Chiao-Lin Chuang

Acute kidney injury network classification predicts in-hospital and long-term mortality in patients undergoing elective coronary artery bypass grafting surgery

OBJECTIVE Acute kidney injury (AKI) is a highly prevalent complication after cardiac surgery. It is associated with substantial morbidity and mortality. However, the definition of AKI has not been well established until the Acute Kidney Injury Network group outlined an easily used consentaneous staging system. The study aims to evaluate the association between this determination and in-hospital as well as long-term mortality in patients receiving elective coronary artery bypass grafting (CABG) surgery. METHODS Patients undergoing elective CABG surgery from January 2003 to December 2007 in a tertiary medical center were studied. The Acute Kidney Injury Network classification was applied for the diagnosis of perioperative AKI. Medical history and intra-operative variables were collected retrospectively. Multivariate analysis was used to identify the independent risk factors of in-hospital and long-term mortality. Long-term survival rates were calculated using the Kaplan-Meier method. RESULTS This study included 964 patients. The incidence of AKI following elective CABG was 19.8%. Only 7% of the study population developed AKI requiring renal replacement therapy after surgery. The overall in-hospital mortality rate was 5.1%. Significant independent risk factors for in-hospital mortality include increasing age, higher serum uric acid, postoperative requirement of intra-aortic balloon pumping (IABP) and extracorporeal membrane oxygenation (ECMO), perioperative AKI, and chronic dialysis (all p<0.05). Significant independent risk factors for long-term mortality include increasing age, lower serum albumin, higher serum uric acid, postoperative requirement of IABP and ECMO, perioperative AKI, and chronic dialysis (all p < 0.005). CONCLUSIONS Acute Kidney Injury Network classification is a powerful tool to evaluate the prognostic impact of AKI on both in-hospital and long-term mortality among patients undergoing elective CABG surgery.

Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats.

Angiogenesis in liver cirrhosis leads to splanchnic hyperemia, increased portal inflow, and portosystemic collaterals formation, which may induce lethal complications, such as gastroesophageal variceal hemorrhage and hepatic encephalopathy. Cannabinoids (CBs) inhibit angiogenesis, but the relevant influences in cirrhosis are unknown. In this study, Spraque‐Dawley rats received common bile duct ligation (BDL) to induce cirrhosis. BDL rats received vehicle, arachidonyl‐2‐chloroethylamide (cannabinoid receptor type 1 [CB1] agonist), JWH‐015 (cannabinoid receptor type 2 [CB2] agonist), and AM630 (CB2 antagonist) from days 35 to 42 days after BDL. On the 43rd day, hemodynamics, presence of CB receptors, severity of portosystemic shunting, mesenteric vascular density, vascular endothelial growth factor (VEGF), VEGFR‐1, VEGFR‐2, phospho‐VEGFR‐2, cyclooxygenase (COX)‐1, COX‐2, and endothelial nitric oxide synthase (eNOS) expressions as well as plasma VEGF levels were evaluated. Results showed that CB1 and CB2 receptors were present in left adrenal veins of sham rats, splenorenal shunts (the most prominent intra‐abdominal shunts) of BDL rats, and mesentery of sham and BDL rats. CB2 receptor was up‐regulated in splenorenal shunts of BDL rats. Both acute and chronic JWH‐015 treatment reduced portal pressure and superior mesenteric arterial blood flow. Compared with vehicle, JWH‐015 significantly alleviated portosystemic shunting and mesenteric vascular density in BDL rats, but not in sham rats. The concomitant use of JWH‐015 and AM630 abolished JWH‐015 effects. JWH‐133, another CB2 agonist, mimicked the JWH‐015 effects. JWH‐015 decreased mesenteric COX‐1, COX‐2 messenger RNA expressions, and COX‐1, COX‐2, eNOS protein expressions. Furthermore, JWH‐015 decreased intrahepatic angiogenesis and fibrosis. Conclusions: CB2 agonist alleviates portal hypertension (PH), severity of portosystemic collaterals and mesenteric angiogenesis, intrahepatic angiogenesis, and fibrosis in cirrhotic rats. The mechanism is, at least partly, through COX and NOS down‐regulation. CBs may be targeted in the control of PH and portosystemic collaterals. (HEPATOLOGY 2012;56:248–258)

Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats

Portal hypertension (PH), a pathophysiological derangement of liver cirrhosis, is characterized by hyperdynamic circulation, angiogenesis, and portosystemic collaterals. These may lead to lethal complications, such as variceal bleeding. Caffeine has been noted for its effects on liver inflammation, fibrogenesis, and vasoreactiveness. However, the relevant influences of caffeine in cirrhosis and PH have not been addressed. Spraque‐Dawley rats with common bile duct ligation–induced cirrhosis or sham operation received prophylactic or therapeutic caffeine treatment (50 mg/kg/day, the first or 15th day since operation, respectively) for 28 days. Compared to vehicle (distilled water), caffeine decreased cardiac index, increased systemic vascular resistance, reduced portal pressure (PP), superior mesenteric artery flow, mesenteric vascular density, portosystemic shunting (PSS), intrahepatic angiogenesis, and fibrosis without affecting liver and renal biochemistry. The beneficial effects were reversed by selective adenosine A1 agonist N6‐cyclopentyladenosine (CPA) or A2A agonist GCS21680. Both prophylactic and therapeutic caffeine treatment decreased portal resistance and PP in thioacetamide (200mg/kg, thrice‐weekly for 8 weeks)‐induced cirrhotic rats. Caffeine down‐regulated endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), phospho‐VEGFR2, and phospho–Akt mesenteric protein expression. Caffeine adversely affected viability of hepatic stellate and sinusoidal endothelial cells, which was reversed by CPA and GCS21680. On the other hand, caffeine did not modify vascular response to vasoconstrictors in splanchnic, hepatic, and collateral vascular beds. Conclusions: Caffeine decreased PP, ameliorated hyperdynamic circulation, PSS, mesenteric angiogenesis, hepatic angiogenesis, and fibrosis in cirrhotic rats. Caffeine may be a feasible candidate to ameliorate PH‐related complications in cirrhosis. (Hepatology 2015;61:1672‐1684)

Disseminated Cryptococcosis Initially Presenting as Cellulitis in a Rheumatoid Arthritis Patient

Infection with Cryptococcus neoformans often occurs in immunocompromised hosts. It is usually acquired by invasion of the respiratory tract, and then the organisms may spread hematogenously to other viscera, mainly the central nervous system. Although there are some reports of primary cutaneous cryptococcosis, cryptococcal skin disease is a rare feature of disseminated cryptococcosis, and has a poor outcome if unrecognized and untreated. We present a case of cryptococcal cellulitis in a patient with rheumatoid arthritis who was receiving long-term steroid treatment. Reviewing the literature, this is the first report of rheumatoid arthritis with disseminated cryptococcosis initially presenting as cellulitis.

Rosuvastatin improves hepatopulmonary syndrome through inhibition of inflammatory angiogenesis of lung.

The hepatopulmonary syndrome (HPS) is characterized by hypoxia and increased intrapulmonary shunts in cirrhotic patients. Emerging evidence showed promising results of treating HPS by abolishment of intrapulmonary inflammation and angiogenesis. Rosuvastatin is a kind of 3-hydroxy-methyl-3-glutamyl coenzyme A reductase inhibitor. In addition to lipid-lowering effects, it has anti-inflammation and anti-angiogenesis properties. We postulated that rosuvastatin treatment can ameliorate HPS. Common bile duct ligation (CBDL) was applied in an experimental HPS animal model. CBDL rats received 2-week rosuvastatin (20 mg/kg/day) treatments from the fifteenth day after operation. The haemodynamic data, blood gas analysis, liver biochemistries, tumour necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) were examined after rosuvastatin treatment. The liver and lung tissues were dissected for histopathological studies and protein analyses. In the parallel groups, intrapulmonary shunts were determined. The haemodynamic and liver biochemistries were not changed after rosuvastatin treatment in CBDL rats, but the alveolar-arterial oxygen pressure gradient was significantly decreased, implying that HPS-induced hypoxia was reversed after rosuvastatin treatment. In addition, rosuvastatin treatment reduced intrapulmonary shunts and plasma levels of VEGF and TNF-α. Besides, the intrapulmonary protein expression of nuclear factor kappa B (NF-κB), VEGF receptor (VEGFR)-1,2 and Rho-associated A kinase were significantly down-regulated and the intrapulmonary angiogenesis was ameliorated. We concluded that rosuvastatin alleviates experimental HPS through blockade of pulmonary inflammatory angiogenesis via TNF-α/NF-κB and VEGF/Rho-associated A kinase pathways down-regulation.

The Beneficial Effects of P2X7 Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis

Splanchnic angiogenesis in liver cirrhosis often leads to complications as gastroesophageal variceal hemorrhage and the treatment efficacy is adversely affected by poor portal-systemic collateral vasoresponsiveness related to nitric oxide (NO). Purinergic receptor subtype P2X7 participates in the modulation of inflammation, angiogenesis, fibrogenesis and vasoresponsiveness, but the relevant influence in cirrhosis is unknown. Common bile duct-ligated (CBDL) or sham-operated Spraque-Dawley rats received brilliant blue G (BBG, a P2X7 antagonist and food additive) or vehicle from the 15th to 28th day after operations, then hemodynamics, mesenteric angiogenesis, portal-systemic shunting, liver fibrosis, and protein expressions of angiogenic and fibrogenic factors were evaluated. The influence of oxidized ATP (oATP, another P2X7 receptor antagonist) on the collateral vasoresponsiveness to arginine vasopressin (AVP) was also surveyed. BBG decreased superior mesenteric artery (SMA) flow, portal-systemic shunting, mesenteric vascular density, and mesenteric protein expressions of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), phospho (p)-VEGFR2, platelet-derived growth factor (PDGF), PDGF receptor beta (PDGFRβ), cyclooxygenase (COX)-1, COX-2, and endothelial NO synthase (eNOS) in CBDL rats. BBG also ameliorated liver fibrosis and down-regulated hepatic interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), PDGF, IL-1β, transforming growth factor-beta (TGF-β), p-extracellular-signal-regulated kinases (ERK), and alpha-smooth muscle actin (α-SMA) expressions in CBDL rats. The collateral vasocontractility to AVP was enhanced by oATP. oATP down-regulated eNOS, inducible NOS (iNOS), VEGF, Akt, p-Akt, and nuclear factor-kappa B (NF-κB) expressions in splenorenal shunt, the most prominent intra-abdominal collateral vessel in rodents. P2X7 antagonism alleviates splanchnic hyperemia, severity of portal-systemic shunting, mesenteric angiogenesis, liver fibrosis, and enhances portal-systemic collateral vasoresponsiveness in cirrhotic rats. P2X7 blockade may be a feasible strategy to control cirrhosis and complications.

Proteinuria predicts postcardiotomy acute kidney injury in patients with preserved glomerular filtration rate

OBJECTIVE Acute kidney injury is a common and serious problem after cardiac surgery. Postoperative acute kidney injury is independently associated with in-hospital mortality and long-term morbidity, even after adjustment for comorbid diseases. Chronic kidney disease has been recognized as a strong risk factor of acute kidney injury after cardiac surgery. The association between proteinuria and postcardiotomy acute kidney injury in patients with preserved glomerular filtration rate remains uncertain. METHODS Patients with an estimated glomerular filtration rate greater than 60 mL/min/1.73 m(2) who underwent cardiac surgery between January 2003 and December 2007 in a tertiary medical center were retrospectively analyzed. Dipstick urinalysis was performed before surgery. Proteinuria was categorized into negative, trace, 1+, 2+, or 3+. Postoperative acute kidney injury was defined by the Acute Kidney Injury Network criteria. Multinomial logistic regression was used to clarify whether proteinuria is an independent risk factor of postoperative acute kidney injury. RESULTS A total of 1246 patients were included in this study, with a mean estimated glomerular filtration rate of 80 ± 13 mL/min/1.73 m(2). Proteinuria was present in 290 patients (23.4%). Postoperative acute kidney injury developed in 434 patients (34.8%), and 36 patients (2.9%) required renal replacement therapy. Proteinuria was independently associated with all stages of postcardiotomy acute kidney injury and dialysis-requiring acute kidney injury. The crude risk of acute kidney injury was greater in patients with a higher grade of proteinuria. In subgroup analysis for gender, diabetes, and surgical type, preoperative proteinuria remains a strong risk factor of acute kidney injury after cardiac surgery. CONCLUSIONS Urine analysis is usually neglected before cardiac surgery despite the fact that proteinuria is the earliest manifestation of kidney dysfunction. In the current study, we show that urine protein is strongly and independently associated with postoperative acute kidney injury in subjects with preserved estimated glomerular filtration rate. These data suggest that such a relatively simple and clinically easy to use tool as a urinary dipstick may be useful to identify patients at high risk of acute kidney injury before cardiac surgery.

Assessment of first-year post-graduate residents: Usefulness of multiple tools

Background: Objective Structural Clinical Examination (OSCE) usually needs a large number of stations with long test time, which usually exceeds the resources available in a medical center. We aimed to determine the reliability of a combination of Direct Observation of Procedural Skills (DOPS), Internal Medicine in‐Training Examination (IM‐ITE®) and OSCE, and to verify the correlation between the small‐scale OSCE+DOPS+IM‐ITE®‐composited scores and 360‐degree evaluation scores of first year post‐graduate (PGY1) residents. Methods: Between 2007 January to 2010 January, two hundred and nine internal medicine PGY1 residents completed DOPS, IM‐ITE® and small‐scale OSCE at our hospital. Faculty members completed 12‐item 360‐degree evaluation for each of the PGY1 residents regularly. Results: The small‐scale OSCE scores correlated well with the 360‐degree evaluation scores (r = 0.37, p < 0.021). Interestingly, the addition of DOPS scores to small‐scale OSCE scores [small‐scale OSCE+DOPS‐composited scores] increased its correlation with 360‐degree evaluation scores of PGY1 residents (r = 0.72, p < 0.036). Further, combination of IM‐ITE® score with small‐scale OSCE+DOPS scores [small‐scale OSCE+DOPS+IM‐ITE®‐composited scores] markedly enhanced their correlation with 360‐degree evaluation scores (r = 0.85, p < 0.016). Conclusion: The strong correlations between 360‐degree evaluation and small‐scale OSCE+DOPS+IM‐ITE®‐composited scores suggested that both methods were measuring the same quality. Our results showed that the small‐scale OSCE, when associated with both the DOPS and IM‐ITE®, could be an important assessment method for PGY1 residents.

Pravastatin for thioacetamide-induced hepatic failure and encephalopathy.

Eur J Clin Invest 2011

Selective cyclooxygenase inhibition improves hepatic encephalopathy in fulminant hepatic failure of rat.

Prostaglandin plays an important role in the pathogenesis of hepatic encephalopathy. This study investigated the therapeutic effects of selective cyclooxygenase (COX) inhibitor on hepatic encephalopathy in thioacetamide-induced fulminant hepatic failure (FHF) rats. The selective COX-1 inhibitor (SC-560), COX-2 inhibitor (NS-398) or distilled water (control) was administered in the normal and FHF rats. The mortality rates were calculated and severity of hepatic encephalopathy was evaluated using Opto-Varimex activity sensors. Besides, the levels of blood ammonia, 6-keto-prostaglandin-F(1α) (PGF(1α), active metabolite of prostacyclin), tumor necrosis factor α (TNF-α) and liver biochemistry tests were measured. The hepatic mRNA expressions of nitric oxide synthase and COX were determined, and the liver histopathological changes were examined. The liver biochemistries and motor activities were similar among COX-1, COX-2 treated and control groups. SC-560 treatment improved the survival of FHF rats (mortality rates: SC-560 group 0%, control 33%; P=0.037). Besides, SC-560 treatment improved hepatic encephalopathy and decrease plasma levels of PGF(1α), but did not change TNF-α levels. There were no significant differences in liver biochemistry and ammonia levels except that the aspartate aminotransferase levels were lower in the NS-398 treated group. Both hepatic COX-1 and COX-2 mRNA expressions were attenuated after SC-560 treatment. The decreased COX-2 and increased constitutive nitric oxide synthase mRNA expressions were found after NS-398 treatment. Besides, the histopathology of liver got improved after selective COX inhibition. In conclusion, COX-1 inhibition by SC-560 decreases the mortalities and improves motor activities, suggesting COX-1, rather than COX-2, plays a major role in hepatic encephalopathy of FHF rats.