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Biomedical subjects

G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 235 records · Page 13Linked to original sources
PubMed1995

The effects of nonsteroidal anti-inflammatory drugs on glomerular filtration of proteins and their therapeutic utility.

Cyclooxygenase inhibitors have long been used in experimental studies as well as in clinical practice to reduce urinary protein excretion in proteinuric renal diseases. However, the mechanisms by which this treatment limits glomerular filtration of proteins are not fully elucidated. We will review the cellular and molecular mechanisms that regulate glomerular permselectivity and the experimental observations available on the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on these glomerular functions. The effects of NSAIDs on glomerular microcirculation will also be analyzed in comparison with another class of drugs used to lower proteinuria in nephrotic patients, the angiotensin converting enzyme inhibitors. Finally, we will analyze the relationship between urinary prostaglandins and thromboxane A2 and discuss the effects of modulating these hormones on glomerular functions.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

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↗
PubMed1995

Cyclosporine-induced renal dysfunction in experimental animals and humans.

Cyclosporine (CsA) has improved one-year allograft survival in renal, liver, heart and pancreas transplantation, and has now also been advocated as a promising treatment for some autoimmune diseases. However, the use of CsA is associated with major nephrotoxicity, very likely a consequence of its toxic effect on vascular endothelium as consistently documented in experimental animals and humans. Evidence is now available that in kidney transplant recipients each oral dose of CsA is followed by a transient reduction in renal plasma flow and glomerular filtration rate that results from a form of acute reversible renal hypoperfusion. The repeated daily episodes of acute renal hypoperfusion might explain the structural alterations of pre-glomerular vessels and glomerular obsolescence well documented in transplant recipients on chronic CsA for more than two years. In heart transplant recipients CsA measurements of renovascular pressures and flows and analysis of transglomerular sieving of dextrans showed that renal vascular resistance was elevated more than twofold, due largely to an increase in pre-glomerular resistance. Three-dimensional reconstruction of individual glomeruli showed a distribution of capillary tuft volume shifted to both smaller and larger glomeruli in CsA-treated patients and 40% of glomeruli had global or segmental sclerotic changes. However, the potential for glomerulosclerosis lesions that may develop in humans given CsA has been a major source of concern, since it has not been considered a direct consequence of CsA toxicity but rather due to the concomitant chronic rejection (as for kidney transplant) or renal hypoperfusion (as for heart transplant). Recent findings in a rat model of renal isograft showed that daily administration of CsA for 12 months induced glomerulosclerosis, and that the lesions are quite comparable to the ones reported in humans with renal and heart transplants. Strategies for optimizing CsA treatment or associated drugs that may reduce pre-glomerular vascular resistance should be part of future approaches for preventing CsA nephrotoxicity.

Animals↗
PubMed1994

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↗
PubMed1994

Mechanisms of acquired thymic unresponsiveness to renal allografts. Thymic recognition of immunodominant allo-MHC peptides induces peripheral T cell anergy.

We have recently shown that a single intrathymic injection of synthetic 25mer peptides, representing full sequences of the hypervariable domain of RT1.BuB (4 peptides) and RT1.Du beta (4 peptides) WF class II MHC molecules, 48 hr before transplantation induces donor-specific unresponsiveness to WF rat renal allografts in adult LEW recipients. The induction of unresponsiveness was abrogated by the recipient's thymectomy within the first week after intrathymic injection. Peripheral T cells of long-term survivors exhibited antigen-specific hyporesponsiveness in the LEW x WF MLR. Studies on the mechanisms of induction of acquired thymic unresponsiveness to alloantigen in vivo and in vitro are now reported. First, since we have previously demonstrated in LEW responders that only 4 of the 8 synthetic 25mer peptides, 2 RT1.Du beta and 2 RT1.Bu beta sequences, were immunogenic in vitro and in vivo, we compared the tolerogenicity of the immunogenic versus the nonimmunogenic peptides. While LEW rats intrathymically injected with the nonimmunogenic peptides acutely rejected their renal allografts within 6-10 days, animals injected with the immunogenic peptides did not reject their grafts and are surviving > 100 days with normal allograft function. In vitro studies established that peripheral T cells from intrathymically tolerized animals exhibited antigen-specific hyporesponsiveness in the LEW x WF MLR starting as early as 1 week posttransplant. Immunohistological evaluation of renal allografts from intrathymically tolerized animals 1 week postengraftment showed marked reduction in mononuclear cell infiltrates with no evidence of tubulitis, and marked reduction in intragraft staining for activation and inflammatory cytokines and alloantibodies, as compared with acutely rejecting controls. Systemic administration of 1000 U of rIL-2 daily for 5 days starting on the day of transplantation abrogated the tolerogenic effect of intrathymic MHC allopeptides. Injection of 100 micrograms of a single immunogenic peptide, RT1.Du beta 2 (residues 20-44), into the thymus of responder LEW rats 48 hrs before immunization with RT1.Du beta 2 effected significant reduction of in vitro proliferation of primed lymphocytes to RT1.Du beta 2, an effect that was abrogated by addition of rIL-2 in vitro. In contrast, thymectomy beyond 2 weeks and administration of rIL-2 at 4-6 weeks after transplantation failed to cause rejection. These observations indicate that thymic recognition of immunodominant class II MHC allopeptides leads to peripheral T cell anergy that mediates the induction phase of systemic unresponsiveness to renal allografts. The maintenance phase appears to be mediated by dense anergy or clonal deletion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Pancreas and kidney/pancreas transplants: experimental medicine or real improvement?

Although 4000 pancreas transplants have now been done, alone or in combination with a kidney transplant, the risk/benefit profile of the procedure has not been established by controlled studies. A solo pancreas transplant abolishes the need for daily insulin but requires chronic immunosuppression, has high failure rates, and is not proved to lessen the chronic complications of diabetes. Thus, it is probably justified only in those diabetic patients with incapacitating disease. For uraemic diabetic patients, combined pancreas and kidney transplantation often removes dependence on both insulin and dialysis, and has lower rejection rates than pancreas transplant alone. However, it needs more immunosuppression than kidney transplant alone, has no proven benefit on chronic complications of diabetes, and carries an increased risk of rejection, infection, and cancer. Living-related-donor kidney transplantation followed by cadaver pancreas transplantation is a possible alternative. Transplantation of pancreatic islets could offer the advantages of strict metabolic control without the drawbacks of immunosuppressive therapy. Thus, research efforts should concentrate on immune-protected islet transplantation. An alternative approach to avoiding long-term immunosuppression is the promotion of allograft tolerance.

Diabetes Mellitus↗
PubMed1994

Following an initial decline, glomerular filtration rate stabilizes in heart transplant patients on chronic cyclosporine.

We previously reported that heart transplant patients given cyclosporine for more than 2 years (short-term evaluation) had severe renal lesions and markedly reduced glomerular filtration rate and renal plasma flow (Kidney Int 40:243-250, 1991). We report the analysis of renal function in the same patients after 3 additional years of follow-up (long-term evaluation) while they continued to take cyclosporine. Since the previous evaluation, the dose of cyclosporine was adjusted to maintain stable trough levels and antihypertensive therapy was unchanged. The mean time-averaged dose of cyclosporine during the follow-up was 4.5 +/- 2.1 mg/kg/d. The systolic blood pressure at long-term evaluation (146 +/- 16 mm Hg) was increased (P < 0.05) compared with that at short-term evaluation (140 +/- 13 mm Hg), whereas diastolic blood pressure (long-term 91 +/- 9 mm Hg v short-term 88 +/- 9 mm Hg) and mean blood pressure (long-term 110 +/- 12 mm Hg v short-term 108 +/- 11 mm Hg) did not change significantly. Serum creatinine concentrations at long-term (1.7 +/- 0.3 mg/dL) and at short-term (1.7 +/- 0.4 mg/dL) evaluations were similar. At long-term evaluation the renal plasma flow (300 +/- 64 mL/min/1.73 m2) was not decreased compared with that at short-term evaluation (325 +/- 94 mL/min/1.73 m2), while the glomerular filtration rate increased significantly (43 +/- 15 mL/min/1.73 m2 v 36 +/- 8 mL/min/1.73 m2, respectively; P < 0.05). None of the patients became proteinuric after short-term evaluation; in those patients who were already proteinuric, urinary protein excretion did not increase over time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Long-term treatment with either enalapril or nitrendipine stabilizes albuminuria and increases glomerular filtration rate in non-insulin-dependent diabetic patients.

The effect of short- (98 days) and long-term (1 year) treatment with nitrendipine (10 to 40 mg/d) and enalapril (5 to 20 mg/d) on kidney function was studied prospectively in a parallel group design in 16 microalbuminuric non-insulin-dependent diabetic patients with mild hypertension and biopsy-proven diabetic glomerulopathy. At the end of the short-term treatment period diastolic blood pressure significantly decreased from 95.4 +/- 2.5 mm Hg to 83.5 +/- 3.5 mm Hg (P < 0.001) in the nitrendipine group and from 96.7 +/- 2.5 to 86.7 +/- 5.6 mm Hg (P < 0.001) in the enalapril group. Both overnight urinary albumin excretion rate and albumin fractional clearance tended to increase in the nitrendipine group and to decrease in the enalapril group, whereas the glomerular filtration rate and the renal plasma flow were similar to baseline in both study groups. At the end of the long-term treatment period diastolic blood pressure significantly decreased from 95.4 +/- 2.5 mm Hg to 86.0 +/- 6 mm Hg (P < 0.005) in the nitrendipine group and from 96.7 +/- 2.1 to 90.8 +/- 4.3 mm Hg (P < 0.05) in the enalapril group. Overnight urinary albumin excretion and albumin fractional clearance were similar to baseline in both study groups. The glomerular filtration rate significantly increased from 70.2 +/- 14.2 to 96.8 +/- 20.4 (P < 0.05) in the nitrendipine group and from 58.9 +/- 10.7 to 78.5 +/- 11.0 (P < 0.05) in the enalapril group. The renal plasma flow also significantly increased from 456.6 +/- 165.3 to 597.2 +/- 178.9 (P < 0.01) in the nitrendipine group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Treatment of idiopathic membranous glomerulopathy.

The treatment of membranous nephropathy, the most common form of glomerular diseases causing nephrotic syndrome in adults, is still debated. A considerable percentage of patients have a spontaneous remission of the disease and reduction of urinary protein excretion with time. Studies in the past have indicated that prednisone may have beneficial effects, but this has not been confirmed by more recent investigation. Others have studied the association of methylprednisolone with cyclophosphamide or chlorambucil, but results are conflicting. The main reasons for the conflicting data are the variety of clinical presentations of the disease and the different study populations. Most trials performed so far have not included enough patients in each category to adequately detect differences between treatment groups and placebo groups. Several studies with few numbers of patients reported that cyclosporine effectively reduced proteinuria and may have less long-term toxicity than more conventional immunosuppressants. This finding, however, must be verified by appropriate clinical trials.

Clinical Trials as Topic↗
PubMed1994

Calcitonin gene-related peptide reduces renal vascular resistance and modulates ET-1-induced vasoconstriction.

Calcitonin gene-related peptide (CGRP) is a novel polypeptide that exerts important effect on the cardiovascular system through its vasorelaxant properties. We studied in vivo in normal rats the effect of acute administration of CGRP on whole kidney function and showed that the intravenous infusion of the peptide resulted in a fall of blood pressure associated with a marked increase in renal plasma flow (RPF) as well as glomerular filtration rate (GFR). These changes were reversible with discontinuation of CGRP infusion. To evaluate whether the renal hemodynamic responses to the peptide were mediated by endogenous vasodilatory prostaglandins of endothelial origin, animals were preexposed to indomethacin, a cyclooxygenase enzyme inhibitor. Inhibition of prostaglandins synthesis with indomethacin failed, however, to prevent the increase in RPF and GFR observed during CGRP infusion. By contrast, NG-nitro-L-arginine methyl ester (L-NAME), which inhibits the synthesis of nitric oxide, a newly discovered endothelium-derived relaxing factor, completely abolished the renal hemodynamic changes induced by CGRP. Moreover, L-arginine infusion in L-NAME-treated rats restored the renal response to CGRP. We have also shown that systemic infusion of CGRP progressively normalized RPF and GFR that were reduced in response to a bolus intravenous injection of the vasoconstrictor endothelin-1. This indicates that CGRP regulates renal hemodynamics and modulates the deleterious effects of vasoconstrictive substances on the kidney.

Animals↗
PubMed1994

Dissociation between antiproteinuric and antihypertensive effect of angiotensin converting enzyme inhibitors in rats.

To clarify whether angiotensin converting enzyme (ACE) inhibitors prevent progressive renal injury directly by their antihypertensive effect we administered the ACE inhibitor lisinopril to male MWF/Ztm rats as a single daily dose that lowered blood pressure for only 9 of 24 h. We investigated the effects of this treatment in short- and long-term studies and compared them with another antihypertensive drug, the calcium channel blocker nitrendipine, given to partially control blood pressure as done with the ACE inhibitor. In untreated animals systemic hypertension, proteinuria, and glomerulosclerosis developed spontaneously with age, and lisinopril reduced systemic hypertension and prevented proteinuria and glomerular lesions. Nitrendipine, despite similar blood pressure control, was ineffective in preventing both proteinuria and glomerulosclerosis. After 2 mo of treatment glomerular capillary pressure was significantly reduced by lisinopril and slightly but significantly increased by nitrendipine, compared with untreated controls. The ultrafiltration coefficient was significantly higher in lisinopril than in controls and not significantly changed by nitrendipine. With both drugs, however, glomerular hemodynamic effects were observed only at a few hours after administration and were abolished before the next administration. No significant changes in glomerular tuft volume were observed in treated and untreated animals after 2 and 6 mo of observation. Thus ACE inhibitor, despite only partial control of systemic blood pressure, effectively prevented proteinuria and glomerular injury. Comparable blood pressure control obtained with a calcium channel blocker was not associated with renal protection. These results suggest that ACE inhibitors could protect glomerular microcirculation by a mechanism that is not directly related to their antihypertensive action.

Alpha-Globulins↗
PubMed1994

Evidence that an angiotensin-converting enzyme inhibitor has a different effect on glomerular injury according to the different phase of the disease at which the treatment is started.

In rats with streptozotocin-induced diabetes, the effect of an angiotensin-converting enzyme (ACE) inhibitor on the evolution of glomerular injury according to the time at which the treatment is started with respect to the onset of the disease was studied. Three groups of animals were used, a control Group 1 and two groups of diabetic rats treated with insulin (Groups 2 and 3). The latter were monitored until urinary protein excretion reached 40 to 50 mg/24 h (on average, 23 wk after the induction of the diabetes). At this time, Group 2 continued to receive insulin alone, whereas Group 3 was also given the ACE inhibitor moexipril for 8 more wk. Untreated diabetic rats showed a moderate increase in systolic blood pressure that was normalized by moexipril administration. Urinary protein excretion progressively increased during the 8-wk follow-up in untreated diabetics that, at the end of the study, developed moderate glomerular sclerosis. Moexipril treatment lowered urinary protein excretion to a normal range and completely prevented glomerular injury. Three other groups of rats were similarly treated, except that moexipril treatment was started later on (when proteinuria reached 100 to 200 mg/24 h, on average, 32 wk after the induction of diabetes), and were monitored for another 8 wk. Untreated and treated diabetics had comparable blood glucose levels throughout. Systolic blood pressure, significantly increased in untreated diabetic rats, was effectively controlled by moexipril administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Effects of angiotensin-converting enzyme inhibition on glomerular capillary wall ultrastructure in MWF/Ztm rats.

Previous studies have documented that treatment with angiotensin-converting enzyme (ACE) inhibitors prevents spontaneous proteinuria and enhances the glomerular ultrafiltration coefficient in male MWF/Ztm rats. The aim of this study was to study whether these beneficial effects of ACE inhibitors on glomerular capillary wall function are derived from the preservation of its ultrastructure. Conventional morphometrical analysis of kidney tissue, by light and electron microscopy, was used to quantify glomerular structural changes in the male MWF/Ztm rats treated with the ACE inhibitor cilazapril for 2 and 6 months and in age-matched untreated controls. At the end of the observation periods, both systolic blood pressure and urinary protein excretion were significantly reduced in treated animals as compared with controls. Glomerular volume increased significantly with time but was comparable in control and in treated rats. Surface area available for filtration (measured as peripheral capillary wall) was comparable in control and in treated animals at the same time and increased significantly with time only in treated rats. Mesangial volume was significantly higher in cilazapril-treated animals than in controls after 2 months of treatment and was comparable after 6 months. ACE inhibitor treatment did not induce significant ultrastructural changes such as basement membrane thickness, configuration of epithelial podocytes, and the width and the frequency of the epithelial slit diaphragms. These results indicate that the previously observed increase in the glomerular ultrafiltration coefficient by an ACE inhibitor in these animals is not the consequence of changes in filtering surface area but likely reflects an increase in membrane hydraulic permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗