Are HUS and TTP genetically determined?
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Hemolytic-Uremic Syndrome↗
Biomedical subjects
M Noris
Publications and source records attributed to M Noris.
Upregulation of renal and systemic cyclooxygenase-2 in patients with active lupus nephritis.
In lupus nephritis (LN), renal thromboxane A2 (TXA2) production is increased, and inhibition of TXA2 activity improves renal function. In patients with LN, renal function depends very much on vasodilatory prostaglandins, and indeed inhibiting the prostaglandin-forming enzyme cyclooxygenase (COX) with aspirin or related compounds was detrimental on renal hemodynamics in these patients. There are no data so far on whether the excessive TXA2 production in LN derives from upregulation of type I or type II isoforms of COX. It was found that TXB2 synthesis and COX-2 gene expression were higher in peripheral blood mononuclear cells from patients with active LN compared to patients in the inactive form of the disease and to healthy subjects. Unlike COX-2, levels of COX-1 mRNA were comparable in lupus patients and control subjects and were not influenced by the disease activity. Immunoperoxidase studies on kidney biopsies showed COX-1 staining in glomerular arterioles and other renal vessels, with no evident difference between lupus biopsies and control specimens taken from either individuals who were free of renal disease or patients with non-lupus nephropathies. In contrast, COX-2 staining was definitely stronger in specimens from patients with active LN than control specimens. In active LN, COX-2-specific staining was localized mainly in the glomeruli, with a weaker signal on tubuli and in the interstitium. Double-staining studies with an antibody against the macrophage marker CD68 and an anti-COX-2 antibody definitely showed that COX-2 and CD68 often colocalized on the same cell, with only occasional glomerular COX-2-stained mesangial areas. Patients with non-lupus nephropathies had no increase in renal COX-2 expression. These results indicate that COX-2 upregulation is a specific finding of active LN and that monocytes infiltrating the glomeruli contribute to the exaggerated local synthesis of TXA2. If this is correct, COX-2 may soon become a target for therapeutic intervention in this disease.
Adult↗
Nitric oxide/endothelin balance after nephron reduction.
Nitric oxide (NO), an L-arginine derivative, is implicated in neuronal transmission, immune response and vasodilation, besides acting as a platelet function modulator. A number of recent studies in the experimental model of renal mass reduction (RMR) in rats have proposed the hypothesis that abnormalities of the NO synthetic pathway could have a key role in mediating the complex hemodynamic and hemostatic disorders associated with the progression of renal disease. Thus, renal NO generation is lower than normal in rats with RMR seven days after surgery, and progressively worsens with time in close correlation with signs of renal injury. This abnormality is due to a strong defect of inducible NO synthase (iNOS) content in the kidney. In the same model, administration of either the NO precursor, L-arginine, or a NO-releasing compound reduces proteinuria, slows renal disease progression and prolongs survival. On the other hand RMR is associated with a progressive increase of renal synthesis of the potent vasoconstrictor peptide, endothelin-1 (ET-1), whose mRNA is expressed in excessive amounts in cortical tubules early after surgical ablation. In this setting, a marked reduction of NO, in the face of continuous local generation of ET-1, may well contribute to intraglomerular capillary hypertension and cell proliferation. Actually, administration of a selective ETA receptor antagonist to RMR rats reduced abnormal permeability to proteins and prevented renal function deterioration. In the same model the ETA receptor antagonist also corrected the impaired renal NO synthesis, suggesting that excessive ET-1 bioactivity might also be responsible for the progressive reduction of renal NO. In keeping with this possibility are recent in vitro data that ET-1 inhibits iNOS transcription, a process mediated by interaction of the peptide with subtype A receptors. Nitric oxide and ET-1 have profound and opposite effects on glomerular and tubular function. Thus, abnormalities of renal NO and ET-1 synthetic pathways, as documented in the RMR model, likely have major and complementary roles in promoting alteration in renal hemodynamics and functions in progressive nephropathies.
Animals↗
Emergency department use of aspirin in patients with possible acute myocardial infarction.
BACKGROUND: Efforts have been made to improve the suboptimal use of aspirin after hospitalization. OBJECTIVE: To assess the frequency and timing of aspirin administration in emergency department patients with possible myocardial infarction. DESIGN: Retrospective record review. SETTING: Emergency departments of four hospitals affiliated with the same university. PATIENTS: All patients who were admitted to the four hospitals in 1994 for evaluation and treatment of suspected acute myocardial infarction. MEASUREMENTS: The frequency and timing of aspirin administration and the definitive diagnosis established before discharge from the hospital. RESULTS: Aspirin was not given to 253 of 463 emergency department patients (55%) who had a definitive diagnosis of acute myocardial infarction. Seventy-eight percent of patients who did receive aspirin received it more than 30 minutes after arrival in the emergency department. CONCLUSION: Aspirin therapy is underutilized as the first intervention in patients who are admitted with suspected myocardial infarction.
Aged↗
Sequential monitoring of urine-soluble interleukin 2 receptor and interleukin 6 predicts acute rejection of human renal allografts before clinical or laboratory signs of renal dysfunction.
BACKGROUND: The significance of noninvasive techniques to the early diagnosis of acute rejection in kidney transplants remains elusive. In this study, we examined whether an early posttransplant increase in serum- and urine-soluble interleukin (IL) 2 receptor (sIL-2R) and IL-6 levels predicted acute rejection. METHODS: Sequential determinations of serum and urine sIL-2R and IL-6 were performed in the first 30 postoperative days in 40 renal transplant patients. Changes during the posttransplant period observed in 26 patients who had one or more episodes of acute rejection (group A) were compared with those recorded in 14 patients who did not experience acute rejection of their graft (group B). RESULTS: Serum sIL-2R was higher than normal in patients of groups A and B without statistical differences between the two groups. In the first 3 days after transplantation, urinary sIL-2R was higher than normal in group A but not in group B. Urinary sIL-2R at days 2 and 3 was significantly higher (P<0.05) in group A than in group B. In the first 5 days after transplantation, urinary IL-6 was persistently higher than normal in group A, whereas it progressively decreased to normal value on day 4 in group B. Sudden increases (doubling within 24 hr) in urine IL-6 preceded clinical diagnosis of acute rejection by a mean period of 2 days, with an 87% sensitivity and a 64% specificity, and also predicted recurrent rejection episodes. CONCLUSIONS: Sequential monitoring of urinary sIL-2R and IL-6 levels does allow very early diagnosis of rejection without invasive procedures. Specifically, high urinary sIL-2R in the first 5 posttransplant days identifies the subgroup of patients at risk. In the subsequent days, a sudden increase in urinary IL-6 occurs in those of the above patients who will indeed reject their graft.
Acute Disease↗
Renal and systemic nitric oxide synthesis in rats with renal mass reduction.
In rats undergoing renal mass reduction (RMR) oral supplementation with the nitric oxide (NO) precursor L-arginine increases glomerular filtration rate and ameliorates signs of glomerular injury, suggesting that chronic renal failure in the rats is a condition of low NO formation in the kidney. On the contrary, data are available that in the systemic circulation of uremics, both rats and human beings, NO is formed in excessive amounts and may contribute to platelet dysfunction and bleeding tendency, well-known complications of uremia. The present study was designed to clarify the pathophysiology of renal and systemic NO synthesis in uremia. We showed that renal ex vivo NO generation, measured as the conversion of [3H] L-arginine to [3H] L-citrulline, was lower than normal in RMR rats, seven days after surgery, and progressively worsened with time in close correlation with signs of renal injury. Consistent with these results, urinary excretion of the stable NO metabolites, NO2-/NO3-, significantly decreased in rats with RMR. To go deeper into the cellular origin and biochemical nature of this abnormality we used two histochemical approaches that could locate either NO synthase (NOS) catalytic activity (NADPH-diaphorase) or NOS isoenzyme expression (immunoperoxidase). NADPH-diaphorase documented a progressive loss of renal NOS activity in RMR rats that co-localized with a strong progressive decrease of inducible NOS isoenzyme (iNOS) immunostaining. At variance with iNOS, endothelial cell NOS (ecNOS) staining was rather comparable in RMR and control kidneys. At variance to the kidney, in the systemic circulation of RMR rats the synthesis of NO increased as reflected by higher than normal plasma NO2-/NO3- concentrations. High systemic NO likely derives from vessels as documented by the increased NOS activity and higher expression of both iNOS and ecNOS in the aorta of RMR rats. Up-regulation of systemic NO synthesis might be an early defense mechanism against hypertension of uremia. On the other hand, more NO available to circulating cells may sustain the bleeding tendency, a well-known complication of uremia.
Animals↗
Platelet-activating factor mediates angiotensin II-induced proteinuria in isolated perfused rat kidney.
Isolated kidney preparations (IPK) from male Sprague Dawley rats perfused at constant pressure were used to evaluate the effect of angiotensin II (AII) and platelet-activating factor (PAF) on renal function and urinary protein excretion. Compared with basal, intrarenal infusion of AII at 8 ng/min caused a progressive increase in protein excretion (11 +/- 6 versus 73 +/- 21 micrograms/min) in parallel with a decline in renal perfusate flow (RPF) (29 +/- 3 versus 18 +/- 3 ml/min). Addition to the perfusate of PAF at 50 nM final concentration also induced proteinuria (9 +/- 4 versus 55 +/- 14 micrograms/min) but did not change RPF (29 +/- 3 versus 30 +/- 3 ml/min). Preexposure of isolated kidneys to the PAF receptor antagonist WEB 2086 prevented the increase in urinary protein excretion induced by AII infusion (basal: 13 +/- 6; post-AII: 12 +/- 7 micrograms/min) but failed to prevent the vasoactive effect of AII (RPF, basal: 30 +/- 2; post-AII: 21 +/- 3 ml/min). In additional experiments, dexamethasone reduced the proteinuric effect of PAF remarkably. These results indicate that in isolated kidney preparation: (1) AII infusion induced proteinuria and decreased RPF; and (2) the effect of AII in enhancing urinary protein excretion was completely prevented by a specific PAF receptor antagonist, which, however, did not influence the AII-induced fall in RPF. It is suggested that PAF plays a major role in AII-induced changes in the permselective function of the glomerular capillary barrier.
Angiotensin II↗
Nitric oxide synthesis and L-arginine in uremia.
Nitric oxide (NO), an L-arginine derivative, is implicated in neuronal transmission, immune response and vasodilation, and acts as a modulator of platelet function. Recent studies in the experimental model of renal mass reduction (RMR) in rats have generated the hypothesis that abnormalities in the NO synthetic pathway could play a key role in mediating the complex hemodynamic and hemostatic disorders associated with the progression of renal disease. Thus, renal NO generation is lower than normal in rats with RMR 7 days after surgery and progressively worsens with time in close correlation with signs of renal injury. This abnormality is due to a major defect in inducible NO synthase (iNOS) content in the kidney. In the same model, administration of either the NO precursor, L-arginine, or a NO-releasing compound reduces proteinuria, slows renal disease progression, and prolongs survival. In contrast, in the systemic circulation of uremic rats, NO is formed in excessive amounts, possibly caused by higher release from systemic vessels due to the augmented expression of both iNOS and endothelial NOS. Up-regulation of systemic NO synthesis might be a defense mechanism against uremic hypertension. On the other hand, a greater availability of NO to circulating cells may sustain the bleeding tendency, a well-known complication of uremia.
Animals↗
Increased nitric oxide formation in recurrent thrombotic microangiopathies: a possible mediator of microvascular injury.
The term thrombotic microangiopathy (TMA) has been used extensively to encompass hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, two syndromes of hemolytic anemia, and thrombocytopenia associated with renal or brain involvement or both. There is evidence that endothelial damage is a crucial feature in the sequence of events that precedes the development of microvascular lesions. More recent studies would suggest that endothelial dysfunction could be a consequence of neutrophil activation. Activated neutrophils generate superoxide anions (O2-) that, combining with endothelial-derived nitric oxide (NO), form the highly cytotoxic hydroxyl radical. Seven patients with recurrent forms of TMA and seven healthy volunteers were studied. Plasma concentrations of the NO metabolites, nitrites/nitrates, were elevated in the acute phase of TMA, indicating an increased NO synthesis in vivo. In addition, elevated serum concentrations of tumor necrosis factor, a potent inducer of endothelial NO synthase, were found in acute TMA. Serum from patients with acute TMA induced NO synthesis in cultured endothelial cells more than normal serum. Enhanced stimulatory activity was no longer found in the recovery phase. Release of O2- by neutrophils ex vivo was higher than normal in patients with acute TMA, but decreased in the recovery phase. Exactly the same trend was observed for plasma malondialdehyde and conjugated dienes, indicating that excessive oxygen radical formation in acute TMA is associated with increased lipid peroxidation. Thus, in recurrent forms of TMA, NO formation was increased as compared with controls. This was associated with signs of lipid peroxidation, likely the consequence of the interaction of NO with neutrophil-derived oxygen products.
3,4-Methylenedioxyamphetamine↗
The role of vasoactive molecules of endothelial origin in the pathophysiology of normal pregnancy and pregnancy-induced hypertension.
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Animals↗
Systemic and fetal-maternal nitric oxide synthesis in normal pregnancy and pre-eclampsia.
OBJECTIVE: To investigate systemic and fetal-placental nitric oxide synthesis by biochemical and molecular biology means in normal human pregnancy and pre-eclampsia. DESIGN AND PARTICIPANTS: Three groups of women were studied: healthy pregnant women (n = 8), pregnant women with pre-eclampsia (n = 8), and age-matched nonpregnant controls (n = 8). Pre-eclamptic patients were treated with nifedipine (30-60 mg/day) for severe hypertension. Systemic nitric oxide synthesis was assessed in normal pregnant women at weeks 18-21, 29-32 and 38-39 and in pre-eclamptic women on admission to the hospital (29-32 weeks, 30 on average), before the morning nifedipine administration. Nonpregnant women were studied twice at four-week intervals as controls. The pattern of nitric oxide biosynthesis in fetal-placental circulation was studied in normal and pre-eclamptic women at the delivery. SETTING: Mario Negri Institute for Pharmacological Research, Bergamo, and the Division of Obstetrics and Gynaecology of the University of Brescia. MAIN OUTCOME MEASURES: Plasma cGMP levels and platelet nitric oxide synthesis, assessed by measuring the conversion of [3H]L-arginine to [3H]L-citrulline as well as intracellular cGMP, were evaluated. Constitutive nitric oxide synthase (EC-NOS) gene expression by Northern blot analysis and nitric oxide release by the conversion of [3H]L-arginine to [3H]L-citrulline were assessed in umbilical vein endothelial cells (HUVEC) and in placenta. Inducible nitric oxide synthase activity was also evaluated in HUVEC exposed to tumour necrosis factor alpha (TNF alpha) and in placenta homogenates incubated in calcium free medium. RESULTS: Plasma cGMP was higher in both normal pregnant and pre-eclamptic women than in nonpregnant controls. In normal pregnancy cGMP rose as early as 18-21 weeks and remained elevated throughout pregnancy. [3H]L-citrulline production and intracellular cGMP were comparable in platelets from all women. EC-NOS gene expression and nitric oxide synthesis were identical in HUVEC and placenta from normal pregnant and pre-eclamptic women. CONCLUSIONS: Systemic levels of CGMP, the nitric oxide second messenger, are increased in normal pregnancy. Excessive nitric oxide production does not derive from platelets. Pre-eclampsia is not associated with changes in fetal-placental nitric oxide synthesis.
Adult↗
Evidence for a role of nitric oxide in hypertension and in renal disease in man.
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Animals↗
alpha 1-Antitrypsin therapy in a case of thrombotic thrombocytopenic purpura.
In thrombotic thrombocytopenic purpura (TTP), activated leucocytes release elastase which mobilises unusually large von Willebrand factor (vWF) multimers from the endothelium. We investigated the effect of an inhibitor of leucocyte elastase (alpha 1-antitrypsin) on circulating vWF and platelet count in a patient with chronic relapsing TTP. alpha 1-antitrypsin consistently normalised vWF multimeric composition but failed to increase platelet count and induce remission. Plasma cryosupernatant, which never normalised vWF, always induced laboratory and clinical remission within 96 hours. In chronic relapsing TTP, unusually large vWF multimers are not the main cause of intravascular platelet aggregation.
Chronic Disease↗
New insights into circulating cell-endothelium interactions and their significance for glomerular pathophysiology.
Neutrophil and monocyte infiltration of kidney glomeruli is a striking pathologic finding in the early stages of most forms of glomerulonephritis and appears to be an important determinant of glomerular injury. Recent research has permitted to clarify the mechanisms of leukocyte trafficking to inflamed glomeruli, which appear to involve several coordinated steps: chemotaxis along a concentration gradient of chemoattractants, adhesion to endothelial cells, diapedesis between endothelial cells, and interaction with resident renal cells. In glomerulonephritis, the deposition of immune complexes within glomerular capillaries triggers the local synthesis of chemotactic factors, including complement fragments, platelet-activating factor, leukotrienes, interleukin-8, and monocyte chemotactic protein-1, which promote attraction of neutrophils and monocytes within the glomerular tuft. Adhesion to resident glomerular cells, a critical step in the process of leukocyte infiltration, is a dynamic process that results from opposite factors: (1) shear forces generated by the movement of blood within the glomerular microcirculation that tend to detach inflammatory cells from the vascular wall and (2) adhesion glycoproteins expressed on the surface of leukocytes and endothelial cells, which are upregulated in human and experimental glomerulonephritis. It has been proposed that P-selectin, which is rapidly expressed on the surface of endothelial cells exposed to various stimuli, is a principal mediator of initial low-affinity binding of leukocytes (rolling). The tethering component mediated by P-selectin facilitates interaction of leukocytes with platelet-activating factor, a biologically active phospholipid that is rapidly synthesized by activated endothelial cells and is coexpressed with P-selectin on the endothelial cell plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
PAF mediates neutrophil adhesion to thrombin or TNF-stimulated endothelial cells under shear stress.
Platelet-activating factor (PAF) is known to modulate polymorphonuclear leukocyte (PMN) adhesion to endothelial cells cultured under static conditions and activated by thrombin. In contrast, there are no data on the role of PAF in PMN adhesion to cells exposed to flow conditions and activated by stimuli other than thrombin. Here we used the PAF receptor antagonist L-659,989 to evaluate PMN adhesion to human umbilical vein endothelial cells (HUVEC) in basal conditions or upon challenge with thrombin or tumor necrosis factor-alpha (TNF-alpha). Experiments were performed under dynamic flow using a parallel-plate flow chamber and a computer-based image analysis system. Rolling and adhesion of PMNs to endothelial cells significantly increased upon stimulation with thrombin. Thrombin-stimulated HUVEC also synthesized higher amounts of PAF than untreated cells. Pretreatment of PMNs with L-659,989 significantly reduced their rolling and adhesion to thrombin-activated HUVEC. Stimulation of HUVEC with TNF-alpha significantly increased the number of rolling and adherent PMNs as compared with untreated cells. Adhesion of PMNs to and migration across TNF-alpha-stimulated HUVEC were reduced by L-659,989, whereas cell rolling was unchanged. We conclude that PAF mediates leukocyte interaction under flow conditions with HUVEC activated by inflammatory stimuli.
Cell Adhesion↗
Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions.
In the present study, we examined the hypothesis that dynamic characteristics of flow modulate the production of vasoactive mediators, namely nitric oxide (NO) and endothelin-1 (ET-1), by human umbilical vein endothelial cells (HUVECs). Cells were exposed for 6 hours in a cone-and-plate apparatus to different types of flow: steady laminar, with shear stresses of 2, 8, and 12 dyne/cm2, pulsatile laminar, with shear stress from 8.2 to 16.6 dyne/cm2 and a frequency of 2 Hz; periodic laminar, with square wave cycles of 15 minutes and shear stress from 2 to 8 dyne/cm2, and turbulent, with shear stress of 8 dyne/cm2 on average. A second culture dish was kept in a normal incubator as a static control for each experiment. Laminar flow induced synthesis of NO by HUVECs that was dependent on shear-stress magnitude. Laminar shear stress at 8 dyne/cm2 also upregulated the level of NO synthase mRNA. As observed with steady laminar flow, pulsatile flow also induced an increase in NO release by endothelial cells. When HUVECs were subjected to step-change increases of laminar shear, a further increase of NO synthesis was observed, compared with steady laminar shear of the same magnitude. Turbulent flow did not upregulate NO synthase mRNA or increase NO release. Both laminar and turbulent shear stress reduced, although not significantly, ET-1 mRNA and ET-1 production compared with the static condition. These results indicate that local blood flow conditions modulate the production of vasoactive substances by endothelial cells. This may affect vascular cell functions such as nonthrombogenicity, regulation of blood flow, and vascular tone.
Amino Acid Oxidoreductases↗
Monocyte chemoattractant protein-1 is excreted in excessive amounts in the urine of patients with lupus nephritis.
BACKGROUND: In patients with lupus nephritis, mononuclear inflammatory cells infiltrate the renal interstitium and glomeruli, and the degree of leukocyte infiltration correlates with the severity of the renal dysfunction. The precise mediator signaling inflammatory cells to migrate into the kidney is not known. Recent findings that monocyte chemoattractant protein-1 (MCP-1), a chemotactic cytokine with a high degree of specificity for lymphocytes and monocytes, is overexpressed in glomeruli from rats with immunecomplex glomerulonephritis prompted us to explore the possibility that MCP-1 could be implicated in the renal inflammatory response of lupus erythematosus. EXPERIMENTAL DESIGN: Serum and urine levels of MCP-1 were evaluated in 10 patients with active lupus nephritis. Patients were studied at admission, before therapy, and at various time points after the first administration of high dose methylprednisolone. There was an additional observation of the four patients who underwent remission of clinical signs of the disease after chronic steroid treatment. Three additional groups, one (n = 9) of patients with inactive lupus nephritis, one (n = 9) of patients with nonlupus glomerulonephritis and high degree proteinuria, and one (n = 10) of healthy subjects, were also studied. RESULTS: In patients with active lupus nephritis, urinary MCP-1 was significantly higher than in lupus patients studied in the inactive phase of the disease or in healthy volunteers. High doses of i.v. methylprednisolone significantly lowered urinary MCP-1 in patients with active lupus nephritis. In patients undergoing remission of lupus nephritis after chronic steroid treatment, urinary MCP-1 did not correlate with either serum MCP-1 levels or proteinuria. Unlike in lupus, in patients with nonlupus forms of glomerulonephritis, urinary MCP-1 was comparable to controls. CONCLUSIONS: Altogether, the present data suggest a role for MCP-1 in mononuclear cell migration into the kidney in lupus nephritis.
Adult↗
Thromboxane A2 receptor blocking abrogates donor-specific unresponsiveness to renal allografts induced by thymic recognition of major histocompatibility allopeptides.
Recent in vitro studies have documented that thromboxane (Tx)A2 induces thymocyte apoptosis by acting on specific receptors abundantly expressed on the surface of immature T lymphocytes. No information is available on the in vivo relevance of this observation in development of self- or acquired tolerance. We and others have previously documented that injection of donor cells into adult thymus of experimental animals induced specific systemic unresponsiveness to allografts in the rat and mouse models. More recently, we have shown that intrathymic injection of synthetic class II major histocompatibility complex (MHC) allopeptides resulted in donor-specific unresponsiveness to renal allografts. The induction of unresponsiveness was abrogated by recipient thymectomy within the first week. We now report the effect of TxA2 blockade on acquired thymic tolerance to renal allografts induced by intrathymic injection of synthetic class II MHC allopeptides in the Wistar-Furth (WF) to Lewis rat strain combination. Administration of the TxA2 receptor blocker prior to transplantation or 2 wk postengraftment completely abrogated the unresponsive state. In addition, inhibiting the TxA2-forming enzyme by aspirin or dexamethasone also abolished the induction of acquired thymic tolerance. Evidence is also provided for a critical "dose" of peptides to be injected into the thymus to induce systemic unresponsiveness to renal allografts. These data, coupled with observations that activated peripheral T cells can circulate through the thymus, provide evidence that TxA2/TxA2 receptor interaction in the thymic microenvironment, leading to anergy/programmed cell death of activated T cells, may play an important role in the development of acquired unresponsiveness in vivo.
Animals↗