REVIEW URRENT C OPINION
Asymmetric dimethylarginine and critical illness Saskia J.H. Brinkmann a,b, Myrte C. de Boer b, Nikki Buijs b, and Paul A.M. van Leeuwen b
Purpose of review Asymmetric dimethylarginine (ADMA) is an analog of arginine and functions as an endogenous inhibitor of the nitric oxide synthase, which forms nitric oxide. Nitric oxide is crucial for perfusion of vital organs and is an important signaling agent in the development of critical illness. The role of ADMA in the pathophysiological mechanisms underlying critical illness is widely studied in the last decades, and recently it has become clear that ADMA should not be overlooked by clinicians working at the ICU. The aim of this review is to describe new insights into the role of ADMA in critical illness and its clinical relevance. Recent findings High levels of ADMA are found in critically ill patients, because of higher levels of protein methylation, increased rate of protein turnover, decreased activity of dimethylamine dimethylaminohydrolase, and impaired renal and hepatic clearance capacity. These high levels are an independent risk factor for cardiac dysfunction, organ failure, and ICU mortality. The arginine : ADMA ratio in particular is of clinical importance and the restoration of this ratio is expedient to restore several functions that are disturbed during critical illness. Summary Elevated ADMA levels occur in critically ill patients, which is detrimental for morbidity and mortality. The arginine : ADMA ratio should be restored to maintain nitric oxide production and therewith improve the clinical outcome of the patient. Keywords asymmetric dimethylarginine, critical illness, humans, ICU
INTRODUCTION Asymmetric dimethylarginine (ADMA) is a naturally occurring guanidino-substituted analog of the conditionally essential amino acid arginine and a metabolic by-product of continual protein turnover processes in the cytoplasm of all human cells. Arginine is the precursor for nitric oxide, an important regulator of immune function and organ circulation. ADMA functions as an endogenous inhibitor of the enzyme nitric oxide synthase (NOS) which forms nitric oxide and can therefore impair the bioavailability of nitric oxide [1]. The discovery of ADMA and the observation of its reductive effects on nitric oxide synthesis in vitro and in vivo led to a large body of research attempting to discover its role in critical illness. This review will provide an overview of ADMA metabolism in humans and most recently discovered features of ADMA in the critically ill patients.
SYNTHESIS OF ASYMMETRIC DIMETHYLARGININE ADMA and other methylarginines are continuously formed from intracellular proteolysis of methylated www.co-clinicalnutrition.com
arginine residues in the nucleus of the cell, by enzymes called protein arginine methyltransferases (PRMTs) (see Fig. 1) [2]. The PRMT family generates three different forms of methylated arginine: monomethylarginine (MMA), symmetric dimethylarginine (SDMA), and ADMA. ADMA is generated when two methyl groups are added to the same nitrogen atom of the arginine skeleton by PRMT Type I enzymes. Type II enzymes add a second methyl group to the other terminal nitrogen of arginine to produce SDMA [3]. MMA only has one methyl group bound to a nitrogen terminal. Methylarginines are released into the cytosol following proteolysis.
a
Department of Plastic and Reconstructive Surgery and bDepartment of Surgery, VU University Medical Center, Amsterdam, the Netherlands Correspondence to Professor Paul A.M. van Leeuwen, MD, PhD, Department of Surgery, VU, University Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands. Tel: +31 20 4444444; fax: +31 20 4443620; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:90–97 DOI:10.1097/MCO.0000000000000020 Volume 17 Number 1 January 2014
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Asymmetric dimethylarginine and critical illness Brinkmann et al.
KEY POINTS ADMA is an inhibitor of NOS, which produces nitric oxide, a gaseous molecule important for organ flow and immune function. ADMA competes with arginine and therefore influences the availability of nitric oxide. ADMA levels are elevated in critical illness, because of higher amounts of protein methylation, increased rate of protein turnover, impaired activity of dimethyl dimethylaminohydrolase (DDAH), impaired renal excretion, and liver failure. ADMA is an independent marker for cardiac dysfunction, organ failure and mortality at the ICU. Mainly the arginine : ADMA ratio, rather than arginine or ADMA alone, showed a strong association with organ dysfunction and mortality at the ICU. Future studies should assess therapeutic agents which restore the arginine : ADMA ratio to improve the outcome of critically ill patients.
METABOLISM OF ASYMMETRIC DIMETHYLARGININE Whereas ADMA competes with arginine for NOS, the bioavailability of nitric oxide depends on the balance between the two, the so-called arginine : ADMA ratio [4–6]. This ratio has been shown to be an indicator for many nitric-oxidedependent physiological systems. In a review ¨ ger et al. [7] identified of the literature, Bode-Bo
585 healthy individuals with a median arginine : ADMA ratio of 183 and 3070 patients with various diseases with a median arginine : ADMA ratio of 73. A lower arginine : ADMA ratio can occur because of low arginine levels, high ADMA levels, or both. This decrease of the arginine : ADMA ratio in disease states induces an inhibition of nitric oxide formation, and this may result in impaired vascular function and dysfunctional organ perfusion. Nitric oxide is a gaseous signaling molecule which is involved in a wide variety of regulatory mechanisms of the cardiovascular system, including regulation of the vasomotor tone, cell adhesion to the endothelium, inhibition of platelet aggregation, and vascular smooth muscle cell proliferation [8,9]. Nitric oxide is linked to several pathophysiological aspects of critical illness, such as infection, inflammation, and organ injury. In humans, nitric oxide is formed by three isoforms of NOS by using arginine as a substrate (endothelial, neuronal, and inducible NOS). Endothelial NOS (eNOS) regulates vascular tone and is therefore important for preservation of organ blood flow. The inducible isoform of NOS (iNOS) is able to produce large amounts of nitric oxide during inflammation. Nitric oxide derived from the neuronal isoform (nNOS) is mainly important in relaxation of smooth muscle cells [10]. ADMA competes with arginine by blocking the formation of nitric oxide from arginine by NOS directly (see Fig. 1). NOS is mainly localized in the cell, so the intracellular ADMA and arginine levels regulate NOS activity [11]. In addition, extracellular ADMA is an antagonist to extracellular arginine on
Cytosol Proteins PRMT Proteins containing methylarginines Hydrolyse Nucleus
DDAH
Renal excretion
SDMA
ADMA
CAT system y+
Arginine
NOS
Citrulline + dimethylarginine
NO + citrulline
CAT system y+
FIGURE 1. Interactions between dimethylarginine dimethylaminohydrolase (DDAH), asymmetric dimethylarginine (ADMA) and nitric oxide synthase (NOS). SDMA, symmetric dimethylarginine; PRMTs, protein arginine methyltransferases. 1363-1950 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Protein, amino acid metabolism and therapy
cell membrane transporter level, whereas they are both transported into the cell via cationic amino acid transporters (CAT) of system yþ and therefore compete with each other. Other methylarginines, such as SDMA and MMA, are also capable of influencing nitric oxide bioavailability by competing with arginine for cellular transport across CAT of system yþ. However, physiological concentrations of ADMA are approximately 10-fold higher than that of other methylarginines, so their effect on the bioavailability of nitric oxide is negligible [3,12].
ELIMINATION OF ASYMMETRIC DIMETHYLARGININE Humans generate approximately 300 mmol of ADMA per day, a small amount of which (10%) is continuously excreted into the urine [13,14]. The primary route of elimination of ADMA is clearance by enzymatic degradation by DDAH. DDAH converts ADMA into citrulline and dimethylamine by replacement of guanidine in ADMA by the cysteine in DDAH [13,15]. DDAH is present in pancreas, spleen, liver, kidney, and endothelium. The metabolic fates of dimethylarginines are not fully understood; however, the kidney and liver seem to play an important role in their metabolism. Patients suffering from kidney disease exhibit impaired urinary excretion, reduced synthesis of arginine, and impaired activity of DDAH, together leading to elevated levels of ADMA. This subsequently leads to decreased production of nitric oxide, eventually causing endothelial dysfunction, cardiovascular risk, and progression of renal damage [16–19]. In humans, ADMA has been proposed as an independent prognostic marker for the progression of renal disease [16,20–22]. The liver has a high net uptake and a substantial fractional extraction rate of ADMA and DDAH is present in high amounts. Therefore, this organ plays a crucial role in the metabolism of ADMA. Kupffer cells, the macrophages of the liver, are important in the body’s defense mechanism during critical illness by the release of large amounts of inflammatory mediators. This induces local pathological processes such as inflammation, oxidative stress, and direct damage to the DDAH protein present in the liver. Subsequent deterioration of DDAH activity leads to elevated levels of ADMA in critically ill patients with hepatic dysfunction. Preservation of liver function is essential for maintaining ADMA levels in the normal range [23].
ASYMMETRIC DIMETHYLARGININE IN CRITICAL ILLNESS ADMA levels, and therefore the arginine–nitric oxide pathway, have been recognized to play a 92
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crucial role during critical illness [24]. It was proven that critically ill patients are exposed to elevated levels of ADMA, which accumulate in serum [8]. Elevated ADMA plasma levels are mainly the result of hepatic and renal failure, organs which play a crucial role in critical illness [23]. In critically ill patients suffering from hepatic failure, highly raised concentrations of ADMA were measured. Removal of liver tissue and prolonged hepatic injury influenced the eliminatory capacity of ADMA of the liver, resulting in higher systemic levels of ADMA. In addition, high levels of ADMA seem to be related to the presence of hepatic failure [25]. Furthermore, in wild-type mice with remnant kidney disease, impaired renal function correlated with reduced renal clearance [26]. In addition, almost all patients at the ICU suffer from insulin resistance resulting in hyperglycemia, which inhibits the function of DDAH [27]. Accordingly, in an animal model, it was found that intensive insulin therapy may improve the functioning of DDAH and lowers the plasma concentrations of ADMA in the critically ill [28]. This was explained by Ellger et al. by the fact that breakdown of ADMA was possibly preserved by maintaining physiological DDAH activity rather than by an effect on dimethylarginine release via protein catabolism [28,29]. Taken together, critically ill patients suffer from high levels of ADMA. This is hypothetically attributable to the catabolic state the patient is in, leading to a high turnover of dimethylarginine-containing proteins and renal and hepatic failure resulting in alterations in DDAH activity and less excretion. Elevated levels of ADMA result in higher ICU morbidity and mortality in human beings [30]. In order to understand the detrimental effects of ADMA and the need for nitric oxide for survival in critical illness, the importance of the arginine : ADMA ratio must be understood. This pathway has been extensively studied in sepsis and organ dysfunction settings in both humans and animals [5,19,31,32]. Critical illness is characterized by vascular and organ dysfunction, caused by endothelial damage and microvascular oxidative stress [1,8]. In this state, regulation of organ perfusion by nitric oxide is of vital importance because organ oxygenation is at risk [8]. High amounts of ADMA in the critically ill state lower the arginine : ADMA ratio, inhibit NOS and CAT, and subsequently nitric oxide production. So, hypothetically, the increased ADMA levels could participate in the pathological processes of critical illness. To better understand the relation of nitric oxide and the arginine : ADMA ratio in sepsis, a study was done in rats. In an isolated perfused rat heart, the effect of inhibition of nitric oxide synthesis after Volume 17 Number 1 January 2014
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Asymmetric dimethylarginine and critical illness Brinkmann et al.
endotoxemia was investigated. A massive coronary vasodilation was seen in the endotoxin-treated rats, which was caused by an increased release of nitric oxide. Inhibition of nitric oxide metabolism after endotoxemia showed a reduction of the coronary flow and caused areas of myocardial ischemia. These areas disappeared after infusion of arginine as a substrate for nitric oxide. In another model of critical ill rats, low arginine plasma levels in combination with high ADMA plasma levels (low arginine : ADMA ratio) deteriorated systemic hemodynamics (heart rate, mean arterial pressure, and cardiac output) and reduced blood flow through the kidney, spleen, and liver. Studies in humans confirmed these findings when volunteers receiving an intravenous low-dose of ADMA showed a reduced heart rate (P < 0.001), cardiac output (P < 0.001), and an increased mean blood pressure (P < 0.005) compared with controls [6,12,15,33,34]. In septic patients, nitric oxide production may be excessively high and this can be harmful [35]. Therefore, inhibition of NOS was proposed as a manner to reduce morbidity and mortality in this patient population. One trial assessed the effect of a NOS inhibitor in a population of 124 septic patients in order to counteract the excessive production of nitric oxide [36]. The trial was stopped preliminary because the 28-day mortality was 59% in the NOS inhibitor group and 49% in the placebo group (P < 0.001). Most patients who died early in this study showed a cardiac cause of death. Overall, many studies have shown that high levels of ADMA can induce detrimental effects. These unfavorable actions are primarily the result of diminished nitric oxide availability, resulting in disturbed vasodilatation and antithrombotic, anti-inflammatory, and antiapoptotic actions that overall may lead to cardiac dysfunction [8,37].
NEW INSIGHTS INTO ASYMMETRIC DIMETHYLARGININE IN CRITICAL ILLNESS In view of this large body of observations on the basal role of ADMA in critical illness, we give an overview of the most recent findings of clinical studies on ADMA in critically ill patients (Table 1). Cardiac dysfunction at the ICU is a main cause of death and could be induced by decreased levels of nitric oxide. Visser et al. [40 ] demonstrated that a decreased arginine : ADMA ratio at ICU admission was associated with circulatory failure, organ failure, and mortality in patients with septic or cardiogenic shock. Whereas ADMA levels were in the normal range, arginine was depleted, implicating that the ratio of arginine and ADMA is more important for microcirculation and macrocirculation than their &
individual concentrations. The ratio showed a strong association and better diagnostic accuracy for hospital mortality in this study, in which the arginine or ADMA concentration alone failed to do so. In children undergoing cardiac surgery, it was found that patients with elevated ADMA levels before surgery were more likely to develop low cardiac output syndrome after surgery [43]. These pediatric patients also required prolonged mechanical ventilation, reoperation, and increased ICU and hospital length of stay. Investigating ADMA levels in sepsis deserves broad interest, whereas the arginine–nitric oxide pathway is disturbed in this condition. In a large prospective cohort study, comparing patients with severe sepsis with controls, it was shown that the arginine : ADMA ratio was lower in septic patients and that this was positively correlated to the Acute Physiology and Chronic Health Evaluation (APACHE) II score [39]. In addition, this decrease in ratio was independently associated with a higher hospital mortality and a higher risk of death over the course of 6 months. A comparable study also demonstrated that the ratio was significantly reduced in septic patients and correlated with the severity of illness as measured by APACHE II score (P ¼ 0.003) and organ failure, as measured by the Sequential Organ Failure Assessment (SOFA) score (P ¼ 0.0001) [38]. Baseline plasma ADMA was independently associated with 28-day mortality for death in the highest quartile (0.66 mmol/l, P ¼ 0.008) and independently correlated with the severity of organ failure. An increase of ADMA levels over time correlated with an increase in organ failure and a decrease in microvascular reactivity. Increased levels of ADMA and a subsequent decreased arginine : ADMA ratio were also found in patients with septic shock compared with healthy volunteers and patients following major abdominal surgery at all time points within the 28-day observation period [41]. In this group, acute liver failure increased the plasma levels of ADMA in comparison to those with an intact hepatic function and this appeared to be an early predictor for survival. Koch et al. [44] demonstrated in a study of 164 critically ill patients and 91 controls that ADMA serum levels were significantly elevated in the critically ill group at admission and were closely related to hepatic and renal dysfunction, metabolism, and clinical scores of disease severity. ADMA serum levels at admission were an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU, but also for long-term survival. Surprisingly, ADMA levels did not differ between patients with or without sepsis in this study. This was explained by the fact that ADMA upregulation
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2
120
44
2
Visser et al., & 2012 [40 ]
Brenner et al., 2012 [41]
159
2
Gough et al., 2011 [39]
98
2
n
Davis et al., 2011 [38]
Source
Oxford level of evidence
1. Septic shock (n ¼ 60)
2. Cardiogenic shock (n ¼ 17)
1. Septic shock (n ¼ 27)
2. Controls (n ¼ 50)
1. Severe sepsis (n ¼ 109)
2. Controls (n ¼ 31)
1. Acute sepsis (n ¼ 67)
Patient groups
Arginine, ADMA levels in multiple organ dysfunction syndrome
Disease severity, organ failure, mortality
Arginine : ADMA ratio in sepsis
Role of ADMA in acute inflammatory states
Outcome
Arginine, ADMA, APACHE-II score, SOFA score
Arginine, ADMA, circulatory markers, APACHE II-, SOFA score, mortality
Arginine, ADMA, SDMA, urinary nitrate, APACHE IIscore, SOFA score, mortality
ADMA, arginine, microvascular reactivity, APACHE-II score, SOFA score, mortality
Parameters
Table 1. Human studies examining ADMA metabolism in the critically ill patient, studies published in 2011–2013
28 Days
6 months
4 Days
Follow-up
Group 1: increased levels of ADMA and decreased arginine : ADMA ratio in comparison to group 2 and 3. Acute liver failure increased plasma levels of ADMA (and arginine) in group 1 in comparison to those with an intact hepatic function and this appeared to be early predictors for survival.
Decreased arginine : ADMA ratio was associated with circulatory failure, severity of disease and organ failure and it predicted mortality.
Decreased arginine : ADMA ratio is associated with severe sepsis and severity of illness and independently predicts both hospital mortality and risk of death over the course of 6 months after diagnosis.
Arginine : ADMA ratio was significantly reduced in sepsis and correlated with the severity of illness and organ failure. Raised ADMA levels and an increase in levels over time, as in group 1, were independently associated with mortality, severity of organ failure and decrease in microvascular reactivity.
Conclusion
Protein, amino acid metabolism and therapy
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2
1
Hassinger et al., 2012 [43]
Koch et al., 2013 [44]
333
100
90
n
3. Healthy controls (n ¼ 78)
2. Without sepsis (n ¼ 91)
1. Sepsis (n ¼ 164)
2. Normal ADMA levels (n ¼ 71)
3. Healthy controls (n ¼ 30) Pediatric cardiac surgery: 1. Preoperative elevated ADMA levels (n ¼ 29)
2. Febrile (n ¼ 30)
Pediatric: 1. (Severe) sepsis (n ¼ 30)
2. Surgical ICU patients (n ¼ 30) 3. Healthy controls (n ¼ 30)
Patient groups
ADMA levels, organ function, clinical scores, mortality
Acute kidney injury, low cardiac output syndrome, LOS, reoperation, mortality
ADMA metabolism
Outcome
ADMA, APACHE-II score, SOFA score mortality
ADMA, blood urea nitrogen, cystatin C, creatinine, mortality
Arginine, ADMA, citrulline, ornithine, AC : FC ratio, PIM-2, PELOD score
Parameters
3 Years
4 Days
7 Days
Follow-up
Elevated ADMA levels in groups 1 and 2 at admission, with no difference between group 1 and 2. ADMA serum levels at admission were an independent prognostic biomarker in critically ill patients for both short-term mortality at the ICU and long-term mortality.
Group 1 was more likely to have prolonged mechanical ventilation, developed low cardiac output syndrome, required an extended length of stay and required more often reoperation.
Decreased levels of ADMA in pediatric sepsis and this was inversely associated with inflammation and organ dysfunction.
Conclusion
AC : FC ratio, acylcarnitine : free carnitine ratio; ADMA, asymmetric dimethylarginine; APACHE, Acute Physiology and Chronic Health Evaluation; LOS, length of hospital stay; PELOD, Pediatric Logistic Organ Dysfunction; PIM-2, Pediatric Index of Mortality; SOFA, Sequential Organ Failure Assessment.
2
Weiss et al., 2012 [42]
Source
Oxford level of evidence
Table 1 (Continued)
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in this study may represent a uniform response in critical illness, independent of the presence of infection. Other studies examining ADMA levels in septic shock in adults also show increased plasma ADMA levels and subsequently a decreased arginine : ADMA ratio [1,38,39,41,45]. Surprisingly, in a study examining children suffering from severe sepsis and septic shock, plasma levels of ADMA were decreased and the arginine : ADMA ratio remained unchanged [42]. This was explained by the authors by the fact that children with sepsis are better in maintaining ADMA homeostasis than adults through a preserved feedback system. Children probably have a decreased protein catabolism, a reduced incidence of renal and hepatic dysfunction, less blood cell-related ADMA release through a lower rate of hemolysis, and are better capable of preserving their DDAH activity in their body compared with adults.
CONCLUSION Critically ill patients suffer from high levels of ADMA, presumably because of higher amounts of protein methylation, increased rate of protein turnover, impaired activity of DDAH, impaired renal excretion, and liver failure. By being a predictor of morbidity and mortality in critically ill patients, ADMA should not be overlooked by clinicians working at the ICU. New insights in ADMA in the critically ill revealed that mainly the arginine : ADMA ratio is of clinical importance. So, restoration of this ratio by increasing the endogenous arginine production or decreasing the circulating levels of ADMA is a possible option to improve recovery. Future trials should consider modulation of the ratio with as main goal normalization of nitric oxide production, and therewith improve clinical outcome and survival of the patient. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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Asymmetric dimethylarginine and critical illness Saskia J.H. Brinkmann a,b, Myrte C. de Boer b, Nikki Buijs b, and Paul A.M. van Leeuwen b
Purpose of review Asymmetric dimethylarginine (ADMA) is an analog of arginine and functions as an endogenous inhibitor of the nitric oxide synthase, which forms nitric oxide. Nitric oxide is crucial for perfusion of vital organs and is an important signaling agent in the development of critical illness. The role of ADMA in the pathophysiological mechanisms underlying critical illness is widely studied in the last decades, and recently it has become clear that ADMA should not be overlooked by clinicians working at the ICU. The aim of this review is to describe new insights into the role of ADMA in critical illness and its clinical relevance. Recent findings High levels of ADMA are found in critically ill patients, because of higher levels of protein methylation, increased rate of protein turnover, decreased activity of dimethylamine dimethylaminohydrolase, and impaired renal and hepatic clearance capacity. These high levels are an independent risk factor for cardiac dysfunction, organ failure, and ICU mortality. The arginine : ADMA ratio in particular is of clinical importance and the restoration of this ratio is expedient to restore several functions that are disturbed during critical illness. Summary Elevated ADMA levels occur in critically ill patients, which is detrimental for morbidity and mortality. The arginine : ADMA ratio should be restored to maintain nitric oxide production and therewith improve the clinical outcome of the patient. Keywords asymmetric dimethylarginine, critical illness, humans, ICU
INTRODUCTION Asymmetric dimethylarginine (ADMA) is a naturally occurring guanidino-substituted analog of the conditionally essential amino acid arginine and a metabolic by-product of continual protein turnover processes in the cytoplasm of all human cells. Arginine is the precursor for nitric oxide, an important regulator of immune function and organ circulation. ADMA functions as an endogenous inhibitor of the enzyme nitric oxide synthase (NOS) which forms nitric oxide and can therefore impair the bioavailability of nitric oxide [1]. The discovery of ADMA and the observation of its reductive effects on nitric oxide synthesis in vitro and in vivo led to a large body of research attempting to discover its role in critical illness. This review will provide an overview of ADMA metabolism in humans and most recently discovered features of ADMA in the critically ill patients.
SYNTHESIS OF ASYMMETRIC DIMETHYLARGININE ADMA and other methylarginines are continuously formed from intracellular proteolysis of methylated www.co-clinicalnutrition.com
arginine residues in the nucleus of the cell, by enzymes called protein arginine methyltransferases (PRMTs) (see Fig. 1) [2]. The PRMT family generates three different forms of methylated arginine: monomethylarginine (MMA), symmetric dimethylarginine (SDMA), and ADMA. ADMA is generated when two methyl groups are added to the same nitrogen atom of the arginine skeleton by PRMT Type I enzymes. Type II enzymes add a second methyl group to the other terminal nitrogen of arginine to produce SDMA [3]. MMA only has one methyl group bound to a nitrogen terminal. Methylarginines are released into the cytosol following proteolysis.
a
Department of Plastic and Reconstructive Surgery and bDepartment of Surgery, VU University Medical Center, Amsterdam, the Netherlands Correspondence to Professor Paul A.M. van Leeuwen, MD, PhD, Department of Surgery, VU, University Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands. Tel: +31 20 4444444; fax: +31 20 4443620; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:90–97 DOI:10.1097/MCO.0000000000000020 Volume 17 Number 1 January 2014
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Asymmetric dimethylarginine and critical illness Brinkmann et al.
KEY POINTS ADMA is an inhibitor of NOS, which produces nitric oxide, a gaseous molecule important for organ flow and immune function. ADMA competes with arginine and therefore influences the availability of nitric oxide. ADMA levels are elevated in critical illness, because of higher amounts of protein methylation, increased rate of protein turnover, impaired activity of dimethyl dimethylaminohydrolase (DDAH), impaired renal excretion, and liver failure. ADMA is an independent marker for cardiac dysfunction, organ failure and mortality at the ICU. Mainly the arginine : ADMA ratio, rather than arginine or ADMA alone, showed a strong association with organ dysfunction and mortality at the ICU. Future studies should assess therapeutic agents which restore the arginine : ADMA ratio to improve the outcome of critically ill patients.
METABOLISM OF ASYMMETRIC DIMETHYLARGININE Whereas ADMA competes with arginine for NOS, the bioavailability of nitric oxide depends on the balance between the two, the so-called arginine : ADMA ratio [4–6]. This ratio has been shown to be an indicator for many nitric-oxidedependent physiological systems. In a review ¨ ger et al. [7] identified of the literature, Bode-Bo
585 healthy individuals with a median arginine : ADMA ratio of 183 and 3070 patients with various diseases with a median arginine : ADMA ratio of 73. A lower arginine : ADMA ratio can occur because of low arginine levels, high ADMA levels, or both. This decrease of the arginine : ADMA ratio in disease states induces an inhibition of nitric oxide formation, and this may result in impaired vascular function and dysfunctional organ perfusion. Nitric oxide is a gaseous signaling molecule which is involved in a wide variety of regulatory mechanisms of the cardiovascular system, including regulation of the vasomotor tone, cell adhesion to the endothelium, inhibition of platelet aggregation, and vascular smooth muscle cell proliferation [8,9]. Nitric oxide is linked to several pathophysiological aspects of critical illness, such as infection, inflammation, and organ injury. In humans, nitric oxide is formed by three isoforms of NOS by using arginine as a substrate (endothelial, neuronal, and inducible NOS). Endothelial NOS (eNOS) regulates vascular tone and is therefore important for preservation of organ blood flow. The inducible isoform of NOS (iNOS) is able to produce large amounts of nitric oxide during inflammation. Nitric oxide derived from the neuronal isoform (nNOS) is mainly important in relaxation of smooth muscle cells [10]. ADMA competes with arginine by blocking the formation of nitric oxide from arginine by NOS directly (see Fig. 1). NOS is mainly localized in the cell, so the intracellular ADMA and arginine levels regulate NOS activity [11]. In addition, extracellular ADMA is an antagonist to extracellular arginine on
Cytosol Proteins PRMT Proteins containing methylarginines Hydrolyse Nucleus
DDAH
Renal excretion
SDMA
ADMA
CAT system y+
Arginine
NOS
Citrulline + dimethylarginine
NO + citrulline
CAT system y+
FIGURE 1. Interactions between dimethylarginine dimethylaminohydrolase (DDAH), asymmetric dimethylarginine (ADMA) and nitric oxide synthase (NOS). SDMA, symmetric dimethylarginine; PRMTs, protein arginine methyltransferases. 1363-1950 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Protein, amino acid metabolism and therapy
cell membrane transporter level, whereas they are both transported into the cell via cationic amino acid transporters (CAT) of system yþ and therefore compete with each other. Other methylarginines, such as SDMA and MMA, are also capable of influencing nitric oxide bioavailability by competing with arginine for cellular transport across CAT of system yþ. However, physiological concentrations of ADMA are approximately 10-fold higher than that of other methylarginines, so their effect on the bioavailability of nitric oxide is negligible [3,12].
ELIMINATION OF ASYMMETRIC DIMETHYLARGININE Humans generate approximately 300 mmol of ADMA per day, a small amount of which (10%) is continuously excreted into the urine [13,14]. The primary route of elimination of ADMA is clearance by enzymatic degradation by DDAH. DDAH converts ADMA into citrulline and dimethylamine by replacement of guanidine in ADMA by the cysteine in DDAH [13,15]. DDAH is present in pancreas, spleen, liver, kidney, and endothelium. The metabolic fates of dimethylarginines are not fully understood; however, the kidney and liver seem to play an important role in their metabolism. Patients suffering from kidney disease exhibit impaired urinary excretion, reduced synthesis of arginine, and impaired activity of DDAH, together leading to elevated levels of ADMA. This subsequently leads to decreased production of nitric oxide, eventually causing endothelial dysfunction, cardiovascular risk, and progression of renal damage [16–19]. In humans, ADMA has been proposed as an independent prognostic marker for the progression of renal disease [16,20–22]. The liver has a high net uptake and a substantial fractional extraction rate of ADMA and DDAH is present in high amounts. Therefore, this organ plays a crucial role in the metabolism of ADMA. Kupffer cells, the macrophages of the liver, are important in the body’s defense mechanism during critical illness by the release of large amounts of inflammatory mediators. This induces local pathological processes such as inflammation, oxidative stress, and direct damage to the DDAH protein present in the liver. Subsequent deterioration of DDAH activity leads to elevated levels of ADMA in critically ill patients with hepatic dysfunction. Preservation of liver function is essential for maintaining ADMA levels in the normal range [23].
ASYMMETRIC DIMETHYLARGININE IN CRITICAL ILLNESS ADMA levels, and therefore the arginine–nitric oxide pathway, have been recognized to play a 92
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crucial role during critical illness [24]. It was proven that critically ill patients are exposed to elevated levels of ADMA, which accumulate in serum [8]. Elevated ADMA plasma levels are mainly the result of hepatic and renal failure, organs which play a crucial role in critical illness [23]. In critically ill patients suffering from hepatic failure, highly raised concentrations of ADMA were measured. Removal of liver tissue and prolonged hepatic injury influenced the eliminatory capacity of ADMA of the liver, resulting in higher systemic levels of ADMA. In addition, high levels of ADMA seem to be related to the presence of hepatic failure [25]. Furthermore, in wild-type mice with remnant kidney disease, impaired renal function correlated with reduced renal clearance [26]. In addition, almost all patients at the ICU suffer from insulin resistance resulting in hyperglycemia, which inhibits the function of DDAH [27]. Accordingly, in an animal model, it was found that intensive insulin therapy may improve the functioning of DDAH and lowers the plasma concentrations of ADMA in the critically ill [28]. This was explained by Ellger et al. by the fact that breakdown of ADMA was possibly preserved by maintaining physiological DDAH activity rather than by an effect on dimethylarginine release via protein catabolism [28,29]. Taken together, critically ill patients suffer from high levels of ADMA. This is hypothetically attributable to the catabolic state the patient is in, leading to a high turnover of dimethylarginine-containing proteins and renal and hepatic failure resulting in alterations in DDAH activity and less excretion. Elevated levels of ADMA result in higher ICU morbidity and mortality in human beings [30]. In order to understand the detrimental effects of ADMA and the need for nitric oxide for survival in critical illness, the importance of the arginine : ADMA ratio must be understood. This pathway has been extensively studied in sepsis and organ dysfunction settings in both humans and animals [5,19,31,32]. Critical illness is characterized by vascular and organ dysfunction, caused by endothelial damage and microvascular oxidative stress [1,8]. In this state, regulation of organ perfusion by nitric oxide is of vital importance because organ oxygenation is at risk [8]. High amounts of ADMA in the critically ill state lower the arginine : ADMA ratio, inhibit NOS and CAT, and subsequently nitric oxide production. So, hypothetically, the increased ADMA levels could participate in the pathological processes of critical illness. To better understand the relation of nitric oxide and the arginine : ADMA ratio in sepsis, a study was done in rats. In an isolated perfused rat heart, the effect of inhibition of nitric oxide synthesis after Volume 17 Number 1 January 2014
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Asymmetric dimethylarginine and critical illness Brinkmann et al.
endotoxemia was investigated. A massive coronary vasodilation was seen in the endotoxin-treated rats, which was caused by an increased release of nitric oxide. Inhibition of nitric oxide metabolism after endotoxemia showed a reduction of the coronary flow and caused areas of myocardial ischemia. These areas disappeared after infusion of arginine as a substrate for nitric oxide. In another model of critical ill rats, low arginine plasma levels in combination with high ADMA plasma levels (low arginine : ADMA ratio) deteriorated systemic hemodynamics (heart rate, mean arterial pressure, and cardiac output) and reduced blood flow through the kidney, spleen, and liver. Studies in humans confirmed these findings when volunteers receiving an intravenous low-dose of ADMA showed a reduced heart rate (P < 0.001), cardiac output (P < 0.001), and an increased mean blood pressure (P < 0.005) compared with controls [6,12,15,33,34]. In septic patients, nitric oxide production may be excessively high and this can be harmful [35]. Therefore, inhibition of NOS was proposed as a manner to reduce morbidity and mortality in this patient population. One trial assessed the effect of a NOS inhibitor in a population of 124 septic patients in order to counteract the excessive production of nitric oxide [36]. The trial was stopped preliminary because the 28-day mortality was 59% in the NOS inhibitor group and 49% in the placebo group (P < 0.001). Most patients who died early in this study showed a cardiac cause of death. Overall, many studies have shown that high levels of ADMA can induce detrimental effects. These unfavorable actions are primarily the result of diminished nitric oxide availability, resulting in disturbed vasodilatation and antithrombotic, anti-inflammatory, and antiapoptotic actions that overall may lead to cardiac dysfunction [8,37].
NEW INSIGHTS INTO ASYMMETRIC DIMETHYLARGININE IN CRITICAL ILLNESS In view of this large body of observations on the basal role of ADMA in critical illness, we give an overview of the most recent findings of clinical studies on ADMA in critically ill patients (Table 1). Cardiac dysfunction at the ICU is a main cause of death and could be induced by decreased levels of nitric oxide. Visser et al. [40 ] demonstrated that a decreased arginine : ADMA ratio at ICU admission was associated with circulatory failure, organ failure, and mortality in patients with septic or cardiogenic shock. Whereas ADMA levels were in the normal range, arginine was depleted, implicating that the ratio of arginine and ADMA is more important for microcirculation and macrocirculation than their &
individual concentrations. The ratio showed a strong association and better diagnostic accuracy for hospital mortality in this study, in which the arginine or ADMA concentration alone failed to do so. In children undergoing cardiac surgery, it was found that patients with elevated ADMA levels before surgery were more likely to develop low cardiac output syndrome after surgery [43]. These pediatric patients also required prolonged mechanical ventilation, reoperation, and increased ICU and hospital length of stay. Investigating ADMA levels in sepsis deserves broad interest, whereas the arginine–nitric oxide pathway is disturbed in this condition. In a large prospective cohort study, comparing patients with severe sepsis with controls, it was shown that the arginine : ADMA ratio was lower in septic patients and that this was positively correlated to the Acute Physiology and Chronic Health Evaluation (APACHE) II score [39]. In addition, this decrease in ratio was independently associated with a higher hospital mortality and a higher risk of death over the course of 6 months. A comparable study also demonstrated that the ratio was significantly reduced in septic patients and correlated with the severity of illness as measured by APACHE II score (P ¼ 0.003) and organ failure, as measured by the Sequential Organ Failure Assessment (SOFA) score (P ¼ 0.0001) [38]. Baseline plasma ADMA was independently associated with 28-day mortality for death in the highest quartile (0.66 mmol/l, P ¼ 0.008) and independently correlated with the severity of organ failure. An increase of ADMA levels over time correlated with an increase in organ failure and a decrease in microvascular reactivity. Increased levels of ADMA and a subsequent decreased arginine : ADMA ratio were also found in patients with septic shock compared with healthy volunteers and patients following major abdominal surgery at all time points within the 28-day observation period [41]. In this group, acute liver failure increased the plasma levels of ADMA in comparison to those with an intact hepatic function and this appeared to be an early predictor for survival. Koch et al. [44] demonstrated in a study of 164 critically ill patients and 91 controls that ADMA serum levels were significantly elevated in the critically ill group at admission and were closely related to hepatic and renal dysfunction, metabolism, and clinical scores of disease severity. ADMA serum levels at admission were an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU, but also for long-term survival. Surprisingly, ADMA levels did not differ between patients with or without sepsis in this study. This was explained by the fact that ADMA upregulation
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2
120
44
2
Visser et al., & 2012 [40 ]
Brenner et al., 2012 [41]
159
2
Gough et al., 2011 [39]
98
2
n
Davis et al., 2011 [38]
Source
Oxford level of evidence
1. Septic shock (n ¼ 60)
2. Cardiogenic shock (n ¼ 17)
1. Septic shock (n ¼ 27)
2. Controls (n ¼ 50)
1. Severe sepsis (n ¼ 109)
2. Controls (n ¼ 31)
1. Acute sepsis (n ¼ 67)
Patient groups
Arginine, ADMA levels in multiple organ dysfunction syndrome
Disease severity, organ failure, mortality
Arginine : ADMA ratio in sepsis
Role of ADMA in acute inflammatory states
Outcome
Arginine, ADMA, APACHE-II score, SOFA score
Arginine, ADMA, circulatory markers, APACHE II-, SOFA score, mortality
Arginine, ADMA, SDMA, urinary nitrate, APACHE IIscore, SOFA score, mortality
ADMA, arginine, microvascular reactivity, APACHE-II score, SOFA score, mortality
Parameters
Table 1. Human studies examining ADMA metabolism in the critically ill patient, studies published in 2011–2013
28 Days
6 months
4 Days
Follow-up
Group 1: increased levels of ADMA and decreased arginine : ADMA ratio in comparison to group 2 and 3. Acute liver failure increased plasma levels of ADMA (and arginine) in group 1 in comparison to those with an intact hepatic function and this appeared to be early predictors for survival.
Decreased arginine : ADMA ratio was associated with circulatory failure, severity of disease and organ failure and it predicted mortality.
Decreased arginine : ADMA ratio is associated with severe sepsis and severity of illness and independently predicts both hospital mortality and risk of death over the course of 6 months after diagnosis.
Arginine : ADMA ratio was significantly reduced in sepsis and correlated with the severity of illness and organ failure. Raised ADMA levels and an increase in levels over time, as in group 1, were independently associated with mortality, severity of organ failure and decrease in microvascular reactivity.
Conclusion
Protein, amino acid metabolism and therapy
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2
1
Hassinger et al., 2012 [43]
Koch et al., 2013 [44]
333
100
90
n
3. Healthy controls (n ¼ 78)
2. Without sepsis (n ¼ 91)
1. Sepsis (n ¼ 164)
2. Normal ADMA levels (n ¼ 71)
3. Healthy controls (n ¼ 30) Pediatric cardiac surgery: 1. Preoperative elevated ADMA levels (n ¼ 29)
2. Febrile (n ¼ 30)
Pediatric: 1. (Severe) sepsis (n ¼ 30)
2. Surgical ICU patients (n ¼ 30) 3. Healthy controls (n ¼ 30)
Patient groups
ADMA levels, organ function, clinical scores, mortality
Acute kidney injury, low cardiac output syndrome, LOS, reoperation, mortality
ADMA metabolism
Outcome
ADMA, APACHE-II score, SOFA score mortality
ADMA, blood urea nitrogen, cystatin C, creatinine, mortality
Arginine, ADMA, citrulline, ornithine, AC : FC ratio, PIM-2, PELOD score
Parameters
3 Years
4 Days
7 Days
Follow-up
Elevated ADMA levels in groups 1 and 2 at admission, with no difference between group 1 and 2. ADMA serum levels at admission were an independent prognostic biomarker in critically ill patients for both short-term mortality at the ICU and long-term mortality.
Group 1 was more likely to have prolonged mechanical ventilation, developed low cardiac output syndrome, required an extended length of stay and required more often reoperation.
Decreased levels of ADMA in pediatric sepsis and this was inversely associated with inflammation and organ dysfunction.
Conclusion
AC : FC ratio, acylcarnitine : free carnitine ratio; ADMA, asymmetric dimethylarginine; APACHE, Acute Physiology and Chronic Health Evaluation; LOS, length of hospital stay; PELOD, Pediatric Logistic Organ Dysfunction; PIM-2, Pediatric Index of Mortality; SOFA, Sequential Organ Failure Assessment.
2
Weiss et al., 2012 [42]
Source
Oxford level of evidence
Table 1 (Continued)
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in this study may represent a uniform response in critical illness, independent of the presence of infection. Other studies examining ADMA levels in septic shock in adults also show increased plasma ADMA levels and subsequently a decreased arginine : ADMA ratio [1,38,39,41,45]. Surprisingly, in a study examining children suffering from severe sepsis and septic shock, plasma levels of ADMA were decreased and the arginine : ADMA ratio remained unchanged [42]. This was explained by the authors by the fact that children with sepsis are better in maintaining ADMA homeostasis than adults through a preserved feedback system. Children probably have a decreased protein catabolism, a reduced incidence of renal and hepatic dysfunction, less blood cell-related ADMA release through a lower rate of hemolysis, and are better capable of preserving their DDAH activity in their body compared with adults.
CONCLUSION Critically ill patients suffer from high levels of ADMA, presumably because of higher amounts of protein methylation, increased rate of protein turnover, impaired activity of DDAH, impaired renal excretion, and liver failure. By being a predictor of morbidity and mortality in critically ill patients, ADMA should not be overlooked by clinicians working at the ICU. New insights in ADMA in the critically ill revealed that mainly the arginine : ADMA ratio is of clinical importance. So, restoration of this ratio by increasing the endogenous arginine production or decreasing the circulating levels of ADMA is a possible option to improve recovery. Future trials should consider modulation of the ratio with as main goal normalization of nitric oxide production, and therewith improve clinical outcome and survival of the patient. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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