL) 6 to assess severity and frequency of inflammation is reasonable in select patients as part of an individualized work-up prompted by specific clinical characteristics, such as PEW. (See 'General markers of inflammation' above.)
●Management issues – The presence of elevated inflammatory markers (eg, CRP >5 mg/L or 0.5 mg/dL) in patients with ESKD or CKD should prompt a search for immediately treatable causes of acute or chronic inflammation, such as occult infections, volume overload, inadequate dialysis treatment, PEW, or the presence of a nonfunctioning kidney allograft. (See 'Management issues' above.)
●Novel approaches – No pharmacologic interventions are currently recommended to specifically target chronic inflammation in patients with CKD or ESKD. However, pharmacologic and nutritional interventions may become available in the future for this indication. (See 'Management issues' above and 'Novel approaches' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Joel Kopple, MD, who contributed to an earlier version of this topic review.
92 : Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment.
101 : Nutritional status as a predictor of morbidity and mortality in maintenance dialysis patients.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟