Clinical review: practical recommendations on the management of perioperative heart failure in cardiac surgery.

Acute cardiovascular dysfunction occurs perioperatively in more than 20% of cardiosurgical patients, yet current acute heart failure (HF) classification is not applicable to this period. Indicators of major perioperative risk include unstable coronary syndromes, decompensated HF, significant arrhythmias and valvular disease. Clinical risk factors include history of heart disease, compensated HF, cerebrovascular disease, presence of diabetes mellitus, renal insufficiency and high-risk surgery. EuroSCORE reliably predicts perioperative cardiovascular alteration in patients aged less than 80 years. Preoperative B-type natriuretic peptide level is an additional risk stratification factor. Aggressively preserving heart function during cardiosurgery is a major goal. Volatile anaesthetics and levosimendan seem to be promising cardioprotective agents, but large trials are still needed to assess the best cardioprotective agent(s) and optimal protocol(s). The aim of monitoring is early detection and assessment of mechanisms of perioperative cardiovascular dysfunction. Ideally, volume status should be assessed by 'dynamic' measurement of haemodynamic parameters. Assess heart function first by echocardiography, then using a pulmonary artery catheter (especially in right heart dysfunction). If volaemia and heart function are in the normal range, cardiovascular dysfunction is very likely related to vascular dysfunction. In treating myocardial dysfunction, consider the following options, either alone or in combination: low-to-moderate doses of dobutamine and epinephrine, milrinone or levosimendan. In vasoplegia-induced hypotension, use norepinephrine to maintain adequate perfusion pressure. Exclude hypovolaemia in patients under vasopressors, through repeated volume assessments. Optimal perioperative use of inotropes/vasopressors in cardiosurgery remains controversial, and further large multinational studies are needed. Cardiosurgical perioperative classification of cardiac impairment should be based on time of occurrence (precardiotomy, failure to wean, postcardiotomy) and haemodynamic severity of the patient's condition (crash and burn, deteriorating fast, stable but inotrope dependent). In heart dysfunction with suspected coronary hypoperfusion, an intra-aortic balloon pump is highly recommended. A ventricular assist device should be considered before end organ dysfunction becomes evident. Extra-corporeal membrane oxygenation is an elegant solution as a bridge to recovery and/or decision making. This paper offers practical recommendations for management of perioperative HF in cardiosurgery based on European experts' opinion. It also emphasizes the need for large surveys and studies to assess the optimal way to manage perioperative HF in cardiac surgery.

ATP-competitive inhibitors of mTOR: new perspectives in the treatment of renal cell carcinoma.

Targeting mTOR (mammalian target of rapamycin) is an effective approach in the treatment of advanced RCC (renal cell carcinoma). Rapamycin-like drugs (rapalogues) have shown clinical activities and have been approved for the treatment of RCC. Recently, with the development of ATP-competitive inhibitors of mTOR, therapies targeting mTOR have entered a new era. Here, we discuss the biological relevance of blocking mTOR in RCC and review the mechanisms of action of rapalogues in RCC. We also advance some perspectives on the use of ATP-competitive inhibitors of mTOR in RCC.

Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans.

Experimentally renal tissue hypoxia appears to play an important role in the pathogenesis of chronic kidney disease (CKD) and arterial hypertension (AHT). In this study we measured renal tissue oxygenation and its determinants in humans using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) under standardized hydration conditions. Four coronal slices were selected, and a multi gradient echo sequence was used to acquire T2* weighted images. The mean cortical and medullary R2* values ( = 1/T2*) were calculated before and after administration of IV furosemide, a low R2* indicating a high tissue oxygenation. We studied 195 subjects (95 CKD, 58 treated AHT, and 42 healthy controls). Mean cortical R2 and medullary R2* were not significantly different between the groups at baseline. In stimulated conditions (furosemide injection), the decrease in R2* was significantly blunted in patients with CKD and AHT. In multivariate linear regression analyses, neither cortical nor medullary R2* were associated with eGFR or blood pressure, but cortical R2* correlated positively with male gender, blood glucose and uric acid levels. In conclusion, our data show that kidney oxygenation is tightly regulated in CKD and hypertensive patients at rest. However, the metabolic response to acute changes in sodium transport is altered in CKD and in AHT, despite preserved renal function in the latter group. This suggests the presence of early renal metabolic alterations in hypertension. The correlations between cortical R2* values, male gender, glycemia and uric acid levels suggest that these factors interfere with the regulation of renal tissue oxygenation.

Influence of age, risk factors, and cardiovascular and renal disease on arterial stiffness: clinical applications.

Age is the main clinical determinant of large artery stiffness. Central arteries stiffen progressively with age, whereas peripheral muscular arteries change little with age. A number of clinical studies have analyzed the effects of age on aortic stiffness. Increase of central artery stiffness with age is responsible for earlier wave reflections and changes in pressure wave contours. The stiffening of aorta and other central arteries is a potential risk factor for increased cardiovascular morbidity and mortality. Arterial stiffening with aging is accompanied by an elevation in systolic blood pressure (BP) and pulse pressure (PP). Although arterial stiffening with age is a common situation, it has now been confirmed that older subjects with increased arterial stiffness and elevated PP have higher cardiovascular morbidity and mortality. Increase in aortic stiffness with age occurs gradually and continuously, similarly for men and women. Cross-sectional studies have shown that aortic and carotid stiffness (evaluated by the pulse wave velocity) increase with age by approximately 10% to 15% during a period of 10 years. Women always have 5% to 10% lower stiffness than men of the same age. Although large artery stiffness increases with age independently of the presence of cardiovascular risk factors or other associated conditions, the extent of this increase may depend on several environmental or genetic factors. Hypertension may increase arterial stiffness, especially in older subjects. Among other cardiovascular risk factors, diabetes type 1 and 2 accelerates arterial stiffness, whereas the role of dyslipidemia and tobacco smoking is unclear. Arterial stiffness is also present in several cardiovascular and renal diseases. Patients with heart failure, end stage renal disease, and those with atherosclerotic lesions often develop central artery stiffness. Decreased carotid distensibility, increased arterial thickness, and presence of calcifications and plaques often coexist in the same subject. However, relationships between these three alterations of the arterial wall remain to be explored.

Metallic renal artery MR imaging stent: artifact-free lumen visualization with projection and standard renal MR angiography.

A cardiac-triggered free-breathing three-dimensional (3D) balanced fast field-echo projection renal magnetic resonance (MR) angiographic sequence was investigated for in-stent lumen visualization of a dedicated metallic renal artery stent. Fourteen prototype stents were deployed in the renal arteries of six pigs (in two pigs, three stents were deployed). Projection renal MR angiography was compared with standard contrast material-enhanced 3D breath-hold MR angiography. Artifact-free in-stent lumen visualization was achieved with both projection MR angiography and contrast-enhanced MR angiography. These promising results warrant further studies for visualization of in-stent restenosis.

Subjective cognitive decline in patients with mild cognitive impairment and healthy older adults: association with personality traits.

AIM: In normal aging, subjective cognitive decline (SCD) might reflect personality traits or affective states rather than objective cognitive decline. However, little is known on the correlates of SCD in mild cognitive impairment (MCI). The present study investigates SCD in MCI patients and healthy older adults, and explores the association of SCD with personality traits, affective states, behavioral and psychological symptoms (BPS), and episodic memory in patients with MCI as compared with healthy older adults. METHODS: A total of 55 patients with MCI and 84 healthy older adults were recruited. Standard instruments were used to evaluate SCD, episodic memory, BPS and affective states. Premorbid and current personality traits were assessed by proxies using the NEO Personality Inventory Revised. RESULTS: Patients with MCI generally reported SCD more often than healthy older adults. SCD was positively associated with depressive symptoms in both groups. With regard to personality, no significant relationship was found in the healthy older group, whereas agreeableness was significantly negatively related to SCD in the MCI group. No significant association was found between SCD and episodic memory. CONCLUSIONS: SCD is more prevalent in patients with MCI than in the healthy elderly, but it does not reflect an objective cognitive impairment. SCD rather echoes depressive symptoms in both patients with MCI and healthy subjects. The negative association of SCD with agreeableness observed in patients with MCI could indicate that MCI patients scoring high on the agreeableness trait would not report SCD in order to prevent their relatives worrying about their increasing cognitive difficulties.

Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress.

BACKGROUND: Depending on its magnitude, lower body negative pressure (LBNP) has been shown to induce a progressive activation of neurohormonal, renal tubular, and renal hemodynamic responses, thereby mimicking the renal responses observed in clinical conditions characterized by a low effective arterial volume such as congestive heart failure. Our objective was to evaluate the impact of angiotensin II receptor blockade with candesartan on the renal hemodynamic and urinary excretory responses to a progressive orthostatic stress in normal subjects. METHODS: Twenty healthy men were submitted to three levels of LBNP (0, -10, and -20 mbar or 0, -7.5, and -15 mm Hg) for 1 hour according to a crossover design with a minimum of 2 days between each level of LBNP. Ten subjects were randomly allocated to receive a placebo and ten others were treated with candesartan 16 mg orally for 10 days before and during the three levels of LBNP. Systemic and renal hemodynamics, renal sodium excretions, and the hormonal response were measured hourly before, during, and for 2 hours after LBNP. RESULTS: During placebo, LBNP induced no change in systemic and renal hemodynamics, but sodium excretion decreased dose dependently with higher levels of LBNP. At -20 mbar, cumulative 3-hour sodium balance was negative at -2.3 +/- 2.3 mmol (mean +/- SEM). With candesartan, mean blood pressure decreased (76 +/- 1 mm Hg vs. 83 +/- 3 mm Hg, candesartan vs. placebo, P < 0.05) and renal plasma flow increased (858 +/- 52 mL/min vs. 639 +/- 36 mL/min, candesartan vs. placebo, P < 0.05). Glomerular filtration rate (GFR) was not significantly higher with candesartan (127 +/- 7 mL/min in placebo vs. 144 +/- 12 mL/min in candesartan). No significant decrease in sodium and water excretion was found during LBNP in candesartan-treated subjects. At -20 mbar, the 3-hour cumulative sodium excretion was + 4.6 +/- 1.4 mmol in the candesartan group (P= 0.02 vs. placebo). CONCLUSION: Selective blockade of angiotensin II type 1 (AT1) receptors with candesartan increases renal blood flow and prevents the antinatriuresis during sustained lower body negative pressure despite a modest decrease in blood pressure. These results thus provide interesting insights into potential benefits of AT1 receptor blockade in sodium-retaining states such as congestive heart failure.

Renal perfusion evaluation with contrast-enhanced ultrasonography.

BACKGROUND: Contrast-enhanced ultrasonography (CEUS) is a novel imaging technique that is safe and applicable on the bedside. Recent developments seem to enable CEUS to quantify organ perfusion. We performed an exploratory study to determine the ability of CEUS to detect changes in renal perfusion and to correlate them with effective renal plasma flow. METHODS: CEUS with destruction-refilling sequences was studied in 10 healthy subjects, at baseline and during infusion of angiotensin II (AngII) at low (1 ng/kg/min) and high dose (3 ng/kg/min) and 1 h after oral captopril (50 mg). Perfusion index (PI) was obtained and compared with the effective renal plasma flow (ERPF) obtained by parallel para-aminohippurate (PAH) clearance. RESULTS: Median PI decreased from 188.6 (baseline) to 100.4 with low-dose AngII (-47%; P < 0.02) and to 66.1 with high-dose AngII (-65%; P < 0.01) but increased to 254.7 with captopril (+35%; P > 0.2). These changes parallelled those observed with ERPF, which changed from a median of 672.1 mL/min (baseline) to 572.3 (low-dose AngII, -15%, P < 0.05) and to 427.2 (high-dose AngII, -36%, P < 0.001) and finally 697.1 (captopril, +4%, P < 0.02). CONCLUSIONS: This study demonstrates that CEUS is able to detect changes in human renal cortical microcirculation as induced by AngII infusion and/or captopril administration. The changes in perfusion indices parallel those in ERPF as obtained by PAH clearance.

Impaired renal function in owl monkeys (Aotus nancymai) infected with Plasmodium falciparum

Impaired renal function was observed in sixteen Aotus nancymai 25 and 3 months following infection with the Uganda Palo Alto strain of Plasmodium falciparum. Decrease were noted in the clearance of endogenous creatinine, creatinine excretion, and urine volume while increases were observed in serum urea nitrogen, urine protein, urine potassium, fractional excretion of phosphorus and potassium, and activities of urinary enzymes. The results were suggestive of glomerulonephropathy and chronic renal disease.

Dose-dependent acute and sustained renal effects of the endothelin receptor antagonist avosentan in healthy subjects.

The endothelin receptor antagonist avosentan may cause fluid overload at doses of 25 and 50 mg, but the actual mechanisms of this effect are unclear. We conducted a placebo-controlled study in 23 healthy subjects to assess the renal effects of avosentan and the dose dependency of these effects. Oral avosentan was administered once daily for 8 days at doses of 0.5, 1.5, 5, and 50 mg. The drug induced a dose-dependent median increase in body weight, most pronounced at 50 mg (0.8 kg on day 8). Avosentan did not affect renal hemodynamics or plasma electrolytes. A dose-dependent median reduction in the fractional renal excretion of sodium was found (up to 8.7% at avosentan 50 mg); this reduction was paralleled by a dose-related increase in proximal sodium reabsorption. It is suggested that avosentan dose-dependently induces sodium retention by the kidney, mainly through proximal tubular effects. The potential clinical benefits of avosentan should therefore be investigated at doses of <or= 5 mg.

Transplantation rénale pédiatrique: expérience lausannoise de 1971 à 1998 [Pediatric renal transplantation: Experience in Lausanne 1971 to 1998].

AIMS OF THE STUDY: Analysis of indications and results of paediatric renal transplantation in a single centre, before and after the introduction of cyclosporine A (CSA). METHODS: Historical retrospective study. RESULTS: 19 transplantations were performed in 14 patients (5 second grafts) between 1971 and 1987 (group I). 13 patients were transplanted between 1988 and 1998 (no second transplant) (group II). In group II, all the patients had immunosuppression with CSA, but none in group I. Group II, with CSA, showed better renal survival than patients without CSA. In group I, obstructive uropathies (posterior urethral valves, pyelo-ureteral junction stenosis, vesico-ureteral reflux) represent a common cause (35%) of terminal chronic renal failure (TCRF), whereas in group II they represent only 15% of the causes and chronic glomerulonephritis is the most common cause (69%) of TCRF. Acute and chronic graft rejections were the cause of 9 and 1 graft losses in group I and II respectively. Living related donors account for 14% of all renal transplantations in group I and 46% in group II. CONCLUSIONS: The incidence of paediatric patients referred to Lausanne for TCRF is stable. We have observed a constant and steady decrease in obstructive uropathies leading to TCRF and renal transplantations, whereas glomerulonephritis are increasingly frequent. Graft survival has much improved since the introduction of cyclosporine A, without an increase in morbidity. In carefully selected cases, intrafamilial renal transplantation provides good results and helps to shorten the time spent on dialysis.

The NLRP3 inflammasome promotes renal inflammation and contributes to CKD.

Inflammation significantly contributes to the progression of chronic kidney disease (CKD). Inflammasome-dependent cytokines, such as IL-1β and IL-18, play a role in CKD, but their regulation during renal injury is unknown. Here, we analyzed the processing of caspase-1, IL-1β, and IL-18 after unilateral ureteral obstruction (UUO) in mice, which suggested activation of the Nlrp3 inflammasome during renal injury. Compared with wild-type mice, Nlrp3(-/-) mice had less tubular injury, inflammation, and fibrosis after UUO, associated with a reduction in caspase-1 activation and maturation of IL-1β and IL-18; these data confirm that the Nlrp3 inflammasome upregulates these cytokines in the kidney during injury. Bone marrow chimeras revealed that Nlrp3 mediates the injurious/inflammatory processes in both hematopoietic and nonhematopoietic cellular compartments. In tissue from human renal biopsies, a wide variety of nondiabetic kidney diseases exhibited increased expression of NLRP3 mRNA, which correlated with renal function. Taken together, these results strongly support a role for NLRP3 in renal injury and identify the inflammasome as a possible therapeutic target in the treatment of patients with progressive CKD.

Impairment and disability in 20 CIDP patients according to disease activity status.

Twenty patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) meeting the EFNS/PNS criteria were examined in order to assess differences/similarities between the various grading systems according to CIDP disease activity status (CDAS). A principal component (PC) analysis and the correlations between the following scores were performed: Neurological Symptom Score; MRC sum score; Neurological Impairment Score; Hammersmith Functional Motor Scale; Inflammatory Neuropathy Cause and Treatment (INCAT) Sensory Sum Score; Overall Disability Sum Score; INCAT Disability Score; Rasch-built Overall Disability Scale. Our analysis outlined two main sets of scales, with high influence in the top two PCs. The first PC that best explained the variability within the cohort consisted of CDAS, general disability scores and motor scores; these parameters were also strongly correlated amongst each other. The second PC explained less the variability and consisted mainly of sensory scores and disease duration; these parameters did not correlate with the scores of the first PC or with the CDAS. Our findings suggest separating screening for motor and sensory deficits when evaluating CIDP patients, as only the motor scores correlate with CDAS.

Short-course thymoglobulin induction and steroid-free immunosuppressive regimen in renal transplantation

Purpose: Optimal induction and maintenance immunosuppressive therapies in renal transplantation are still a matter of debate.Chronic corticosteroid usage is a major cause of morbidity but steroid-free immunosuppression (SF) can result in unacceptably high rates of acute rejection and even graft loss. Methods and materials: We have conducted a prospective openlabelled clinical trial in the Geneva-Lausanne Transplant Network from March 2005 to May 2008. 20 low immunological risk (<20% PRA, no DSA) adult recipients of a primary kidney allograft received a 4-day course of thymoglobulin (1.5 mg/kg/d) with methylprednisolone and maintenance based immunosuppression of tacrolimus and entericcoated mycophenolic acid (MPA). The control arm consisted of 16 matched recipients treated with basiliximab induction, tacrolimus, mycophenolate mofetil and corticosteroids. Primary endpoints were the percentage of recipients not taking steroids and the percentage of rejection-free recipients at 12 months.Secondary end points were allograft survival at 12 months and significant thymoglobulin and/or other drugs side effects. Results: In the SF group, 85% of the kidney recipients remained steroid-free at 12 months. The 3 cases of steroids introduction were due to one acute tubulo-interstitial rejection occurring at day 11, one tacrolimus withdrawal due to thrombotic microangiopathy and one MPA withdrawal because of multiple sinusitis and CMV reactivations. No BK viremia was detected nor CMV disease. The 6 CMV negative patients who received a positive CMV allograft had a symptomatic primoinfection after their 6-month course valgancyclovir prophylaxis. In the steroid-based group, 3 acute rejection episodes (acute humoral rejection, acute tubulointerstitial Banff IA and vascular Banff IIA) occurred in 2 recipients, 3 BK virus nephropathies were diagnosed between 45 and 135 days post transplant No side effects were associated with thymoglobulin infusion.In the SF group, 4 recipients presented severe leukopenia or agranulocytosis and one recipient had febrile hepatitis leading to transient MPA withdrawal. Discontinuation of MPA was needed in 2 patients for recurrent sinusitis and CMV reactivations. Patient and graft survival was 100% in both groups at 12 month follow-up. Conclusion: Steroid-free with short-course thymoglobulin induction therapy was a safe protocol in low-risk renal transplant recipients. Lower rates of acute rejection and BK virus infections episodes were seen compared to the steroid-based control group. A longer follow-up will be needed to determine whether this SF immunosuppressive regimen will result in higher graft and patient survival.