Proteins abnormally filtered throughout glomerular capillary have an intrinsic renal toxicity.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
G Remuzzi
Publications and source records attributed to G Remuzzi.
Evidence for a role of nitric oxide in hypertension and in renal disease in man.
Explore the source record for details and available documents.
Animals↗
The kidney triggers graft-versus-host disease in experimental combined transplantation of kidney and stem cell-enriched peripheral leukocytes.
As a preclinical step to human studies with combined stem cell-enriched peripheral leukocytes and organ transplantation from the same donor, a series of studies in rats was undertaken. These studies indicated that Lewis rats infused intravenously with major histocompatibility complex-incompatible (from Brown-Norway rats), stem cell-enriched peripheral leukocyte preparation alone never developed graft-versus-host disease (GHVD). However, GVHD invariably manifested in all animals a few days after the kidney was transplanted in rats that had been previously primed with stem cell-enriched peripheral leukocytes from the same kidney donor strain. GVHD was prevented by substituting the crude preparation of stem cell-enriched peripheral leukocytes with a purified preparation that was almost completely free of T lymphocytes. However, in these latter experiments all rats rejected their kidney graft within 10 days from the surgery. In rats previously given the crude stem cell-enriched peripheral leukocyte preparation, perioperative administration of the fusion protein CTLA4lg also prevented GVHD and prolonged kidney graft survival up to 106 to 175 days. By contrast, animals with kidney transplants, which were given CTLA4lg without stem cells, rejected their grafts within 35 days. All together, these findings may possibly contribute to the creation of rationally designed strategies of combining organ and bone marrow from the same donor to enhance mixed chimerism and prolong survival after organ transplantation.
Abatacept↗
Glomerular filtration rate determined from a single plasma sample after intravenous iohexol injection: is it reliable?
The iohexol injection plasma clearance method is a good alternative to the inulin clearance method for determination of GFR, but requires multiple blood samples. To avoid this, methods have been developed which derive GFR from a formula that uses a single plasma concentration of the tracer and anthropometric data. The aim of this study was to evaluate whether a single plasma sample taken after iohexol injection allows reliable estimation of GFR. In this study, results of single-point determination were compared with those obtained by multiple-point plasma clearance. The GFR of 686 outpatients with different degrees of renal function were recalculated by use of the Jacobsson formula. The optimum time for sampling was found at 10 h after injection of the marker for clearances < 40 mL/min per 1.73 m2, 4 h for clearances between 40 and 99 mL/min per 1.73 m2, and 3 h for clearances > 100 mL/min per 1.73 m2. Results documented that for 75% of the patients, the simplified technique gave an error between -5% to +5% in the evaluation of GFR; for the remaining 25% of the patients, prediction error ranged from -22% to +40%. Furthermore, despite a highly significant correlation between multiple-point iohexol clearance (six plasma samples) and the single-point method (Y = 0.968X + 1.704, r2 = 0.988), the regression intercept was statistically different from 0 and the standard error of the slope estimate established that 95% confidence interval did not include 1.0 (the line of identity), thus indicating that the model can be rejected by the data at a significance level of 0.05. Thus the single-plasma-sample method to determine GFR after radiocontrast injection does not represent a real advantage over the multiple-point method and may lead to unacceptable errors in GFR calculation.
Adult↗
Colchicine interferes with L-selectin and leukocyte function-associated antigen-1 expression on human T lymphocytes and inhibits T cell activation.
Colchicine, which inhibits cell microtubule assembly by preventing polymerization of tubulin monomers, inhibits cell-mediated immune responses and promotes long-term survival of major histocompatibility complex-incompatible renal allografts in rats. Here we evaluated the effect of blocking cell microtubule assembly by colchicine on T cell and endothelial cell adhesion receptors involved in transducing signals for T cell activation. By using immunofluorescence flow cytometry analysis, evidence is presented that colchicine, in a dose-dependent fashion, downregulated L-selectin and leukocyte function-associated antigen-1, but not CD2 and CD44 on the surface of naive human peripheral blood lymphocytes. This effect was confirmed in two subsets of T lymphocytes, namely, CD45RA- and CD45RO-positive cells. However, colchicine did not influence the rapid shedding of L-selectin from T lymphocytes exposed to activating stimuli. Colchicine inhibited expression of interleukin-2 receptor on activated T lymphocytes. This effect was observed when T lymphocytes were stimulated with both anti-CD3 and anti L-selectin monoclonal antibodies. Colchicine also inhibited lymphocyte function in vitro as documented by inhibition of the human mixed lymphocyte response in a dose-dependent fashion. Moreover, colchicine downregulated surface expression of intercellular adhesion molecule-1 and E-selectin on activated human umbilical vein endothelial cells. These results indicate that blocking cell microfubule assembly inhibits surface expression of adhesion molecules on T cells and endothelial cells, and provides insights into the complex mechanisms of the action of colchicine in vivo.
Antibodies, Monoclonal↗
Angiotensin II modulates glomerular capillary permselectivity in rat isolated perfused kidney.
Studies in experimental animals and humans have documented that inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors reduces urinary protein excretion rate and retards the development of renal injury. Here we sought to investigate whether angiotensin II (All) modified the size-selective properties to macromolecules of the glomerular capillary barrier in isolated perfused rat kidney preparation. Compared with basal values, continuous All infusion into the renal artery at the rate of 3 or 8 ng/min, but not at 0.6 ng/min, induced a progressive and significant increase in urinary protein excretion rate. Evaluation of the sieving properties of the glomerular barrier by fractional clearance of polydisperse Ficoll showed that All significantly enhanced the filtration of tracer molecules of radil > or = 34A. All-induced changes in urinary protein excretion rate and in Ficoll fractional clearance were completely prevented by pretreatment with the specific All Type 1 receptor antagonist SR 47436.
Angiotensin II↗
A logistic-regression model provides novel guidelines to maximize the anti-acute rejection properties of cyclosporine with a minimum of toxicity.
Although cyclosporine has become the mainstay of immunosuppression in organ transplantation, there is still no consensus on the criteria to optimize its anti-rejection activity with minimum toxicity. A clear and objective definition of target cyclosporine trough levels at different times from renal transplantation is still lacking, primarily because of the lack of a model correlating cyclosporine levels with probability of rejection or toxicity. In this study, logistic-regression model was developed that was applied to data collected retrospectively from two postoperative periods, i.e., Days 0 to 9 and 10 to 30, in 135 consecutive cadaveric renal transplant recipients, for a total of 1851 determinations. Only minimum and maximum trough levels were considered for each period. Concentration-response curves were estimated for Days 0 to 9 (P = 0.0001 for efficacy and P = 0.028 for toxicity) and for Days 10 to 30 (P = 0.015 for efficacy and P = 0.037 for toxicity). Therapeutic intervals of 330 to 430 ng/mL (parent compound in whole blood) for Days 0 to 9 and 260 to 390 ng/mL for Days 10 to 30 predicted an incidence of acute rejection of 22% and 12%, respectively, with a reasonably low toxicity that primarily consisted of elevation of serum aminotransferases.
Adult↗
Acceleration of recovery in acute renal failure: from cellular mechanisms of tubular repair to innovative targeted therapies.
Kidney repair from injury is a major focus of interest for research, both clinical and basic, in the field of acute renal failure. This is so because very little progress has been made during the past several years to improve mortality in hospitalized patients with acute renal failure despite the unique potential of the kidney for complete structural and functional recovery. Novel therapeutic options have recently emerged from the knowledge of molecular mechanisms of tissue injury after ischemia, including pathways of endothelial-leukocyte interaction and epithelial cell aggregation mediated by integrin molecules. These strategies are promising because they may target early mechanisms of leukocyte infiltration and tubular obstruction. However, it seems clear that additional interventions should address the reparative program that potentially leads to the full restoration of kidney structure and function. Thus, acceleration of repair from acute renal failure is achieved experimentally by growth factors which besides different renal actions seem to have in common the ability to stimulate proliferation of surviving tubular epithelial cells. We direct attention to cellular processes which characterize, and possibly have role in, renal repair from acute tubular injury as potential targets of therapy. In addition to proliferation, they include epithelial differentiation and apoptosis. Further investigation in the biology of repair should set the stage for rational design of targeted therapies which may accelerate the pace of recovery and hopefully decrease mortality in such a dramatic and potentially reversible setting.
Acute Kidney Injury↗
Glomerular protein trafficking and progression of renal disease to terminal uremia.
Experimental and human studies indicate that altered glomerular permeability to proteins correlates with tubulointerstitial injury and subsequent glomerular scarring. Maneuvers that restore the selectivity of glomerular barrier to macromolecules limit renal injury in progressive nephropathies. The abnormal traffic of proteins through the glomerular capillary has an intrinsic renal toxicity linked to the process of over-reabsorption by proximal tubular cells. Excessive protein reabsorption induces functional alterations of tubular cells that overexpress inflammatory and vasoactive molecules, as indicated by in vitro or in vivo studies. Thus monocyte chemoattractant protein-1 and osteopontin may attract inflammatory cells into renal interstitium. Enhanced tubular endothelin-1 secretion, mainly toward the basolateral membrane of the cell, may stimulate interstitial macrophage infiltration and in addition may promote interstitial fibroblast proliferation and extracellular matrix synthesis, thus amplifying tubulointerstitial inflammation and injury.
Angiotensin-Converting Enzyme Inhibitors↗
Nitrendipine and enalapril improve albuminuria and glomerular filtration rate in non-insulin dependent diabetes.
The effects of 3, 15, and 27 months of treatment with nitrendipine (10 to 40 mg/day) and enalapril (5 to 20 mg/day) on diastolic blood pressure (DBP), overnight urinary albumin excretion (UAE) rate, glomerular filtration rate (GFR), and renal plasma flow (RPF) were studied prospectively in a parallel group design in 13 microalbuminuric non-insulin dependent diabetic patients with mild hypertension and biopsy-proven diabetic glomerulopathy. Throughout the study period DBP decreased in both groups to < 95 mm Hg. At three months UAE, GFR, and RPF did not change significantly. At 15 and 27 months UAE (microgram/min, geometric mean and 95% C.I.) decreased respectively from 47.4 (23.4 to 95.9) to 28.6 (10.3 to 79.4), and to 22.3 (10.9 to 45.2; P = 0.0005) with nitrendipine, and from 58.3 (30.3 to 110.9) to 44.1 (22.9 to 84.8), and to 14.7 (4.4 to 49.3; P = 0.0025) with enalapril. Four patients in each group were normoalbuminuric at 27 months and none became macroalbuminuric. At 15 months the GFR (ml/min/1.73 m2, mean +/- SD) increased from 69.5 +/- 15.2 to 96.6 +/- 22.0 (P < 0.05) with nitrendipine and from 58.9 +/- 10.7 to 78.5 +/- 11.0 (P < 0.05) with enalapril. At 27 months the GFR was still numerically higher that at baseline either with nitrandipine (81.2 +/- 7.8) and with enalapril (79.9 +/- 17.7) (P = 0.7). The RPF (ml/min/1.73 m2, mean +/- SD) at baseline and at 27 months was comparable either with nitrendipine (456.6 +/- 165.3 vs. 400.9 +/- 112.9) and with enalapril (400.3 +/- 81.3 vs. 399.0 +/- 123.7). Both treatments were well tolerated. This is the first evidence that long-term effective control of arterial blood pressure by a calcium channel blocker or by an angiotensin converting enzyme inhibitor, in addition to reducing albuminuria, also improves GFR in incipient nephropathy.
Adult↗
Early ganciclovir therapy effectively controls viremia and avoids the need for cytomegalovirus (CMV) prophylaxis in renal transplant patients with cytomegalovirus antigenemia.
Cytomegalovirus (CMV) infection is still a problem for organ transplant recipients despite studies that long-term prophylaxis with high dose of acyclovir or ganciclovir given to all organ recipients may limit the consequences of infection and disease. In the present report of 160 consecutive renal transplant patients, we used a diagnostic assay for CMV antigenemia (detection of CMV antigen in peripheral blood leukocytes) and treated with ganciclovir only those patients who had a positive test. No patient in this series had routine prophylaxis. Out of 160 patients, 71 had clinical and/or laboratory signs of infection, and were tested for early antigen in peripheral leukocytes. The test was positive in 35, all of whom received a course of 3 wk ganciclovir treatment which effectively cured CMV in 34 count of 35. One patient was ganciclovir-resistant, but responded to foscarnet. None of the 36 patients who had no early antigenemia and did not receive treatment developed the disease. The treatment was extremely well tolerated in all our patients with no adverse events. Thus, even though this was not a controlled study, our present results may be taken to indicate that long-term acyclovir or ganciclovir for all organ transplant recipients might be no longer totally justified. We conclude that detecting viral antigen in circulating leukocytes identifies patients who are indeed at risk of developing severe CMV disease. When these patients are treated early enough, CMV is eliminated with a relatively short course of ganciclovir, which has virtually no side effects.
Adolescent↗
The renoprotective action of angiotensin-converting enzyme inhibitors in diabetes.
Chronic renal diseases evolve to terminal renal failure by a process leading to progressive parenchymal damage which appears relatively independent of the initial insult. When glomerular permselectivity is lost, proteins filtered through the glomerular capillary, via proximal tubular cell activation and upregulation of genes of inflammatory and vasoactive mediators, may give rise to an inflammatory reaction that in the long-term can contribute to renal scarring. If this interpretation is correct, the best approach to try to retard the progression of several renal diseases would be to limit the excessive traffic of macromolecules throughout the glomerular capillary by molecules such as the angiotensin-converting-enzyme (ACE) inhibitors, which may help restore permselective properties to normal. Thus, the present review addresses the mechanism(s) of the renal protective effect of ACE inhibitors and analyzes the evidence so far available of their salutary effect in human nephropathies, with particular focus on diabetic nephropathy.
Albuminuria↗
Verotoxin-1 promotes leukocyte adhesion to cultured endothelial cells under physiologic flow conditions.
Hemolytic uremic syndrome (HUS), which is the most common cause of acute renal failure in infants and small children, is caused by verotoxin (VT)-producing Escherichia coli infection. Endothelial injury determines microvascular thrombosis and evidence is available from recent studies that suggests that leukocyte activation participates in endothelial damage. We studied here the effect of VT-1 on leukocyte adhesion to vascular endothelium under physiologic flow conditions. Human umbilical vein endothelial cells (HUVECs) were incubated for 24 hours with VT-1 (0.1, 1, and 10 pmol/L) and then exposed to a total leukocyte suspension in a parallel plate flow chamber under laminar flow conditions (1.5 dynes/cm2). Adherent cells were counted by digital image processing. Results showed that VT-1 dose-dependently increased the number of adhering leukocytes to HUVECs as compared with unstimulated cells. The adhesive response elicited by VT-1 was comparable to that of interleukin-1 beta (IL-1 beta), one of the most potent inducers of endothelial cell adhesiveness. Exposure of HUVECs to VT-1 did not affect the number of rolling leukocytes, which was similar to that of control values. To examine the role of adhesion molecules in VT-1-induced leukocyte adhesion, HUVECs were incubated with mouse monoclonal antibodies against E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) before adhesion assay. Functional blocking of E-selectin, ICAM-1, and VCAM-1 on endothelial cells significantly inhibited VT-1-induced increase in leukocyte adhesion. In some experiments, before VT-1 incubation, HUVECs were pretreated for 24 hours with tumor necrosis factor alpha (TNF alpha; 100 U/mL), which is known to increase VT receptor expression on HUVECs. The number of adhering leukocytes on HUVECs exposed to TNF alpha and VT-1 significantly increased as compared with HUVECs incubated with VT-1 and TNF alpha alone. These results suggest that VT-1 modulates leukocyte-endothelium interaction, thus increasing leukocyte adhesion and upregulating adhesive proteins on endothelial surface membrane.
Animals↗
Clinical problem solving. The girl with the curl.
Explore the source record for details and available documents.
Acyclovir↗
Fluid shear stress modulates surface expression of adhesion molecules by endothelial cells.
We investigated the effect of hemodynamic shear forces on the expression of adhesive molecules, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) on human umbilical vein endothelial cells (HUVEC) exposed to laminar (8 dynes/cm2) or turbulent shear stress (8.6 dynes/cm2 average), or to a static condition. Laminar flow induced a significant time-dependent increase in the surface expression of ICAM-1, as documented by flow cytometry studies. Endothelial cell surface expression of ICAM-1 in supernatants of HUVEC exposed to laminar flow was not modified, excluding the possibility that HUVEC exposed to laminar flow synthetize factors that upregulate ICAM-1. The effect of laminar flow was specific for ICAM-1, while E-selectin expression was not modulated by the flow condition. Turbulent flow did not affect surface expression of either E-selectin or ICAM-1. To evaluate the functional significance of the laminar-flow-induced increase in ICAM-1 expression, we studied the dynamic interaction of total leukocyte suspension with HUVEC exposed to laminar flow (8 dynes/cm2 for 6 hours) in a parallel-plate flow chamber or to static condition. Leukocyte adhesion to HUVEC pre-exposed to flow was significantly enhanced, compared with HUVEC maintained in static condition (233 +/- 67 v 43 +/- 16 leukocytes/mm2, respectively), and comparable with that of interleukin-1 beta treated HUVEC. Mouse monoclonal antibody anti-ICAM-1 completely blocked flow-induced upregulation of leukocyte adhesion. Interleukin-1 beta, which upregulated E-selectin expression, caused leukocyte rolling on HUVEC that was significantly lower on flow-conditioned HUVEC and almost absent on untreated static endothelial cells. Thus, laminar flow directly and selectively upregulates ICAM-1 expression on the surface of endothelial cells and promotes leukocyte adhesion. These data are relevant to the current understanding of basic mechanisms that govern local inflammatory reactions and tissue injury.
Antibodies, Monoclonal↗
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↗
Role of platelets in progressive glomerular diseases.
There is increasing evidence that platelets are involved in the pathogenesis of glomerulonephritis. Intraglomerular platelets or their degradation products are observed in biopsies from patients with lupus nephritis, mesangioproliferative, membranous or IgA nephropathy. Moreover shortened platelet survival in patients with various glomerular diseases has also been described. In models of experimental glomerulonephritis, platelets may participate in glomerular injury, together with other mediators, by complex mechanisms. As extensively documented, platelets release within the glomerulus vasoactive, chemotactic and mitogenic substance that interact with a number of soluble mediators generated by renal resident or inflammatory cells and contribute to amplify glomerular injury. Thus platelet-activating factor and other platelet secretory products, polycationic macromolecules, platelet factor 4 and beta-thromboglobulin, alter glomerular permeability to proteins and enhance immune-mediated glomerular injury. Platelet-derived factors, like platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF beta) mediate renal disease progression in experimental and human glomerulonephritis via their chemotactic activity for infiltrating leucocytes and their effect of promoting extracellular matrix synthesis by resident renal cells. In these settings increased renal expression of PDGF and TGF beta has correlated with clinical features. Specific PDGF and TGF beta inhibitors ameliorated experimental glomerular disease. A wide variety of therapies to inhibit platelet function have been employed over the years, however the results of clinical studies are controversial and do not allow conclusions to be drawn about the efficacy of anti-platelet agents in progressive renal disease. Identification of specific platelet inhibitors or interventions specific for platelet secretory products and their target cells will be crucial for understanding the exact role of platelets and their products in glomerular disease.
Animals↗
Proximal tubular cell synthesis and secretion of endothelin-1 on challenge with albumin and other proteins.
Abnormal traffic of proteins through the glomerular capillary has an intrinsic renal toxicity possibly linked to the subsequent process of over-reabsorption by proximal tubular cells. We investigated in vitro the effect of different protein concentrations on proximal tubular cell endothelin-1 (ET-1) synthesis. Rabbit proximal tubular RC.SV1 cell line was grown to confluence in serum-free hormonally defined medium. Cells were incubated for 6 and 24 hours with serum-free medium containing bovine serum albumin (BSA, 0.1 to 10 mg/mL). ET-1, a locally released hormone that stimulates cell proliferation and promotes extracellular matrix protein synthesis, was measured in cell supernatant by radioimmunoassay. BSA induced a significant dose-dependent increase in proximal tubular cell ET-1 synthesis. BSA and fatty acid-free BSA stimulated tubular ET-1 synthesis and release to a comparable extent, indicating that the lipid component of the molecule is not involved in the observed phenomenon. Experiments in which tubular cells grown on filters in bicameral systems were incubated with BSA (10 mg/mL) showed that ET-1 release was predominantly basolateral. The stimulatory effect on tubular ET-1 synthesis and release was not specific to albumin but was shared by immunoglobulin (Ig) G and transferrin. Exposure of proximal tubular cells for 6 and 24 hours to both proteins (1 and 10 mg/mL) resulted in a dose-dependent increase in ET-1 synthesis. These data suggest that overexposure of proximal tubular cells to proteins, as it occurs in vivo in proteinuric renal diseases, may promote excessive tubular synthesis of ET-1, which is mostly secreted toward the interstitial compartment.(ABSTRACT TRUNCATED AT 250 WORDS)
Albumins↗