Louis Legault

Changes in plasma endothelin-1 and Big endothelin-1 induced by transjugular intrahepatic portosystemic shunts in patients with cirrhosis and refractory ascites

BACKGROUND/AIMS Endothelin-1 (ET-1) is a potent vasoconstrictor that may be involved in the pathogenesis of splanchnic and renal hemodynamic changes associated with portal hypertension. The aim of this study was to measure the concentration of ET-1 and of its precursor Big endothelin-1 (Big ET-1) in the systemic circulation as well as in the splanchnic and renal venous beds and to evaluate changes after the relief of portal hypertension following transjugular intrahepatic portosystemic shunt placement. METHODS Plasma concentrations of ET-1 and of Big ET-1 were measured in the vena cava, renal vein, hepatic vein and portal vein in ten patients with cirrhosis and refractory ascites before and 1-2 months after transjugular intrahepatic portosystemic shunt. The porto-caval gradient, creatinine clearance, plasma aldosterone and renin activity, as well as daily urinary sodium excretion were measured at the same time. RESULTS The plasma concentration of ET-1 and Big ET-1, respectively, in peripheral blood of normal volunteers were 0.28 +/- 03 and 3.95 +/- 0.34 pg/ml; the concentrations of both peptides were higher in patients with cirrhosis, both in vena cava (0.61 +/- 0.14 and 10.01 +/- 1.47 pg/ml), hepatic vein (0.62 +/- 0.13 and 13.93 +/- 1.77 pg/ml), portal vein (1.21 +/- 0.12 and 17.84 +/- 1.98 pg/ml) and renal vein (0.76 +/- 0.12 and 14.21 +/- 1.55 pg/ml). Moreover ET-1 and Big ET-1 concentrations were more elevated in the portal vein than in the vena cava (+98% and +70%) and slightly higher in the renal vein as compared to the vena cava (+25% and +42%). After transjugular intrahepatic portosystemic shunt, a rise in creatinine clearance and urinary sodium excretion (+49%; and +53%) was observed together with a marked reduction in plasma aldosterone and renin activity (-59% and -49%). ET-1 and Big ET-1 concentrations remained unchanged in the vena cava whereas a significant reduction of ET-1 and Big ET-1 occurred both in the portal vein (-43% and -44%) and in the renal vein (-53% and -29%). Portal vein and renal vein concentrations of both peptides became similar to vena cava levels. CONCLUSIONS Splanchnic and renal hemodynamic changes occurring in patients with cirrhosis and refractory ascites could be related to the production of ET-1 by splanchnic and renal vascular beds. This was abolished by transjugular intrahepatic portosystemic shunt, which could explain the exacerbation of systemic vasodilation and the improvement in renal perfusion observed after the procedure.

Renal tubular responsiveness to atrial natriuretic peptide in sodium-retaining chronic caval dogs. A possible role for kinins and luminal actions of the peptide.

60% of chronic caval dogs with ascites did not respond to atrial natriuretic peptide (ANP) (75 ng.kg-1.min-1) with a natriuresis (TIVC-NR; delta UNaV = 2 +/- 0.8 mu eq/min) whereas the remaining 40% responded normally (TIVC-R; delta UNaV = 216 +/- 50 mu eq/min). Since proximal tubule neutral endopeptidase 24:11 (NEP) destroys most of intrarenal luminal ANP and kinins, we attempted to convert TIVC-NR into TIVC-R by providing NEP inhibition with SQ 28603 at 30 mg/kg. This potent and specific NEP inhibitor produced a natriuresis when administered alone to nine TIVC-NR dogs (delta UNaV = 67 +/- 2 mu eq/min) and permitted a natriuresis in the presence of ANP (delta UNaV = 97 +/- 18 mu eq/min). A natriuretic response to ANP could also be induced in TIVC-NR dogs by providing renal arterial bradykinin or intravenous captopril, a kininase inhibitor. Urodilatin, a natriuretic peptide not destroyed by intrarenal NEP was without effect in TIVC-NR dogs but increased UNaV when given to TIVC-R and normal dogs. Providing bradykinin to TIVC-NR now permitted an increment in delta UNaV (62 mu eq/min) when urodilatin was reinfused. TIVC-R dogs could be converted into TIVC-NR by pretreating with a specific bradykinin antagonist before infusing ANP. We conclude that TIVC-NR dogs are deficient in intrarenal kinins but are converted to responding dogs after NEP inhibition because of increased kinin delivery to the inner medullary collecting duct.

Rat natriuretic peptide receptor genes are regulated by glucocorticoids in vitro

The effects of glucocorticoids on NPR-A and NPR-B mRNA transcription and natriuretic peptides ANP and CNP mediated cGMP production by intact vascular smooth muscle cells (VSMC) were studied in rat. Cultured VSMC were prepared from rat mesenteric arteries of 12-week-old Sprague-Dawley rats by enzymatic digestion. Dexamethasone-induced NPR-A mRNA increase was detectable early in the incubation periods and reached a plateau after 48 hours of glucocorticoid administration. This mRNA increase was mimicked by cortisol and inhibited by the glucocorticoid receptors antagonist RU 38,486. The levels of NPR-B mRNA remained unchanged during all the periods of stimulation. However, cGMP generated by both receptors in dexamethasone treated cells was higher than in control cells and this production was mimicked by cortisol and also blocked by RU 38,486. Desoxycorticosterone acetate (DOCA) had no effect on the levels of cGMP production. The results suggest that glucocorticoids have transcriptional and posttranscriptional effects on rat mesenteric arteries cells through glucocorticoid receptors.

Liver blood flow in chronic hemodialysis patients

The purpose of this study was to assess liver blood flow and cardiac output in chronic hemodialysis patients (n = 7) before and after a hemodialysis session, and to compare it to normal volunteers (n = 11). We used the hepatic clearance of sorbitol to calculate liver blood flow and echocardiograms to evaluate cardiac output. The latter was higher in hemodialysis patients (predialysis 4.7 +/- 1.8 liters/min, postdialysis 4.5 +/- 0.9 liters/min) compared to normal subjects (3.8 +/- 0.9 liters/min, p = 0.09 and p = 0.05). Hepatic blood clearance of sorbitol was similar in hemodialysis patients before and after dialysis (1,610 +/- 266 and 1,541 +/- 415 ml/min) as well as in normal volunteers (1,565 +/- 313 ml/min). The hepatic extraction ratio of sorbitol is slightly decreased in hemodialysis patients (n = 3) (0.87 +/- 0.03) compared to values reported in the literature for healthy subjects. We conclude that liver blood flow is not significantly altered in hemodialysis patients.

Severe skin necrosis associated with heparin in hemodialysis

Skin necrosis is a well-recognized although rare complication of continuous heparin therapy. We report the case of a 66-year-old diabetic woman with end-stage renal failure who received intermittent intravenous heparin during hemodialysis. She developed severe necrotic cutaneous ulcers over both legs, with typical histological findings. Thrombocytopenia never occurred but platelet studies demonstrated enhanced aggregation when heparin was added in vitro. Platelet-aggregating immunoglobulins produced in response to heparin can lead to thrombotic events. Thrombocytopenia usually develops prior to the onset of cutaneous lesions, but as in this case, may be absent. Heparin should be discontinued when the condition is recognized. Unfortunately, a poor outcome is frequently observed.

Acetazolamide in Hemodialysis Patients: A Rational Use After Ocular Surgery

Acetazolamide is a weak diuretic used to decrease production of aqueous humor in the eye. Hemodialysis patients undergoing ocular surgery may benefit from acetazolamide; however, no pharmacokinetic data are available for this group of patients. We report a patient who received acetazolamide 250 mg every 6 hours after ophthalmic surgery and developed reversible neurological side effects associated with very high plasma concentrations. Using pharmacokinetic analysis, we suggest an alternate administration of acetazolamide for end-stage renal patients.

A Simplified Approach to Extravascular Lung Water Assessment Using Point-of-Care Ultrasound in Patients with End-Stage Chronic Renal Failure Undergoing Hemodialysis

Background: Fluid overload leading to pulmonary congestion is an important issue in patients undergoing hemodialysis. This study aimed to determine if a simplified method of extravascular lung water assessment using ultrasound provided clinically relevant information. Methods: This prospective study recruited 47 patients from a single hemodialysis center. Pulmonary ultrasound was performed before and after 2 hemodialysis sessions in 28 regions on the thorax. The B-line score was defined as the percentage regions where B-lines were present. Results: When B-lines were detected before hemodialysis, a significant relationship was found between fluid removal and the change in B-line score. Patients with a B-line score of ≥21.4% (4th quartile) after the second hemodialysis session were more likely to be hospitalized for pulmonary edema or acute coronary syndrome. Conclusions: A simplified pulmonary assessment using ultrasound provides relevant information about pulmonary congestion in hemodialysis patients and identifies patients at risk of hospitalization for heart-related problems.

Acute Kidney Injury Due to Inferior Vena Cava Stenosis After Liver Transplantation: A Case Report About the Importance of Hepatic Vein Doppler Ultrasound and Clinical Assessment

Rationale: Acute kidney injury (AKI) is a frequent complication after liver transplantation. In some patients, prompt intervention targeted at a specific etiology is of paramount importance. Presenting concerns of the patients: A 25 years old man with advanced liver cirrhosis caused by sclerosing cholangitis and autoimmune hepatitis underwent orthotopic liver transplantation. One month after surgery, severe AKI developed in conjunction with recurrent ascites and lower extremity edema. Notable clinical findings included a persistently low urinary sodium excretion, a bland urinary sediment, and an abnormally monophasic hepatic vein waveform on Doppler ultrasound. Diagnoses: Inferior vena cava stenosis. Interventions: Angioplasty with stent installation. Outcomes: Rapid improvement of renal function after stent installation. Lessons learned: The following case illustrates the importance of integrating clinical cues, ultrasound features, and laboratory findings. The combination of AKI associated with lower extremity edema, abnormal monophasic hepatic vein flow on Doppler ultrasound, and a low urinary sodium excretion after liver transplantation should evoke the possibility of inferior vena cava stenosis as the etiologic factor.