Blockade of the renin-angiotensin system and renal tissue oxygenation as measured with BOLD-MRI in patients with type 2 diabetes.

AIM: To assess whether blockade of the renin-angiotensin system (RAS), a recognized strategy to prevent the progression of diabetic nephropathy, affects renal tissue oxygenation in type 2 diabetes mellitus (T2DM) patients. METHODS: Prospective randomized 2-way cross over study; T2DM patients with (micro)albuminuria and/or hypertension underwent blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) at baseline, after one month of enalapril (20mgqd), and after one month of candesartan (16mgqd). Each BOLD-MRI was performed before and after the administration of furosemide. The mean R2* (=1/T2*) values in the medulla and cortex were calculated, a low R2* indicating high tissue oxygenation. RESULTS: Twelve patients (mean age: 60±11 years, eGFR: 62±22ml/min/1.73m(2)) completed the study. Neither chronic enalapril nor candesartan intake modified renal cortical or medullary R2* levels. Furosemide significantly decreased cortical and medullary R2* levels suggesting a transient increase in renal oxygenation. Medullary R2* levels correlated positively with urinary sodium excretion and systemic blood pressure, suggesting lower renal oxygenation at higher dietary sodium intake and blood pressure; cortical R2* levels correlated positively with glycemia and HbA1c. CONCLUSION: RAS blockade does not seem to increase renal tissue oxygenation in T2DM hypertensive patients. The response to furosemide and the association with 24h urinary sodium excretion emphasize the crucial role of renal sodium handling as one of the main determinants of renal tissue oxygenation.

Transjugular liver biopsy: prospective evaluation of the angle formed between the hepatic veins and the vena cava main axis and modification of a semi-automated biopsy device in cases of an unfavorable angle.

In cases of transjugular liver biopsies, the venous angle formed between the chosen hepatic vein and the vena cava main axis in a frontal plane can be large, leading to technical difficulties. In a prospective study including 139 consecutive patients who underwent transjugular liver biopsy using the Quick-Core biopsy set, the mean venous angle was equal to 49.6 degrees. For 21.1% of the patients, two attempts at hepatic venous catheterization failed because the venous angle was too large, with a mean of 69.7 degrees. In all of these patients, manual reshaping of the distal curvature of the stiffening metallic cannula, by forming a new mean angle equal to 48 degrees , allowed successful completion of the procedure in less than 10 min.

Impact of restrictive intravenous fluid replacement and combined epidural analgesia on perioperative volume balance and renal function within a Fast Track program.

BACKGROUND AND OBJECTIVE: Key factors of Fast Track (FT) programs are fluid restriction and epidural analgesia (EDA). We aimed to challenge the preconception that the combination of fluid restriction and EDA might induce hypotension and renal dysfunction. METHODS: A recent randomized trial (NCT00556790) showed reduced complications after colectomy in FT patients compared with standard care (SC). Patients with an effective EDA were compared with regard to hemodynamics and renal function. RESULTS: 61/76 FT patients and 59/75 patients in the SC group had an effective EDA. Both groups were comparable regarding demographics and surgery-related characteristics. FT patients received significantly less i.v. fluids intraoperatively (1900 mL [range 1100-4100] versus 2900 mL [1600-5900], P < 0.0001) and postoperatively (700 mL [400-1500] versus 2300 mL [1800-3800], P < 0.0001). Intraoperatively, 30 FT compared with 19 SC patients needed colloids or vasopressors, but this was statistically not significant (P = 0.066). Postoperative requirements were low in both groups (3 versus 5 patients; P = 0.487). Pre- and postoperative values for creatinine, hematocrit, sodium, and potassium were similar, and no patient developed renal dysfunction in either group. Only one of 82 patients having an EDA without a bladder catheter had urinary retention. Overall, FT patients had fewer postoperative complications (6 versus 20 patients; P = 0.002) and a shorter median hospital stay (5 [2-30] versus 9 d [6-30]; P< 0.0001) compared with the SC group. CONCLUSIONS: Fluid restriction and EDA in FT programs are not associated with clinically relevant hemodynamic instability or renal dysfunction.

Functional renal failure and haemorrhagic gastritis associated with endotoxaemia in cirrhosis

Forty-three patients with cirrhosis and ascites, 21 with normal renal function, 10 with a progressive functional renal failure (FRF), and 12 with a steady FRF, were investigated for the presence of endotoxaemia by the Limulus lysate test. Endotoxaemia was found in nine patients with FRF and in none of the 21 with normal renal function (P less than 0-01). A positive Limulus test was almost exclusively associated with a progressive FRF (eight of 10 patients) and all but one of them died. Renal function improved as endotoxaemia disappeared in the survivor. Endotoxaemia was also associated with haemorrhage due to acute erosions of the gastric mucosa, being present in six of the seven patients who had this complication. Intravascular coagulation was not found in any patient. The Limulus test was positive in the ascitic fluid in 18 of 21 patients tested, although only two of them had peritonitis. These results suggest that endotoxaemia may play a critical role in the development of progressive renal failure and haemorrhagic gastritis in cirrhosis, and emphasise the potential risk of procedures involving reinfusion of ascitic fluid.

Abnormalities of sodium excretion and other disorders of renal function in fulminant hepatic failure

Renal function was evaluated in 40 patients with fulminant hepatic failure, They were divided into two groups on the basis of glomerular filtration rates greater than 40 ml/min or less than 25 ml/min. A number of patients in group 1 had markedly abnormal renal retention of sodium together with a reduced free water clearance and low potassium excretion which could be explained by increased proximal tubular reabsorption of sodium. The patients in group 2 had evidence that renal tubular integrity was maintained when the glomerular filtration rate was greater than or equal ml/min (functional renal failure), but evidence of tubular damage was present when this was less than 3 ml/min (acute tubular necrosis).

Prognostic Importance of the Cuse of Renal Failure in Patients With Cirrhosis

BACKGROUND & AIMS: The prognostic value of the different causes of renal failure in cirrhosis is not well established. This study investigated the predictive value of the cause of renal failure in cirrhosis. METHODS: Five hundred sixty-two consecutive patients with cirrhosis and renal failure (as defined by serum creatinine 1.5 mg/dL on 2 successive determinations within 48 hours) hospitalized over a 6-year period in a single institution were included in a prospective study. The cause of renal failure was classified into 4 groups: renal failure associated with bacterial infections, renal failure associated with volume depletion, hepatorenal syndrome (HRS), and parenchymal nephropathy. The primary end point was survival at 3 months. RESULTS: Four hundred sixty-three patients (82.4%) had renal failure that could be classified in 1 of 4 groups. The most frequent was renal failure associated with infections (213 cases; 46%), followed by hypovolemia-associated renal failure (149; 32%), HRS (60; 13%), and parenchymal nephropathy (41; 9%). The remaining patients had a combination of causes or miscellaneous conditions. Prognosis was markedly different according to cause of renal failure, 3-month probability of survival being 73% for parenchymal nephropathy, 46% for hypovolemia-associated renal failure, 31% for renal failure associated with infections, and 15% for HRS (P .0005). In a multivariate analysis adjusted for potentially confounding variables, cause of renal failure was independently associated with prognosis, together with MELD score, serum sodium, and hepatic encephalopathy at time of diagnosis of renal failure. CONCLUSIONS: A simple classification of patients with cirrhosis according to cause of renal failure is useful in assessment of prognosis and may help in decision making in liver transplantation.

A young man with a renal colic

We report the case of a 35-year-old man with no cardiovascular morbidity, presenting with acute flank pain, microscopic haematuria and normal blood pressure. Initially diagnosed as a ureteral colic, the patient was recovered 6 weeks later with severe hypertensive crisis. Further investigations revealed a massive renal infarction secondary to medial fibromuscular dysplasia (FMD). Several aspects of this presentation are intriguing. Renal infarcts are usually seen in older patients having cardiac problems and/or major atheromatous plaques. In addition, FMD is mainly observed in young females and rarely progresses to renal artery occlusion. Furthermore, in this case, FMD remained silent until the acute renal infarction occurred, despite a significant kidney size reduction at the time of diagnosis. Finally, the observation of a delayed hypertensive response to a major renovascular insult provides incentives to discuss possible pathophysiological mechanisms involved in renovascular hypertension.

Urate-induced acute renal failure and chronic inflammation in liver-specific Glut9 knockout mice.

Plasma urate levels are higher in humans than rodents (240-360 vs. â^¼30 μM) because humans lack the liver enzyme uricase. High uricemia in humans may protect against oxidative stress, but hyperuricemia also associates with the metabolic syndrome, and urate and uric acid can crystallize to cause gout and renal dysfunctions. Thus, hyperuricemic animal models to study urate-induced pathologies are needed. We recently generated mice with liver-specific ablation of Glut9, a urate transporter providing access of urate to uricase (LG9KO mice). LG9KO mice had moderately high uricemia (â^¼120 μM). To further increase their uricemia, here we gavaged LG9KO mice for 3 days with inosine, a urate precursor; this treatment was applied in both chow- and high-fat-fed mice. In chow-fed LG9KO mice, uricemia peaked at 300 μM 2 h after the first gavage and normalized 24 h after the last gavage. In contrast, in high-fat-fed LG9KO mice, uricemia further rose to 500 μM. Plasma creatinine strongly increased, indicating acute renal failure. Kidneys showed tubule dilation, macrophage infiltration, and urate and uric acid crystals, associated with a more acidic urine. Six weeks after inosine gavage, plasma urate and creatinine had normalized. However, renal inflammation, fibrosis, and organ remodeling had developed despite the disappearance of urate and uric acid crystals. Thus, hyperuricemia and high-fat diet feeding combined to induce acute renal failure. Furthermore, a sterile inflammation caused by the initial crystal-induced lesions developed despite the disappearance of urate and uric acid crystals.

The effects of losartan on renal function in the newborn rabbit.

The low GFR of newborns is maintained by various factors including the renin-angiotensin system. We previously established the importance of angiotensin II in the newborn kidney, using the angiotensin-converting enzyme inhibitor perindoprilat. The present study was designed to complement these observations by evaluating the role of angiotensin-type 1 (AT(1)) receptors, using losartan, a specific AT(1)-receptor blocker. Increasing doses of losartan were infused into anesthetized, ventilated, newborn rabbits. Renal function and hemodynamic variables were assessed using inulin and para-aminohippuric acid clearances as markers of GFR and renal plasma flow, respectively. Losartan 0.1 mg/kg slightly decreased mean blood pressure (-11%) and increased diuresis (+22%). These changes can be explained by inhibition of the AT(1)-mediated vasoconstrictive and antidiuretic effects of angiotensin, and activation of vasodilating and diuretic AT(2) receptors widely expressed in the neonatal period. GFR and renal blood flow were not modified. Losartan 0.3 mg/kg decreased mean blood pressure significantly (-15%), probably by inhibiting systemic AT(1) receptors. GFR significantly decreased (-25%), whereas renal blood flow remained stable. The decrease in filtration fraction (-21%) indicates predominant efferent vasodilation. At 3 mg/kg, the systemic hypotensive effect of losartan was marked (mean blood pressure, -28%), with decreased GFR and renal blood flow (-57% and -51%, respectively), a stable filtration fraction, and an increase in renal vascular resistance by 124%. The renal response to this dose can be considered as reflex vasoconstriction of afferent and efferent arterioles, rather than specific receptor antagonism. We conclude that under physiologic conditions, the renin-angiotensin is critically involved in the maintenance of GFR in the immature kidney.

La néphropathie ischémique par athérosclérose aortorénale : acquisitions thérapeutiques [Atherosclerotic renal artery disease management update]

In the case of atherosclerotic renal artery disease, the best conclusive results lie principally not in the degree of the stenosis but rather in the degree the renal parenchymal disease beyond the stenosis itself. These determining factors involve the controlling of the patients blood pressure, the improvement in the renal function and the beneficial results to the cardiovascular system. Besides the indispensable medical treatment, a revascularisation by angioplasty may be indicated. This procedure with or without vascular stent often allows satisfactory angiographic results. A treatment by surgical revascularisation is only recommended in the case of extensive atherosclerotic lesions of the aorta, complex lesions of the latter or an abdominal aortic aneurism. Although the frequency of restenosis of angioplasty with stent remains extremely low, the risk of cholesterol emboli due to the diffuse atherosclerotic lesions of the abdominal aorta, must be considered at the time of each aortic catheterization. The therapeutic approach of atherosclerotic renal artery disease must be dictated by the whole cardiovascular risk factors and by the threat of target organs. The control of the blood pressure and the maintenance of the renal function must be integrated in the decisional algorithm as well as the possible risks in carrying out an eventual revascularisation procedure. Finally, the renal angioplasty should in numerous situations be integrated in the overall assumption of responsibility of the atherosclerotic vascular diseases, and should be part of the medical treatment. Several questions still do exist; at what moment an atherosclerotic renal artery stenosis should and e considered critical, and which procedure should be considered for which patient? The purpose of this review is to propose a decisional tool for individualized treatments in the light of results from randomized and controlled studies.

Innappropriate renin secretion unmasked by captopril (SQ 14 225) in hypertension of chronic renal failure

Captopril (SQ 14 225), an orally active inhibitor of angiotensin-converting enzyme, was given to 7 hypertensive patients with chronic renal failure whose plasma-creatinine ranged from 1.5--7.4 mg/dl; whose plasma-renin activity was normal; whose hypertension was not controlled by previous therapy consisting in 5 patients of three or more antihypertensive drugs; and whose blood-pressures averaged 176/111 +/- 11/3 mm Hg. Inhibition of converting enzyme by oral captopril, 200 mg twice daily, reduced blood-pressure to 156/100 +/- 9/5 mm Hg. 5 patients needed additional treatment by frusemide 40--250 mg/day orally. With this combined regimen the blood-pressure of all patients averaged 126/85 +/- 4/3 mm Hg after 8 +/- 2 weeks of captopril. The drug was well tolerated. These results suggest that inhibition of angiotensin-converting enzyme with or without sodium depletion is an efficient treatment for hypertension associated with chronic renal failure. It appears that although renin levels in patients with this condition may be "normal", they are inappropriate in relation to the subtle degree of sodium retention that occurs with this disorder.

Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma.

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.

Effectiveness of substituting cyclosporin A with tacrolimus in reducing gingival overgrowth in renal transplant patients

Objectives: This study aims to evaluate the effectiveness of periodontal therapy combined with tacrolimus in the suppression of gingival overgrowth (GO) and the effect on GO of changing from cyclosporin A to tacrolimus. Patients and Methods: Sixteen renal transplant patients, averaging 52 years of age, whose kidney function was stable and were receiving treatment with cyclosporin A, were randomly assigned to one of two groups. In the experimental group, patients were instructed in oral hygiene and underwent periodontal treatment, whereas in the control group, only oral hygiene instructions were given. After the first visit and the change of medication from cyclosporine to tacrolimus in both groups, periodic clinical revisions were carried out for 3 months in order to assess the evolution of GO. Results: All patients showed a progressive decrease in GO. There were no statistically significant differences between the two groups (p>0.05). A greater decrease in GO occurred within the first month after changing the medication. Conclusions: No improved effectiveness in reducing GO was observed for periodontal therapy in combination with tacrolimus. Tacrolimus is an alternative to cyclosporine when attempting to avoid GO in patients with kidney transplants