Clinicopathologic correlations of renal microthrombosis and inflammatory markers in proliferative lupus nephritis.

INTRODUCTION Microthrombosis is often observed in lupus nephritis (LN) lesions, but its clinical significance is unknown. We evaluated the clinicopathologic correlations of renal microthrombosis and inflammatory markers in LN. METHODS Kidney biopsies from 58 patients with systemic lupus erythematosus (SLE) proliferative nephritis were analyzed with immunohistochemistry (IHC) for intravascular platelet aggregates (CD61), macrophagic infiltration (CD68), and activated complement deposition (C4d). Clinical data at the time of kidney biopsy and follow-up were analyzed with regard to pathologic IHC data. RESULTS Microthrombosis was present in 52% of the tissues. It was significantly more prevalent in patients with antiphospholipid antibodies (aPLs) (62% versus 42%). The presence of microthrombosis significantly correlated with higher macrophagic infiltration. Macrophagic infiltration but not microthrombosis was significantly correlated with C4d deposition. Only macrophagic infiltration showed a correlation with SLE and renal activity (proteinuria and active sediment), whereas neither the presence of CD61+ microthrombi nor the extent of C4d deposition correlated with LN severity or outcome. CONCLUSIONS Microthrombosis is associated with higher macrophagic infiltration in LN but does not seem to increase independently the severity of renal damage. Macrophagic infiltration was the best marker of SLE and renal activity in this LN series.

Chronic nitric oxide synthase inhibition and carotid artery distensibility in renal hypertensive rats.

The goal of the present study was to examine the viscoelastic properties of the carotid artery in genetically identical rats exposed to similar levels of blood pressure sustained by different mechanisms. Eight-week old male Wistar rats were examined 2 weeks after renal artery clipping (two-kidney, one clip [2K1C] Goldblatt rats, n = 53) or sham operation (n = 49). One half of the 2K1C and sham rats received the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 1.48 mmol/L) in their drinking water for 2 weeks after the surgical procedure. Mean blood pressure increased significantly in the 2K1C-water (182 mm Hg), 2K1C-L-NAME (197 mm Hg), and sham-L-NAME (170 mm Hg) rats compared with the sham-water rats (127 mm Hg). Plasma renin activity was not altered by L-NAME but significantly enhanced after renal artery clipping. A significant and similar increase in the cross-sectional area of the carotid artery was observed in L-NAME and vehicle-treated 2K1C rats. L-NAME per se did not modify cross-sectional area in the sham rats. There was a significant upward shift of the distensibility-pressure curve in the L-NAME- and vehicle-treated 2K1C rats compared with the sham-L-NAME rats. L-NAME treatment did not alter the distensibility-pressure curve in the 2K1C rats. These results demonstrate that the mechanisms responsible for artery wall hypertrophy in renovascular hypertension are accompanied by an increase in arterial distensibility that is not dependent on the synthesis of nitric oxide.

PARP inhibition attenuates histopathological lesion in ischemia/reperfusion renal mouse model after cold prolonged ischemia.

We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN) and other renal lesions related to prolonged cold ischemia/reperfusion (IR) in kidneys preserved at 4°C in University of Wisconsin (UW) solution. Material and Methods. We used 30 male Parp1(+/+) wild-type and 15 male Parp1(0/0) knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ). We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp1(0/0) knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation.

The appropriateness of renal angioplasty: the ANPARIA software: a multidisciplinary expert panel approach

Percutaneous transluminal renal angioplasty (PTRA) is an invasive technique that is costly and involves the risk of complications and renal failure. The ability of PTRA to reduce the administration of antihypertensive drugs has been demonstrated. A potentially greater benefit, which nevertheless remains to be proven, is the deferral of the need for chronic dialysis. The aim of the study (ANPARIA) was to assess the appropriateness of PTRA to impact on the evolution of renal function. A standardized expert panel method was used to assess the appropriateness of medical treatment alone or medical treatment with revascularization in various clinical situations. The choice of revascularization by either PTRA or surgery was examined for each clinical situation. Analysis was based on a detailed literature review and on systematically elicited expert opinion, which were obtained during a two-round modified Delphi process. The study provides detailed responses on the appropriateness of PTRA for 1848 distinct clinical scenarios. Depending on the major clinical presentation, appropriateness of revascularization varied from 32% to 75% for individual scenarios (overal 48%). Uncertainty as to revascularization was 41% overall. When revascularization was appropriate, PTRA was favored over surgery in 94% of the scenarios, except in certain cases of aortic atheroma where sugery was the preferred choice. Kidney size [7 cm, absence of coexisting disease, acute renal failure, a high degree of stenosis (C70%), and absence of multiple arteries were identified as predictive variables of favorable appropriateness ratings. Situations such as cardiac failure with pulmonary edema or acute thrombosis of the renal artery were defined as indications for PTRA. This study identified clinical situations in which PTRA or surgery are appropriate for renal artery disease. We built a decision tree which can be used via Internet: the ANPARIA software (http://www.chu-clermontferrand.fr/anparia/). In numerous clinical situations uncertainty remains as to whether PTRA prevents deterioration of renal function.

Hemodynamic, renal, and endocrine effects of 4-h infusions of human atrial natriuretic peptide in normal volunteers.

A synthetic human atrial natriuretic peptide of 26 aminoacids [human (3-28)ANP or hANP] was infused into normal male volunteers. Six subjects were infused for 4 h at 1-wk intervals with either hANP at the rate of 0.5 or 1.0 microgram/min or its vehicle in a single-blind randomized order. Human (3-28)ANP at the dose of 0.5 microgram/min raised immunoreactive plasma ANP levels from 104 +/- 17 to 221 +/- 24 pg/ml (mean +/- SEM), but it induced no significant change in blood pressure, heart rate, effective renal plasma flow, glomerular filtration rate, or renal electrolyte excretion. At the rate of 1.0 microgram/min, human (3-28)ANP increased immunoreactive plasma ANP levels from 89 +/- 12 to 454 +/- 30 pg/ml. It reduced effective renal plasma flow from 523 +/- 40 to 453 +/- 38 ml/min (P less than 0.05 vs. vehicle), but left glomerular filtration rate unchanged. Natriuresis rose from 207 +/- 52 to 501 +/- 69 mumol/min (P less than 0.05 vs. vehicle) and urinary magnesium excretion from 3.6 +/- 0.5 to 5.6 +/- 0.5 mumol/min (P less than 0.01 vs. vehicle). The excretion rate of the other electrolytes, blood pressure, and heart rate were not significantly modified. At both doses, human (3-28)ANP tended to suppress the activity of the renin-angiotensin-aldosterone system. In 3 additional volunteers, the skin blood flow response to human (3-28)ANP, infused for 4 h at the rate of 1.0 microgram/min, was studied by means of a laser-doppler flowmeter. The skin blood flow rose during the first 2 h of peptide administration, then fell progressively to values below baseline. After the infusion was discontinued, it remained depressed for more than 2 h. Thus, in normal volunteers, human (3-28)ANP at the dose of 1.0 microgram/min produced results similar to those obtained previously with rat (3-28)ANP. It enhanced natriuresis without changing the glomerular filtration rate while effective renal plasma flow fell. It also induced a transient vasodilation of the skin vascular bed.

Effect of oral calcium carbonate on aortic calcification in apolipoprotein E-deficient (apoE-/-) mice with chronic renal failure.

BACKGROUND: In chronic kidney disease (CKD) patients, the intake of calcium-based phosphate binders is associated with a marked progression of coronary artery and aortic calcification, in contrast to patients receiving calcium-free phosphate binders. The aim of this study was to reexamine the role of calcium carbonate in vascular calcification and to analyse its effect on aortic calcification-related gene expression in chronic renal failure (CRF). METHODS: Mice deficient in apolipoprotein E underwent either sham operation or subtotal nephrectomy to create CRF. They were then randomly assigned to one of the three following groups: a control non-CRF group and a CRF group fed on standard diet, and a CRF group fed on calcium carbonate enriched diet, for a period of 8 weeks. Aortic atherosclerotic plaque and calcification were evaluated using quantitative morphologic image processing. Aortic gene and protein expression was examined using immunohistochemistry and Q-PCR methods. RESULTS: Calcium carbonate supplementation was effective in decreasing serum phosphorus but was associated with a higher serum calcium concentration. Compared with standard diet, calcium carbonate enriched diet unexpectedly induced a significant decrease of both plaque (p<0.05) and non-plaque-associated calcification surface (p<0.05) in CRF mice. It also increased osteopontin (OPN) protein expression in atherosclerotic lesion areas of aortic root. There was also a numerical increase in OPN and osteoprotegerin gene expression in total thoracic aorta but the difference did not reach the level of significance. Finally, calcium carbonate did not change the severity of atherosclerotic lesions. CONCLUSION: In this experimental model of CRF, calcium carbonate supplementation did not accelerate but instead decreased vascular calcification. If our observation can be extrapolated to humans, it appears to question the contention that calcium carbonate supplementation, at least when given in moderate amounts, necessarily enhances vascular calcification. It is also compatible with the hypothesis of a preponderant role of phosphorus over that of calcium in promoting vascular calcification in CRF.

Indicadores para avaliação do acesso vascular de usuários em hemodiálise

Os objetivos deste estudo foram construir indicadores para avaliar a qualidade das práticas assistenciais relacionadas ao acesso vascular de usuários em hemodiálise (HD) e proceder à validação dos indicadores. As etapas para elaborar os indicadores constituíram-se de seleção das práticas assistenciais relacionadas ao acesso vascular, fundamentação teórica dessas práticas e construção de quatro indicadores, segundo o modelo Donabediano: desempenho de cateter temporário duplo lúmen para HD, manutenção de cateter temporário de duplo lúmen, monitoramento de fístula arteriovenosa e complicações de fístula arteriovenosa. A coleta de dados ocorreu entre outubro e novembro de 2008, por meio de um questionário composto pelo julgamento do manual operacional, dos atributos dos indicadores e de seus componentes. A validação foi realizada por nove juízes, e todos os indicadores foram validados sob o consenso mínimo de 75%. Acredita-se que o emprego dessa ferramenta contribua para a avaliação e gestão da qualidade nos serviços de hemodiálise.

Upregulation of vasopressin V1A receptor mRNA and protein in vascular smooth muscle cells following cyclosporin A treatment.

1. The major side effects of the immunosuppressive drug cyclosporin A (CsA) are hypertension and nephrotoxicity. It is likely that both are caused by local vasoconstriction. 2. We have shown previously that 20 h treatment of rat vascular smooth muscle cells (VSMC) with therapeutically relevant CsA concentrations increased the cellular response to [Arg8]vasopressin (AVP) by increasing about 2 fold the number of vasopressin receptors. 3. Displacement experiments using a specific antagonist of the vasopressin V1A receptor (V1AR) showed that the vasopressin binding sites present in VSMC were exclusively receptors of the V1A subtype. 4. Receptor internalization studies revealed that CsA (10(-6) M) did not significantly alter AVP receptor trafficking. 5. V1AR mRNA was increased by CsA, as measured by quantitative polymerase chain reaction. Time-course studies indicated that the increase in mRNA preceded cell surface expression of the receptor, as measured by hormone binding. 6. A direct effect of CsA on the V1AR promoter was investigated using VSMC transfected with a V1AR promoter-luciferase reporter construct. Surprisingly, CsA did not increase, but rather slightly reduced V1AR promoter activity. This effect was independent of the cyclophilin-calcineurin pathway. 7. Measurement of V1AR mRNA decay in the presence of the transcription inhibitor actinomycin D revealed that CsA increased the half-life of V1AR mRNA about 2 fold. 8. In conclusion, CsA increased the response of VSMC to AVP by upregulating V1AR expression through stabilization of its mRNA. This could be a key mechanism in enhanced vascular responsiveness induced by CsA, causing both hypertension and, via renal vasoconstriction, reduced glomerular filtration.

Calcifications vasculaires et déficit en vitamine K: un facteur de risque modifiable dans l'insuffisance rénale chronique [Vascular calcifications and vitamin K deficiency: a modifiable risk factor in chronic kidney disease].

The mechanisms of vascular calcifications in chronic renal failure are complex. Apart for clotting factors, vitamin K-dependent proteins include matrix Gla protein. Glutamic acid residues in matrix Gla protein are carboxylated by vitamin K-dependent gamma-carboxylase, which enables it to inhibit calcification. The purpose of this review is to discuss available evidence implicating vitamin K as a modifiable risk factor in the pathogenesis of vascular calcification in renal diseases.

Sténose de l'artère rénale: indications pour une revascularisation [Atherosclerotic renal stenosis: indications for revascularisation]

La sténose de l'artère rénale (SAR) est souvent associée à une maladie athéromateuse diffuse et, en conséquence, à une morbidité et une mortalité cardiovasculaires accrues. Le nombre de revascularisations de l'artère rénale a considérablement augmenté ces dernières années. Mais les succès rapportés par cette procédure, par rapport à un traitement médical seul, semblent modestes tant sur le contrôle de la pression artérielle que sur la progression de l'insuffisance rénale. La mise en évidence d'une SAR ne représente pas systématiquement une indication à une revascularisation. Plusieurs critères doivent être pris en compte, dont la localisation de la sténose, son retentissement hémodynamique, la fonction rénale, la sévérité de l'hypertension artérielle et la facilité avec laquelle le traitement antihypertenseur parvient à normaliser la pression artérielle. Atherosclerotic renal artery stenosis is often associated with diffuse atherosclerotic disease and consequently an increased cardiovascular morbidity and mortality. Despite evidence of only moderate clinical benefit in comparison with medical treatment to control the blood pressure and to prevent renal failure, renal endovascular revascularisation has become more and more popular. The decision to treat an atherosclerotic renal stenosis by revascularisation should be taken only after a close examination of the hemodynamic impact of the stenosis, the renal function, the severity of hypertension and the quality of blood pressure control achieved by the medical treatment

The PPARgamma agonist pioglitazone modifies the vascular sodium-angiotensin II relationship in insulin-resistant rats.

Glitazones are efficient insulin sensitizers that blunt the effects of angiotensin II (ANG II) in the rat. Sodium chloride is another important modulator of the systemic and renal effects of ANG II. Whether glitazones interfere with the interaction between sodium and the response to ANG II is not known. Therefore, we investigated the effects of pioglitazone on the relationship between sodium and the systemic and renal effects of ANG II in rats. Pioglitazone, or vehicle, was administered for 4 wk to 8-wk-old obese Zucker rats. Animals were fed a normal-sodium (NS) or a high-sodium (HS) diet. Intravenous glucose tolerance tests, systemic and renal hemodynamic responses to ANG II, and the renal ANG II binding and expression of ANG II type 1 (AT(1)) receptors were measured. The results of our study were that food intake and body weight increased, whereas blood pressure, heart rate, filtration fraction, and insulin levels decreased significantly with pioglitazone in obese rats on both diets. Pioglitazone blunted the systemic response to ANG II and abolished the increased responsiveness to ANG II induced by a HS diet. Pioglitazone modified the renal hemodynamic response to changes in salt intake while maintaining a lower filtration fraction with ANG II perfusion. These effects were associated with a decrease in the number and expression of the AT(1) receptor in the kidney. In conclusion, these data demonstrate that the peroxisome proliferator-activated receptor-gamma agonist pioglitazone modifies the physiological relationship between sodium chloride and the response to ANG II in insulin-resistant rats.

Difference in the homocysteine-lowering effect of folic acid in haemodialysis patients with and without occlusive vascular disease.

BACKGROUND: Hyperhomocysteinaemia has been identified as an independent cardiovascular risk factor and is found in more than 85% of patients on maintenance haemodialysis. Previous studies have shown that folic acid can lower circulating homocysteine in dialysis patients. We evaluated prospectively the effect of increasing the folic acid dosage from 1 to 6 mg per dialysis on plasma total homocysteine levels of haemodialysis patients with and without a history of occlusive vascular artery disease (OVD). METHODS: Thirty-nine stable patients on high-flux dialysis were studied. Their mean age was 63 +/-11 years and 17 (43%) had a history of OVD, either coronary and/or cerebral and/or peripheral occlusive disease. For several years prior to the study, the patients had received an oral post-dialysis multivitamin supplement including 1 mg of folic acid per dialysis. After baseline determinations, the folic acid dose was increased from 1 to 6 mg/dialysis for 3 months. RESULTS: After 3 months, plasma homocysteine had decreased significantly by approximately 23% from 31.1 +/- 12.7 to 24.5 +/- 9 micromol/l (P = 0.0005), while folic acid concentrations had increased from 6.5 +/- 2.5 to 14.4+/-2.5 microg/l (P < 0.0001). However, the decrease of homocysteine was quite different in patients with and in those without OVD. In patients with OVD, homocysteine decreased only marginally by approximately 2.5% (from 29.0 +/- 10.3 to 28.3 +/- 8.4 micromol/l, P = 0.74), whereas in patients without OVD there was a significant reduction of approximately 34% (from 32.7+/-14.4 to 21.6+/-8.6 micromol/l, P = 0.0008). Plasma homocysteine levels were reduced by > 15% in three patients (18%) in the group with OVD compared with 19 (86%) in the group without OVD (P = 0.001), and by > 30% in none of the patients (0%) in the former group compared with 13 (59%) in the latter (P = 0.001). CONCLUSIONS: These results indicate that the homocysteine-lowering effect of folic acid administration appears to be less effective in haemodialysis patients having occlusive vascular disease than in those without evidence of such disease.

Role of intra-operative duplex ultrasound in living renal donor transplantation

Objective: The treatment of choice in end-stage renal disease is¦transplantation.¦Hemodynamic disturbances can evoke graft loss, while early ultrasound¦identification of vascular problems improves outcome. The primary endpoint¦of this study was to identify differences in post-op complications with and¦without systematic, intraoperative Doppler ultrasound use. A secondary aim¦was to find a predictive resistance index limit which would show where surgical¦reintervention was necessary.¦Methods: Between Jan 2000 and Dec 2010, 108 renal transplants were¦performed from living donors at our institution. In group 1 (n = 67),¦intra-operative duplex ultrasound and intra-parenchymatous resistance index¦measurements assessed patients, while in group 2 (n = 41), no ultrasound was¦performed.¦Results. There were no inter-group differences in the overall post-op¦complication rate or in benefit to graft or patient survival with Doppler use,¦however, significantly more vascular complications (10% vs. 0%, p = 0·02) and¦more acute rejections (37% vs. 10%) occurred in group 2 than in group 1,¦respectively. When the resistance index was <0·5 intra-operatively, immediate¦surgical revision was undertaken to raise the index >0·6.¦Results: There were no inter-group differences in the overall post-op¦complication rate or in benefit to graft or patient survival with Doppler use,¦however, significantly more vascular complications (10% vs. 0%, p = 0·02) and¦more acute rejections (37% vs. 10%) occurred in group 2 than in group 1,¦respectively. When the resistance index was <0·5 intra-operatively, immediate¦surgical revision was undertaken to raise the index >0·6.¦Conclusion: This is the first report demonstrating benefits of systematic¦intraoperative Doppler ultrasound on post-operative complications in renal¦transplantation from living donors. Our results support surgical revision with a¦resistance index <0·5.

Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites

Normalization of the increased vascular nitric oxide (NO) generation with low doses of NG-nitro-L-arginine methyl ester (L-NAME) corrects the hemodynamic abnormalities of cirrhotic rats with ascites. We have undertaken this study to investigate the effect of the normalization of vascular NO production, as estimated by aortic cyclic guanosine monophosphate (cGMP) concentration and endothelial nitric oxide synthase (eNOS) protein expression in the aorta and mesenteric artery, on sodium and water excretion. Rats with carbon tetrachloride-induced cirrhosis and ascites were investigated using balance studies. The cirrhotic rats were separated into two groups, one receiving 0.5 mg/kg per day of L-NAME (CIR-NAME) during 7 d, whereas the other group (CIR) was administrated the same volume of vehicle. Two other groups of rats were used as controls, one group treated with L-NAME and another group receiving the same volume of vehicle. Sodium and water excretion was measured on days 0 and 7. On day 8, blood samples were collected for electrolyte and hormone measurements, and aorta and mesenteric arteries were harvested for cGMP determination and nitric oxide synthase (NOS) immunoblotting. Aortic cGMP and eNOS protein expression in the aorta and mesenteric artery were increased in CIR as compared with CIR-NAME. Both cirrhotic groups had a similar decrease in sodium excretion on day 0 (0.7 versus 0.6 mmol per day, NS) and a positive sodium balance (+0.9 versus +1.2 mmol per day, NS). On day 7, CIR-NAME rats had an increase in sodium excretion as compared with the CIR rats (sodium excretion: 2.4 versus 0.7 mmol per day, P < 0.001) and a negative sodium balance (-0.5 versus +0.8 mmol per day, P < 0.001). The excretion of a water load was also increased after L-NAME administration (from 28+/-5% to 65+/-7, P < 0.05). Plasma renin activity, aldosterone and arginine vasopressin were also significantly decreased in the CIR-NAME, as compared with the CIR rats. The results thus indicate that normalization of aortic cGMP and eNOS protein expression in vascular tissue is associated with increased sodium and water excretion in cirrhotic rats with ascites.