Use of Palliative Chemotherapy and ICU Admissions in Gastric and Esophageal Cancer Patients in the Last Phase of Life: A Nationwide Observational Study.

Since intensive care unit (ICU) admission and chemotherapy use near death impair the quality of life, we studied the prevalence of both and their correlation with hospital volume in incurable gastroesophageal cancer patients as both impair the quality of life. We analyzed all Dutch patients with incurable gastroesophageal cancer who died in 2017-2018. National insurance claims data were used to determine the prevalence of ICU admission and chemotherapy use (stratified on previous chemotherapy treatment) at three and one month(s) before death. We calculated correlations between hospital volume (i.e., the number of included patients per hospital) and both outcomes. We included 3748 patients (mean age: 71.4 years; 71.4% male). The prevalence of ICU admission and chemotherapy use were, respectively, 5.6% and 21.2% at three months and 4.2% and 8.0% at one month before death. Chemotherapy use at three and one months before death was, respectively, 4.3 times (48.0% vs. 11.2%) and 3.7 times higher (15.7% vs. 4.3%), comparing patients with previous chemotherapy treatment to those without. Hospital volume was negatively correlated with chemotherapy use in the final month (rweighted = -0.23, p = 0.04). ICU admission and chemotherapy use were relatively infrequent. Oncologists in high-volume hospitals may be better equipped in selecting patients most likely to benefit from chemotherapy.

Human taurine metabolism: fluxes and fractional extraction rates of the gut, liver, and kidneys.

Taurine is involved in numerous biological processes. However, taurine plasma level decreases in response to pathological conditions, suggesting an increased need. Knowledge on human taurine metabolism is scarce and only described by arterial-venous differences across a single organ. Here we present taurine organ fluxes using arterial-venous concentration differences combined with blood flow measurements across the 3 major organ systems involved in human taurine metabolism in patients undergoing hepatic surgery. In these patients, we collected blood from an arterial line, portal vein, hepatic vein, and renal vein, and determined blood flow of the hepatic artery, portal vein, and renal vein using Doppler ultrasound. Plasma taurine was determined by high-performance liquid chromatography, and net organ fluxes and fractional extraction rates were calculated. Seventeen patients were studied. No differences were found between taurine concentrations in arterial, portal venous, hepatic venous, and renal venous plasma. The only significant finding was a release of taurine by the portally drained viscera (P = .04). Our data show a net release of taurine by the gut. This probably is explained by the enterohepatic cycle of taurine. Future studies on human taurine metabolism are required to determine whether taurine is an essential aminosulfonic acid during pathological conditions and whether it should therefore be supplemented.

Accurate perioperative flow measurement of the portal vein and hepatic and renal artery: a role for preoperative MRI?

BACKGROUND: Quantification of abdominal blood flow is essential for a variety of gastrointestinal and hepatic topics such as liver transplantation or metabolic flux measurement, but those need to be performed during surgery. It is not clear whether Duplex Doppler Ultrasound during surgery or MRI before surgery is the tool to choose. OBJECTIVE: To examine whether preoperative evaluation of abdominal blood flow using MRI could prove to be a useful and reliable alternative for the perioperative sonographic approach. METHODS: In this study portal and renal venous flow and hepatic arterial flow were sequentially quantified by preoperative MRI, preoperative and perioperative Duplex Doppler Ultrasound (DDUS). 55 Patients scheduled for major abdominal surgery were studied and methods and settings were compared. Additionally, average patient population values were compared. RESULTS: Mean (±SD) plasmaflow measured by perioperative DDUS, preoperative DDUS and MRI, respectively was 433±200/423±162/507±96 ml/min (portal vein); 96±70/74±41/108±91 ml/min (hepatic artery); 248±139/201±118/219±69 ml/min (renal vein). No differences between the different settings of DDUS measurement were detected. Equality of mean was observed for all measurements. Bland Altman Plots showed widespread margins. Hepatic arterial flow measurements correlated with each other, but portal and renal venous flow correlations were absent. CONCLUSIONS: Surgery and method (DDUS vs. MRI) do not affect mean flow values. Individual comparison is restricted due to wide range in measurements. Since MRI proves to be more reliable with respect to inter-observer variability, we recommend using mean MRI results in experimental setups.

Transjugular intrahepatic portosystemic shunt-placement increases arginine/asymmetric dimethylarginine ratio in cirrhotic patients.

AIM: To analyze the change of dimethylarginine plasma levels in cirrhotic patients receiving transjugular intrahepatic portosystemic shunt (TIPS). METHODS: To determine arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and nitric oxide (NO) plasma levels, blood samples were collected from the superior cava, hepatic, and portal vein just before, directly after, and 3 mo after TIPS-placement. RESULTS: A significant increase in the arginine/ADMA ratio after TIPS placement was shown. Moreover, TIPS placement enhanced renal function and thereby decreased systemic SDMA levels. In patients with renal dysfunction before TIPS placement, both the arginine/ADMA ratio and creatinine clearance rate increased significantly, while this was not the case in patients with normal renal function before TIPS placement. Hepatic function did not change significantly after TIPS placement and no significant decline in ADMA plasma levels was measured. CONCLUSION: The increase of the arginine/ADMA ratio after TIPS placement suggests an increase in intracellular NO bioavailability. In addition, this study suggests that TIPS placement does not alter dimethylarginine dimethylaminohydrolase (DDAH) activity and confirms the major role of the liver as an ADMA clearing organ.

The prominent role of the liver in the elimination of asymmetric dimethylarginine (ADMA) and the consequences of impaired hepatic function.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), the enzyme which converts the amino acid arginine into nitric oxide (NO). ADMA has been identified as an important risk factor for cardiovascular diseases. Besides the role of ADMA in cardiovascular diseases, it also seems to be an important determinant in the development of critical illness, (multiple) organ failure, and the hepatorenal syndrome. ADMA is eliminated from the body by urinary excretion, but it is mainly metabolized by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes that convert ADMA into citrulline and dimethylamine. DDAH is highly expressed in the liver, which makes the liver a key organ in the regulation of the plasma ADMA concentration. The prominent role of the liver in the elimination of ADMA and the consequences of impaired hepatic function on ADMA levels will be discussed in this article.

Low plasma concentrations of arginine and asymmetric dimethylarginine in premature infants with necrotizing enterocolitis.

Several studies have described reduced plasma concentrations of arginine, the substrate for nitric oxide synthase (NOS) in infants with necrotizing enterocolitis (NEC). No information on the plasma concentrations of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) in patients with NEC is currently available. We investigated whether plasma concentrations of arginine, ADMA, and their ratio differ between premature infants with and without NEC, and between survivors and non-survivors within the NEC group. In a prospective case-control study, arginine and ADMA concentrations were measured in ten premature infants with NEC (median gestational age 193 d, birth weight 968 g), and ten matched control infants (median gestational age 201 d, birth weight 1102 g), who were admitted to the Neonatal Intensive Care Unit. In the premature infants with NEC, median arginine and ADMA concentrations (micromol/l), and the arginine:ADMA ratio were lower compared to the infants without NEC: 21.4 v. 55.9, P= 0.001; 0.59 v. 0.85, P=0.009 and 36.6 v. 72.3, P=0.023 respectively. In the NEC group, median arginine (micromol/l) and the arginine:ADMA ratio were lower in non-surviving infants than in surviving infants: 14.7 v. 33.8, P=0.01 and 32.0 v. 47.5, P=0.038 respectively. In premature infants with NEC not only the NOS substrate arginine, but also the endogenous NOS inhibitor ADMA and the arginine:ADMA ratio were lower than in infants without NEC. In addition, low arginine and arginine:ADMA were associated with mortality in infants with NEC. Overall, these data suggest that a diminished nitric oxide production may be involved in the pathophysiology of NEC, but this needs further investigation.

Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism.

BACKGROUND: The liver plays a central role in amino acid metabolism. However, because of limited accessibility of the portal vein, human data on this subject are scarce. OBJECTIVE: We studied hepatic amino acid metabolism in noncirrhotic fasting patients undergoing liver surgery. DESIGN: Twenty patients undergoing hepatectomy for colorectal metastases in a normal liver were studied. Before resection, blood was sampled from a radial artery, portal vein, hepatic vein, and renal vein. Organ blood flow was measured by duplex ultrasound scan. RESULTS: The intestine consumed glutamine and released citrulline. Citrulline was taken up by the kidney. This was accompanied by renal arginine release, which supports the view that glutamine is a precursor for arginine synthesis through an intestinal-renal pathway. The liver was found to extract citrulline from this pathway at a rate that was dependent on intestinal citrulline release (P < 0.0001) and hepatic citrulline influx (P = 0.03). Fractional hepatic extractions of citrulline (8.4%) and arginine (11.5%) were not significantly different. Eighty-eight percent of arginine reaching the liver passed it unchanged. Splanchnic citrulline release could account for one-third of renal citrulline uptake. CONCLUSIONS: This is the first study of hepatic and interorgan amino acid metabolism in humans with a normal liver. The data indicate that glutamine is a precursor of ornithine, which can be converted to citrulline by the intestine; citrulline is transformed in the kidneys to arginine. Hepatic citrulline uptake limits the amount of gut-derived citrulline reaching the kidney. These findings may have implications for interventions aimed at increasing systemic arginine concentrations.

The clinical significance of asymmetric dimethylarginine.

In 1992, asymmetrical dimethylarginine (ADMA) was first described as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. From then, its role in regulating NO production has attracted increasing attention. Nowadays, ADMA is regarded as a novel cardiovascular risk factor. The role of the kidney and the liver in the metabolism of ADMA has been extensively studied and both organs have proven to play a key role in the elimination of ADMA. Although the liver removes ADMA exclusively via degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the kidney uses both metabolic degradation via DDAH and urinary excretion to eliminate ADMA. Modulating activity and/or expression of DDAH is still under research and may be a potential therapeutic approach to influence ADMA plasma levels. Interestingly, next to its association with cardiovascular disease, ADMA also seems to play a role in other clinical conditions, such as critical illness, hepatic failure, and preeclampsia. To elucidate the clinical significance of ADMA in these conditions, the field of research must be enlarged.

Hypertaurinemia in bile duct-ligated rats after surgery: the effect of gut endotoxin restriction on organ fluxes and oxidative status.

Surgery in obstructive jaundice is associated with complications related to gut-derived endotoxemia. The organs involved in these complications, including liver, kidneys, and gut, are important in the metabolism of taurine, which is implicated in bile acid conjugation and has antioxidative effects. Taurine organ metabolism and liver oxidative status were studied in bile duct-ligated rats (BDL) after laparotomy. Oral cholestyramine treatment inhibits gut-derived endotoxemia and was used to evaluate the role of endotoxin. In BDL rats, postoperative plasma taurine levels were higher compared with SHAM (p < .0001). Cholestyramine treatment reduced plasma taurine in BDL rats (p < .005), but levels remained higher compared with SHAM groups (p < .0001). In contrast to a liver uptake of taurine in SHAM rats, a release from livers of BDL rats was found (p < .005). Cholestyramine treatment in BDL rats resulted in a liver uptake of taurine (p < .05 vs BDL). A higher uptake of taurine by the kidneys was found in both BDL animals after surgery and SHAM controls (p < .005); however, cholestyramine had no effect. A release of taurine from the gut was found in the SHAM groups, which was reversed in both BDL groups (p < .01). Cholestyramine lowered the elevated levels of hepatic enzymes in BDL rats (ALT and AST: p < .05). Total liver glutathione levels were lower in BDL rats (p < .0001) compared with SHAM groups, and cholestyramine significantly attenuated this decrease (p < .01). Liver malondialdehyde levels were higher in BDL rats compared with SHAM (p < .01), whereas cholestyramine completely prevented this increase in lipid peroxidation (p < .0001). Hypertaurinemia in BDL rats after surgery is most likely explained by reduced bile acid conjugation and hepatocellular leakage. Cholestyramine treatment reduced hepatocellular damage by inhibiting gut-derived endotoxemia, and reversed the release of taurine from the jaundiced liver into an uptake and consequently lowered plasma taurine levels. This uptake may contribute to the improved antioxidant status in cholestyramine-treated BDL rats.

No compensatory upregulation of placental dimethylarginine dimethylaminohydrolase activity in preeclampsia.

BACKGROUND/AIMS: Placental dysfunction of the asymmetric dimethylarginine (ADMA) degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) has been suggested as one of the initiating events in the development of preeclampsia (PE). Our primary aim was to investigate the role of the placenta in the metabolism of ADMA during normal pregnancy and PE. METHODS: We studied 27 nonpregnant healthy women (C), 15 normotensive pregnant females (P), 16 patients with PE, and 7 patients with the 'hemolysis, elevated liver enzymes and low platelets' syndrome (H). RESULTS: There were no significant differences between P and PE with respect to fetomaternal gradient of ADMA, placental DDAH activity and placental ADMA content. During the first stage of labour, mean (+/-SD) plasma ADMA (micromol/l) was higher in H (0.69 +/- 0.22; p < 0.05) compared with C (0.44 +/- 0.07), P (0.37 +/- 0.06), and PE (0.40 +/- 0.06). ADMA was significantly associated with laboratory parameters of hepatic and renal function and with clinical parameters, including systolic and diastolic blood pressure, gestational age, birth weight, and placenta weight. CONCLUSIONS: A compensatory upregulation of placental DDAH activity is absent in patients suffering from PE and levels of ADMA in plasma and placenta are normal in patients suffering from PE. However, when the course of PE deteriorates and organ dysfunction (especially liver and kidney) becomes involved, such as during the hemolysis, elevated liver enzymes and low platelets syndrome, ADMA levels increase.

Modulation of asymmetric dimethylarginine in critically ill patients receiving intensive insulin treatment: a possible explanation of reduced morbidity and mortality?

OBJECTIVE: Asymmetric dimethylarginine, which inhibits production of nitric oxide, has been shown to be a strong and independent predictor of mortality in critically ill patients with clinical evidence of organ dysfunction. Interestingly, intensive insulin therapy in critically ill patients improved morbidity and mortality, but the exact mechanisms by which these beneficial effects are brought about remain unknown. Therefore, we aimed to investigate whether modulation of asymmetric dimethylarginine concentrations by intensive insulin therapy is involved in these effects. DESIGN: A prospective, randomized, controlled trial. SETTING: A 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital. PATIENTS: From a study of 1,548 critically ill patients who were randomized to receive either conventional or intensive insulin therapy, we included 79 patients who were admitted to the intensive care unit after complicated pulmonary and esophageal surgery and required prolonged (>/=7 days) intensive care. INTERVENTIONS: Determination of asymmetric dimethylarginine concentrations. MEASUREMENTS AND MAIN RESULTS: Asymmetric dimethylarginine concentrations were determined with high-performance liquid chromatography on the day of admission, on day 2, on day 7, and on the last day at the intensive care unit. Although the asymmetric dimethylarginine levels did not change between day 0 and day 2 in patients receiving intensive insulin treatment, there was a significant increase during this period in the conventionally treated patients (p = .043). Interestingly, the mean daily insulin dose was inversely associated with the asymmetric dimethylarginine concentration on the last day (r = -.23, p = .042), and the asymmetric dimethylarginine concentration on the last day at the intensive care unit was significantly lower in the intensive insulin treatment group (p = .048). Furthermore, asymmetric dimethylarginine was positively associated with duration of intensive care unit stay, duration of ventilatory support, duration of inotropic and vasopressor treatment, number of red cell transfusions, duration of antibiotic treatment, presence of critical illness polyneuropathy, mean Acute Physiology and Chronic Health Evaluation II score, and cumulative Therapeutic Intervention Scoring System-28 score. In addition, asymmetric dimethylarginine levels in patients who died were significantly higher compared with survivors, and changes in the course of asymmetric dimethylarginine plasma concentrations were predictive for adverse intensive care unit outcome. CONCLUSIONS: Modulation of asymmetric dimethylarginine concentration by insulin at least partly explains the beneficial effects found in critically ill patients receiving intensive insulin therapy.

The human liver clears both asymmetric and symmetric dimethylarginine.

Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) inhibit production of nitric oxide. The concentration of both dimethylarginines is regulated by urinary excretion, although ADMA, but not SDMA, is also subject to degradation by dimethylarginine dimethylaminohydrolase, which is highly expressed in the liver but also present in the kidney. The exact roles of the human liver and kidney in the metabolism of dimethylarginines are currently unknown. Therefore, we aimed to investigate renal and hepatic handling of ADMA and SDMA in detail in 24 patients undergoing hepatic surgery. To calculate net organ fluxes and fractional extraction (FE) rates, blood was collected from an arterial line, the portal vein, hepatic vein, and renal vein, and blood flow of the hepatic artery, portal vein, and renal vein was determined using Doppler ultrasound techniques. Results showed a significant net uptake (median [IQR]) of ADMA in both the liver (9.6 nmol/min [5.6-13.2]) and the kidney (12.1 nmol/min [1.3-17.1]). SDMA uptake was present not only in the kidney (12.7 nmol/min [3.5-25.4]), but also in the liver (7.7 nmol/min [2.8-16.4]). FE rates of ADMA for the liver and kidney were 5.0% (3.5%-7.4%) and 8.4% (1.3%-13.9%), respectively. For SDMA, hepatic and renal FE rates were 3.4% (2.1%-7.5%) and 12.5% (3.6%-16.2%), respectively. In conclusion, this study gives a detailed description of the hepatic and renal elimination of dimethylarginines and shows that the clearing of SDMA is not only confined to the kidney, but the human liver also takes up substantial amounts of SDMA from the portal and systemic circulation.

The role of Kupffer cells after major liver surgery.

BACKGROUND: Kupffer cells (KCs) are the resident macrophages of the liver. KCs have an enormous endotoxin eliminating capacity. Endotoxins play an important role in the development of systemic complications after partial hepatectomy by activating KCs. The role of KCs and endotoxins after partial hepatectomy is investigated. METHODS: Wistar rats (n = 16, 250-275 g) were randomly assigned to have 1 mL dichloromethylene-diphosphonate (CL2MDP) or 1 mL NaCl 0.9% i.v. Forty-eight hours later, all rats received a two-thirds liver resection. Twenty-four hours later, rats received at random 50 microg/kg endotoxin (LPS) in 1 mL or 1 mL of NaCl 0.9% IV. The rats were killed 4 hours after LPS or SAL infusion. RESULTS: CL2MDP infusion resulted in a complete KC elimination. KC-depleted rats had the lowest mean arterial pressure, the highest heart and ventilatory rate after endotoxemia. All rats were able to maintain pH in normal ranges. The KC-depleted rats after partial hepatectomy had the lowest CO2 levels and the highest levels of lactate during endotoxemia. Oxygen levels were similar in all groups. Hepatic, pulmonary, and renal mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta were decreased in KC-depleted rats. Plasma levels of TNF-alpha were significantly decreased in KC-depleted rats. Furthermore, the highest influx of macrophages and polymorphonuclear cells in the lung and kidney were measured in KC-depleted rats during endotoxemia. CONCLUSIONS: Partial hepatectomy in KC-depleted rats result in a more pronounced endotoxin-mediated systemic inflammation and decreased synthesis of cytokines.

Elevation of asymmetric dimethylarginine (ADMA) in patients developing hepatic failure after major hepatectomy.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of the arginine-nitric oxide pathway. It is conceivable that its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase, which is highly expressed in the liver. In rats, we showed a high net hepatic uptake of ADMA. Therefore, we aimed to confirm the role of the liver in humans and hypothesized elevated ADMA levels after major liver resection by a reduction of functional liver mass and injury to the remnant liver. METHODS: Patients undergoing a major hepatic resection (HEP, n = 17) or major abdominal surgery (MAS, n = 12) were included and followed in time. In addition, ADMA levels were measured in 4 patients having severe hepatic failure after a liver resection. Plasma ADMA concentration was measured by high-performance liquid chromatography. RESULTS: Preoperatively and on days 1, 3, and 5, plasma levels of ADMA were higher in HEP patients when compared with MAS patients. In HEP patients with prolonged (>7 days) hepatic injury, ADMA levels were especially elevated. On the first postoperative day, ADMA significantly correlated to bilirubin concentration (r = .528, p < .05) as a marker of postoperative hepatic function. Besides, in patients with severe hepatic failure, ADMA levels were highly elevated. CONCLUSIONS: In the present study, evidence was found for the role of the liver in the elimination of ADMA in humans. Increased levels of ADMA occur in the postoperative course after a major hepatic resection, especially when liver function is severely impaired. Further studies need to assess the role of ADMA in the development of complications after liver surgery.

The transplanted liver graft is capable of clearing asymmetric dimethylarginine.

Asymmetric dimethylarginine (ADMA) has been recognized as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. Its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which is highly expressed in the liver. Considering the liver as a crucial organ in the clearing of ADMA, we hypothesized increased ADMA levels during hepatic failure and, consequently, a decline of ADMA concentrations after successful liver transplantation. The aim of the present study was to investigate the role of the liver in the metabolism of ADMA in patients undergoing liver transplantation. In this prospective study, we investigated the course of ADMA concentrations in 42 patients undergoing liver transplantation and results showed that preoperative ADMA concentrations were higher in patients with acute (1.26 micromol/L, P < .001) and in patients with chronic (.69 micromol/L, P < .001) hepatic failure compared with healthy volunteers (.41 micromol/L). In addition, ADMA concentrations decreased from the preoperative day to the first postoperative day in both the acute (Delta(ADMA): -.63 micromol/L, P = .005) and the chronic hepatic failure group (Delta(ADMA): -0.15 micromol/L, P < .001). Furthermore, in patients who experienced acute rejection, ADMA concentrations were higher during the whole first postoperative month compared with nonrejectors (P = .012). Moreover, in 11 of 13 rejectors (85%) a clear increase in ADMA concentration preceded the onset of the first episode of rejection, which was confirmed by liver biopsy. In conclusion, our results indicate that the transplanted liver graft is quickly capable of clearing ADMA, suggesting preservation of DDAH. In addition, increased ADMA concentrations in the posttransplantation period reflect serious dysfunction of the liver graft during acute rejection.

Gut and liver handling of asymmetric and symmetric dimethylarginine in the rat under basal conditions and during endotoxemia.

INTRODUCTION/AIM: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase enzymes, whereas symmetric dimethylarginine (SDMA) competes with arginine transport. Although both dimethylarginines may be important regulators of the arginine-NO pathway, their metabolism is largely unknown. In previous studies, evidence was found for the liver in the metabolism of dimethylarginines. We aimed to investigate dimethylarginine handling of the gut and the liver in detail under basal conditions and during endotoxemia. METHODS: Twenty-one male Wistar rats were used for this study. Endotoxemia was induced by lipopolysaccharide (LPS) infusion (8 mg/kg). Blood flow was measured using radiolabeled microspheres according to the reference sample method. Concentration of dimethylarginines were measured by high-performance liquid chromatography. The combination of arteriovenous concentration difference and organ blood flow allowed calculation of net organ fluxes and fractional extraction (FE) rates. RESULTS: Arterial plasma concentration of ADMA was lower in LPS rats, in contrast to a higher SDMA concentration. For the gut, net release of ADMA was found, which was higher in LPS rats. In contrast, for the gut, net uptake of SDMA was found, which was lower in LPS rats. For the liver, a high net uptake of ADMA was found in both groups, while FE was significantly increased in LPS rats. Hepatic handling of SDMA was negligible. CONCLUSION: The liver plays an important role in eliminating ADMA from the circulation and endotoxemia stimulates this capacity. In contrast to the liver, the gut releases ADMA. Endotoxemia results in a reduced systemic ADMA concentration.

Elimination of asymmetric dimethylarginine by the kidney and the liver: a link to the development of multiple organ failure?

Asymmetric dimethylarginine (ADMA) is a recently recognized endogenous inhibitor of nitric oxide production. Its role in cardiovascular disease is emerging, and ADMA appears to be an important causal factor in dysfunction of the vascular system. Several studies show that ADMA accumulates during renal failure, and ADMA has been identified as causing the cardiovascular complications accompanying renal failure. In addition to the kidney, we recently suggested an important role for the liver as an ADMA-eliminating organ. In a population of critically ill patients, hepatic failure was the most prominent determinant of ADMA concentration, and, notably, high ADMA concentration proved to be a strong and independent risk factor for intensive care unit mortality in these patients. We here summarize the role of both the kidney and the liver in the regulation of ADMA levels. In addition, the potential central role of ADMA as a causative factor in the development of multiple organ failure is discussed.