ACEI和（或）ARB基础上联合安体舒通治疗IgA肾病的研究

目的探讨应用血管紧张素转化酶抑制剂（ACEI）和（或）血管紧张素受体拮抗剂（ARB）联合安体舒通治疗IgA肾病患者,观察其降低尿蛋白及肾脏保护作用。方法将54例IgA肾病患者随机分为安体舒通组（A组）27例,对照组（B组）27例。A组在应用ACEI和（或）ARB基础上联合安体舒通20mg／d;B组按原量服用ACEI和（或）ARB药物。检测2组在第0、4、8、12、16周时24h尿蛋白、血肌酐、血钾、血浆醛固酮、血压、估算肾小球滤过率（eGFR）。结果A组治疗后第8周时尿蛋白较治疗前下降18．5％（P〈0．05）,至第16周时下降35．1％（P〈0．01）;B组至治疗终点仅下降5．3％,无统计学差异（P〉0．05）。2组血钾、血肌酐、eGFR、血浆醛固酮、血压较治疗前无显著变化（P〉0．05）。结论在应用ACEI和（或）ARB基础上联合安体舒通对降低kA肾病患者尿蛋白有显著作用。     

Renal expression of matrix metalloproteinases in human ANCA-associated glomerulonephritis.

BACKGROUND: Expression of matrix metalloproteinases (MMPs) by infiltrating and intrinsic renal cells is increased in inflammatory conditions, and may correlate with disease activity of glomerulonephritis. We analysed renal expression of MMPs, tissue inhibitor of metalloproteinase-1 (TIMP-1) and markers of neutrophil and monocyte infiltration in renal biopsies of patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: Immunohistochemical expression of MMP-2, -3, -9, TIMP-1, the neutrophil- and monocyte-derived MMP activators cathepsin G, neutrophil elastase and myeloperoxidase (MPO), and the monocyte marker CD14 was determined in renal biopsies of active proteinase 3 (PR3)-ANCA (n = 7) and MPO-ANCA (n = 6) associated glomerulonephritis, and in normal renal tissue (n = 4). Double labelling experiments of MMPs and TIMP-1 were performed with MPO and CD68, labelling neutrophils and macrophages. RESULTS: MMP-2-, MMP-3-, MMP-9- and TIMP-1-positive cells were detected in ANCA-associated glomerulonephritis in glomeruli with active inflammation (cellular crescents or fibrinoid necrosis), only occasionally in normal appearing glomeruli, and not in sclerotic glomeruli and positive cells were found in the tubulo-interstitium. MMPs and TIMP-1 were expressed predominantly by MPO-and CD68-positive cells. In normal renal tissue, no expression was detected, with the exception of weak mesangial staining for MMP-2. In ANCA-associated glomerulonephritis, glomerular MMP-2, -9 and TIMP-1 correlated with glomerular cathepsin G expression, while the number of MMP-9-expressing cells per glomerulus correlated with the percentage of crescentic glomeruli. Tubulo-interstitial expression of MMPs correlated with all markers of neutrophil and monocyte infiltration, and interstitial MMP-9 and TIMP-1 expression correlated with renal function at the time of renal biopsy. CONCLUSIONS: Expression of glomerular and interstitial MMP-2, -3, -9 and TIMP-1 is increased in active ANCA-associated glomerulonephritis and correlates with inflammatory activity.     

No impact of hyperkalaemia with renin-angiotensin system blockades in maintenance haemodialysis patients.

BACKGROUND: Renin-angiotensin system (RAS) blockades, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are well accepted for the cardiorenal-protective benefits added to antihypertensive effects in chronic kidney diseases (CKD), but associated with an increased risk of hyperkalaemia. However, few studies have investigated the effect of RAS blockades on serum potassium in dialysis patients. METHODS: Hyperkalaemia associated with RAS blockades by ACEI and/or ARB was evaluated in 69 patients on maintenance haemodialysis, who underwent a three-period crossover study in four groups (no exposure to RAS blockades, ACEI or ARB alone and ACEI plus ARB treatments), lasting one month in each period. RESULTS: Sixty-two patients completed this prospective 3-month study, and no one stopped the study because of the development of hyperkalaemia and/or complications. Mean serum K was similar among the four periods (no exposure, 5.54+/-0.67 mmol/l; ACEI alone, 5.54+/-0.75 mmol/l; ARB alone, 5.50+/-0.66 mmol/l; ACEI+ARB combination, 5.42+/-0.66 mmol/l) and was also equal when compared between the two groups with and without exposure to RAS blockades (5.48+/-0.68 vs 5.54+/-0.67 mmol/l, P=NS). The incidence of severe hyperkalaemic episodes (>6.0 mmol/l) upon monthly predialysis serum K determination was 25.8% with no exposure to RAS blockades, 29.8% for ACEI alone, 19.6% for ARB alone and 17.7% for ACEI+ARB combination without statistically significant differences among the four periods (P=NS). Among covariables, the degree of Kt/V, intakes of other medications interfering with potassium homeostasis and diabetes mellitus did not result in any significant hyperkalaemic changes during the 3-month study period except anuric patients compared with non-anuric patients (5.58+/-0.69 vs 5.19+/-0.65 mmol/l, P<0.001). CONCLUSION: Neither monotherapy (ACEI or ARB) nor combination therapy (ACEI plus ARB) is associated with the additional risk of hyperkalaemia in patients on maintenance haemodialysis. However, those patients with anuria on RAS blockades warrant the cautious monitoring of serum K to prevent hyperkalaemia.     

Expression of MMP-9 in mesangial cells and its changes in anti-GBM glomerulonephritis in WKY rats

Background Matrix metalloproteinase (MMP)-9, a member of the MMP family with specificity towards type IV collagen, is implicated in the turnover of the extracellular matrix in the kidney. To elucidate its physiological and pathophysiological significance, we examined the expression and localization of MMP-9 in the normal kidney and the changes in these features during the course of anti-glomerular basement membrane (GBM) glomerulonephritis induced in WKY rats, along with the changes in these features of tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-2.Methods The expression of MMP-9, TIMP-1 and MMP-2 mRNA was quantified by ribonuclease protection assay, and the gelatinolytic activities of MMP-9 and MMP-2 were evaluated by gelatin zymography. The localization of MMP-9 was visualized by immunohistochemistry and immunofluorescence microscopy.Results The ribonuclease protection assay indicated the almost exclusive expression of MMP-9 mRNA in the glomerulus of normal kidneys. Immunohistochemistry and double-label immunofluorescence microscopy showed that MMP-9 was localized in the mesangial cells. During the course of anti-GBM glomerulonephritis, the expression of MMP-9 mRNA in glomeruli increased on day 1, peaked on days 3 to 7, and then decreased on day 14. The change in MMP-9 mRNA expression was accompanied by parallel changes in the gelatinolytic activity of the active form of MMP-9, TIMP-1 mRNA expression, and MMP-9 immunoreactivity in mesangial cells. In contrast, glomerular MMP-2 mRNA expression and its activity increased after the decline of MMP-9.Conclusions MMP-9 mRNA was predominantly expressed in the glomerulus in normal rat kidneys and MMP-9 was present in the mesangium. The MMP-9 mRNA expression increased in the glomerulus 3 to 7 days after the induction of anti-GBM glomerulonephritis in WKY rats, in parallel with the development of abnormal glomerular histology and injury, suggesting a role of MMP-9 in proteolysis of the GBM during glomerulonephritis. MMP-2 may participate in the later phase of the nephritis.     

Basic fibroblast growth factor mediates carotid plaque instability through metalloproteinase-2 and -9 expression.

OBJECTIVE(S): We hypothesized that basic fibroblast growth factor (bFGF) may exert a role in carotid plaque instability by regulating the expression of matrix metalloproteinases (MMP). METHODS: Plaques obtained from 40 consecutive patients undergoing carotid endarterectomy were preoperatively classified as soft or hard. Serum bFGF was pre- and postoperatively measured. The release of MMP-2 and MMP-9 in the blood serum, and the activity, production and expression in the carotid specimens was analyzed. Specific anti-bFGF inhibition tests were performed in vitro on human umbilical artery smooth muscle cells (HUASMC) to evaluate the role of bFGF in the activity, production and expression of MMP-2 and -9. RESULTS: Twenty-one (53%) patients had a soft carotid plaque and 19 (48%) a hard plaque. Preoperative bFGF serum levels were higher in patients with soft plaques [soft=34 (28-39) pg/mL and hard=20 (17-22) pg/mL-p<0.001] and postoperatively returned to normal values (when compared to 10 healthy volunteers). The serum levels of MMP-2 in patients' with soft plaques were higher than those in patients' with hard plaques [soft=1222 (1190-1252) ng/mL and hard=748 (656-793)ng/mL-p<0.0001]. MMP-9 serum values were 26 (22-29) ng/mL for soft plaques and 18 (15-21) ng/mL for hard plaques (p<0.0001). We found increased activity, production and expression of MMP-2 and -9 in soft plaques compared to hard plaques (p<0.001). In vitro inhibition tests on HUASMC showed the direct influence of bFGF on the activity, production and expression of MMP-2 and -9 (p<0.001). CONCLUSIONS: bFGF seems to exert a key role in carotid plaque instability regulating the activity, production and expression of MMP thus altering the physiologic homeostasis of the carotid plaque.     

Serum matrix metalloproteinase MMP-2 and MMP-9 in the late phase of ischemia and reperfusion injury in human orthotopic liver transplantation

INTRODUCTION: Ischemia and reperfusion (I/R) injury during orthotopic liver transplantation (OLT) is accompanied by neutrophil infiltration and degradation of extracellular matrix. Matrix metalloproteinases (MMP) play an important role in the turnover of extracellular matrix components. We assessed the changes in level and composition of serum MMP-2 and MMP-9 in relation with I/R injury after human OLT. METHODS: Thirty-three patients were separated into two groups according to their peak level of aspartate aminotransferase (AST) after OLT (AST < 1500 IU/L: n = 22; AST > 1500 IU/L: n = 11). Serum MMP-2 and MMP-9 were measured before transplantation as well as 2 days and 1 week after OLT using ELISA (MMP protein) and BIA (enzymatic activity of MMP). RESULTS: MMP-2 and MMP-9 protein concentrations were comparable before and 2 days after OLT, whereas at 1 week MMP-2 decreased and MMP-9 increased significantly. However, there were no significant differences between patients with high or low peak AST at all time points. Also, the composition of MMP-2 and MMP-9 did not differ over time between the groups of patients. CONCLUSION: Serum MMP-2 and MMP-9 do not relate to the late phase of hepatic I/R injury after human OLT.     

Characterization of matrix metalloproteinases in human urine: alterations during adolescence

 Matrix metalloproteinases (MMPs) are a family of at least 14 zinc-dependent proteinases that have been implicated in matrix turnover under both normal and pathological conditions. Previous studies have shown that several MMPs are produced in various cell types in the kidney, suggesting that MMPs may be involved in renal morphogenesis and remodelling. Using a variety of techniques, including gelatin and casein zymography, gelatin affinity chromatography, immunoblotting, and immunoprecipitation, we have identified the major gelatinases in human urine as MMP-2 and MMP-9. Latent forms of both enzymes were detected in urine, as well as lower molecular mass species of each, consistent with activated forms of MMP-2 and MMP-9. MMP-2 and MMP-9 were also measured in individual human urine samples (n=40). No significant gender differences in MMP concentrations were detected. However, renal MMP expression appeared to be age dependent; the highest average amounts of urine MMP-2 were detected during adolescence, while the converse was true of urine MMP-9. Together, these findings indicate that under normal conditions, human urine contains MMP-2 and/or MMP-9, suggesting that these two MMPs are normally produced within the kidney, where they may regulate normal renal remodelling and matrix homeostasis in an age-specific manner. Received: 9 February 1998 / Revised: 27 July 1998 / Accepted: 28 July 1998     

Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor in patients with chronic glomerulonephritis

Angiotensin II type-1 receptor blocker (ARB) and angiotensin-converting enzyme inhibitor (ACEI) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis. Recently, an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy, but the mechanism responsible for the effect has not yet been determined. In this study, we examined additive effect of these two drugs in chronic glomerulonephritis patients. Ten patients with biopsy-proven primary glomerulonephritis (eight IgA nephropathy patients, two membranous nephropathy patients), non-nephrotic proteinuria (protein, 0.5 to 3.5 g/day) received candesartan cilexetil (2 or 4 mg) for 8 weeks. After the 8 weeks, a combination of perindopril erbumine (1 or 2 mg) and candesartan cilexetil was administered to the patients. Perindopril was stopped after the 8-week administration of the two drugs. Candesartan alone reduced proteinuria by 13%. Combination of these two drugs induced a more remarkable reduction of proteinuria (48%; p < 0.05 vs other periods). The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria. The combination of drugs also reduced the amount of urinary type-IV collagen excretion. An additive effect of ACEI and ARB on proteinuria and urinary type-IV collagen excretion was recognized in patients with chronic glomerulonephritis.     

Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism

We investigated the effect of the angiotensin type 1 (AT-1) receptor antagonist, irbesartan, on matrix metalloproteinase (MMP) activity and cardiac cytokines in an animal model of diabetic cardiomyopathy. Diabetes was induced in 20 C57/bl6 mice by injection of streptozotocin (STZ). These animals were treated with irbesartan or placebo and were compared with nondiabetic controls. Left ventricular (LV) function was measured by pressure-volume loops with parameters for systolic function (end systolic elastance [Ees]) and diastolic function (cardiac stiffness) 8 weeks after STZ treatment. The cardiac protein content of interleukin (IL)1beta and transforming growth factor (TGF)beta1 were measured by enzyme-linked immunosorbent assay. The total cardiac collagen content and collagen type 1 and 3 were measured by histochemistry, and MMP-2 activity was measured by gelatin zymography. LV dysfunction was documented by impaired Ees and diastolic stiffness in STZ mice compared with controls. This was accompanied by increased TGFbeta, IL1beta, and fibrosis and decreased MMP-2 activity. Treatment with irbesartan attenuated LV dysfunction, IL1beta, TGFbeta, and cardiac fibrosis compared with untreated diabetic animals and normalized MMP activity. These findings present evidence that AT-1 receptor antagonists attenuate cardiac failure by decreasing cardiac inflammation and normalizing MMP activity, leading to normalized cardiac fibrosis in STZ-induced diabetic cardiomyopathy.     

Role of MMP-9 and its tissue inhibitor TIMP-1 in human osteosarcoma: findings in 42 patients followed for 1-16 years

BACKGROUND: The activity of matrix metalloproteinases (MMPs) in degrading extracellular matrix is controlled by activation of proenzymes and inhibition of MMP tissue inhibitors (TIMPs). PATIENTS AND METHODS: To assess the proteolytic cascade imbalance in malignancy progression, tissue expression and serum levels of MMP-2, MMP-9 and of their inhibitors TIMP-2 and TIMP-1 respectively were evaluated in 42 selected patients with high-grade osteosarcoma (OS). MMP-2, MMP-9, TIMP-2 and TIMP-1 were studied in biopsies by immunohistochemistry and in serum by ELISA test. Patients were subdivided into 3 groups according to their follow up: continuously disease-free, diagnosis of metastasis during follow-up, and metastasis at diagnosis. RESULTS: Immunohistochemistry demonstrated an imbalance between MMPs and TIMPs, with a more evident role for MMP-9 than for MMP-2 in tumor progression. TIMP-1 inhibitor in plasma was higher in patients with osteosarcoma than in a control group. This high value of TIMP-1 was particularly evident in the group of patients who later developed metastases and/or local recurrences, and in those with metastases at diagnosis. INTERPRETATION: Our findings confirm the protective action of TIMP-1, as MMP inhibitor, but also show its activity as a growth factor underlining its multifunctional role in OS.     

Role of MMP-9 and its tissue inhibitor TIMP-1 in human osteosarcomaFindings in 42 patients followed for 1–16 years

Background?The activity of matrix metalloproteinases (MMPs) in degrading extracellular matrix is controlled by activation of proenzymes and inhibition of MMP tissue inhibitors (TIMPs). Patients and methods?To assess the proteolytic cascade imbalance in malignancy progression, tissue expression and serum levels of MMP-2, MMP-9 and of their inhibitors TIMP-2 and TIMP-1 respectively were evaluated in 42 selected patients with high-grade osteosarcoma (OS). MMP-2, MMP-9, TIMP-2 and TIMP-1 were studied in biopsies by immunohistochemistry and in serum by ELISA test. Patients were subdivided into 3 groups according to their follow up: continuously disease-free, diagnosis of metastasis during follow-up, and metastasis at diagnosis. Results?Immunohistochemistry demonstrated an imbalance between MMPs and TIMPs, with a more evident role for MMP-9 than for MMP-2 in tumor progression. TIMP-1 inhibitor in plasma was higher in patients with osteosarcoma than in a control group. This high value of TIMP-1 was particularly evident in the group of patients who later developed metastases and/or local recurrences, and in those with metastases at diagnosis. Interpretation?Our findings confirm the protective action of TIMP-1, as MMP inhibitor, but also show its activity as a growth factor underlining its multifunctional role in OS.     

Evidence for a matrix metalloproteinase induction/activation system in arterial vasculature and decreased synthesis and activity in diabetes

Pathological remodeling characterized by extracellular matrix (ECM) deposition contributes to the diabetic vascular complications. Matrix metalloproteinases (MMPs) regulate ECM turnover. However, the expression profile of the MMP system in diabetic human tissue remains unknown. The objectives of this study were 1) to identify a local MMP induction/activation system that exists in arterial vasculature and 2) to determine how the MMP system may be altered in diabetes. Internal mammary artery specimens were obtained from patients who did (n = 14) and did not (n = 14) have diabetes and were undergoing coronary artery bypass grafting surgery. ECM inducer protein (EMMPRIN); membrane-type MMP (MT-MMP); and MMP-1, -2, and -9 were quantified by immunoblotting and densitometric scanning (pixels). Pro-MMP-1 and MMP-2 levels were decreased from 952 +/- 120 and 1,081 +/- 508 pixels, respectively, in nondiabetic tissue to 398 +/- 62 and 249 +/- 42 pixels in the diabetic tissue (P < 0.05). Both EMMPRIN and MT-MMP expression and total MMP activity were decreased by twofold in diabetic patients (P < 0.05). These results demonstrated for the first time that an MMP induction and activation system exists in human arterial vasculature and that it is downregulated in diabetes. Decreased MMP activity may contribute to increased collagen deposition and pathological remodeling in diabetes.     

Renoprotective effect of early inhibition of the renin-angiotensin system in renal transplant recipients

The aim of this work was to study the effect of early administration of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type-I receptors blockers (ARB) on renal function and proteinuria in renal transplant recipients with good, stable renal function and mild proteinuria. Twenty four patients started ACEI/ARB therapy within 14 months after surgery (RAS-). Before (T0) and every month for 2 years after the initiation of ACEI/ARB we evaluated creatinine clearance (CrCl), proteinuria/day (UP), UP/CrCl (FUP), arterial blood pressure, and serum lipid levels. Twenty-eight patients who never received ACEI/ARB (RAS+) were studied in the same fashion. In the RAS+ CrCl was reduced after 2 years compared with T0 (64.5 +/- 2.6 vs 75.0 +/- 3.2 mL/min, P < .003); UP and FUP were both significantly increased (666 +/- 65 vs 132 +/- 20 mg/day 8.8 +/- 1.2 vs 2.6 +/- 0.6 mg/mL x 10(3); P < .001 and .002) compared with T0. Moreover, UP (P < .04), FUP (P < .03), and the percentage reduction of CrCl (11.4% +/- 5% vs 4.6% +/- 1.8%; P < .05) were greater in RAS+ than RAS- subjects at 2 years of the study. The values of other parameters did not show significant differences between the two groups. In conclusion, this study suggested that ACEI/ARB have renoprotective effects, when used in patients with good stable renal function and mild proteinuria. These drugs may play a role to prevent chronic allograft nephropathy.     

Expression of Matrix Metalloproteinases in the Chronic Subdural Haematoma Membrane

To study the role of matrix metalloproteinases (MMP) in the development of chronic subdural haematoma, we investigated the expression and activity of MMPs (MMP-1, -2, -3, -7 and -9) and tissue inhibitors of MMP (TIMP-1 and -2) in capsules of chronic subdural haematoma from 10 patients. Outer membranes of chronic subdural haematoma were immunostained for MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2. Moreover, we confirmed MMP activity in membranes by SDS-PAGE zymography and in situ zymography. These results suggest that MMP degrades extracellular matrix in outer membranes of chronic subdural haematoma, which is thought to decrease their integrity followed by direct haemorrhage and exudation of oedematous fluid from membrane vessels into the haematoma cavity.     

Renin-angiotensin system blockades and contrast-induced nephropathy: a meta-analysis

Objective To evaluate the effects of renin-angiotensin system (RAS) blockades [angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB)]on contrast-induced nephropathy (CIN) in patients undergoing angiography. Methods Pubmed, Embase, Cochrane library, Wanfang database and CNKI were searched. The literature limited range was from their start year to July 2015. Randomized controlled trials (RCTs) and non-randomized controlled trials of renin-angiotensin system blockades in influencing CIN were assessed. Two investigators extracted data and performed quality analysis independently from all trials included. Rev man 5.3 software was used. Results 16 trials with a total of 15 897 patients were identified. There were 7490 patients who received renin-angiotensin system blockades and 8407 patients in control group. The meta analysis revealed a higher CIN incidence in ACEI/ARB group than that in control group (14.35% vs 12.13%, P=0.04, OR=1.44, 95%CI 1.01-2.04). For patients with renal insufficiency, ACEI/ARB group had a higher CIN incidence than control group (12.23% vs 7.32%, P= 0.02, OR=1.80, 95%CI 1.10-2.94), and the serum creatinine changes in ACEI/ARB group were higher than those in control group. There was statistical difference in serum creatinine changes between groups (P=0.02, MD=0.08, 95%CI 0.02-0.15). Conclusions Renin-angiotensin system blockades can increase the incidence of CIN in patients undergoing angiography. Renin-angiotensin system blockades can contribute to CIN for patients with renal insufficiency.     

Matrix metalloproteinases, their tissue inhibitors and colorectal cancer staging

BACKGROUND: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are important in tumour invasion and metastasis. The levels of MMPs, TIMPs and total MMP activity were compared in paired colorectal tumour (n = 50) and normal tissue (n = 49) samples and correlated with clinical and pathological staging. METHODS: Gelatin zymography (MMP-2 and MMP-9), enzyme-linked immunosorbent assays (MMP-1, MMP-3, TIMP-1 and TIMP-2) and quenched fluorescent substrate hydrolysis (total MMP activity) were employed in resection specimens from 50 patients, four with adenomas and 46 with colorectal cancer. RESULTS: The levels of active MMP-2 and MMP-9 and total MMP-1, MMP-3 and TIMP-1 were significantly greater in tumour tissue than in normal colon (e.g. TIMP-1 tumour median 72 (range 25-351) versus normal 26 (4-107) ng per mg total protein content; P<0.05); however, TIMP-2 levels were significantly greater in normal tissue (P<0.05). Total MMP activity was significantly greater in tumour than in normal tissue (15 025 (1750-174 400) versus 7250 (750-354 650) pmol l-1 min-1 mg protein-1; P<0.05). Correlations were found between both MMP and TIMP levels and pathological tumour staging. MMP-1 appeared to be most important as its concentration correlated positively with Dukes staging, tumour differentiation and lymphatic invasion. CONCLUSION: The levels of the studied MMPs and total MMP activity were upregulated in colorectal tumours. MMP-1 is important in colorectal cancer progression.     

The association between angiotensin converting enzyme inhibitor or angiotensin receptor blocker use during postischemic acute transplant failure and renal allograft survival

BACKGROUND: Postischemic acute renal transplant failure occurs in approximately one fourth of all dead donor transplantations. Uncertainty exists regarding the putative association between the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) and kidney transplant graft survival in patients with delayed allograft function. METHODS: We conducted an open cohort study of all 436 patients who experienced an acute renal transplant failure out of all 2,031 subjects who received their first kidney transplant at the Medical University of Vienna between 1990 and 2003. Actual and functional graft survival was compared between users and nonusers of ACEI/ARB using exposure propensity score models and time-dependent Cox regression models. RESULTS: Ten-year actual graft survival averaged 44% in the ACEI/ARB group, but only 32% in patients without ACEI/ARB (P=0.002). The hazard ratio of actual graft failure was 0.58 (95% confidence interval: 0.35-0.80, P=0.002) for ACEI/ARB users compared with nonconsumers. Seventy-one percent of subjects with ACEI/ARB had a functional graft at 10 years versus 64% of ACEI/ARB nonusers (P=0.027). The hazard ratio of functional graft loss was 0.48 (95% confidence interval: 0.24-0.91, P=0.025). CONCLUSIONS: Use of ACEI/ARB in patients experiencing delayed allograft function was associated with longer actual and functional transplant survival.     

ACE inhibitor or angiotensin II receptor blocker use is a risk factor for contrast-induced nephropathy

Background: The aim of the present study was to assess the influence of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) use on the incidence of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography. Methods: A retrospective case control study was conducted on a total of 201 patients divided into 2 groups (CIN group and control group). CIN was defined as an increase in serum creatinine by more than 25% from baseline within 48 hours of radiocontrast exposure. The CIN group had 96 patients, and the control group had 105 patients. The 2 groups were matched for variables such as age, sex, weight, baseline serum creatinine, diabetes, dye load, use of diuretics, statins and preprocedure prophylactic measures for CIN. Results: The incidence of CIN was found to be 4.55%. The CIN group had 96 patients out of which 56 patients (58.3%) were on chronic ACEI or ARB, while the control group had 105 patients, but only 36 of patients (34.3%) were on ACEI or ARB (p<0.001).The odds ratio for development of CIN with respect to ACEI or ARB use was 2.68 (95% confidence interval, 1.51-4.76). Conclusion: Use of ACEI or ARB is an independent risk factor for developing CIN. It is reasonable to discontinue their use 48 hours prior to exposure to radiocontrast agents, especially in patients with multiple risk factors.     

Matrix metalloproteinases in the aneurysm wall of patients treated with low-dose doxycycline

The purpose of this study was to determine the effect of low-dose doxycycline on matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP)-1 expression in the wall of abdominal aortic aneurysms. A double-blind, randomized study was conducted of patients treated with doxycycline (100 mg/d orally) or placebo for 1 month prior to surgery. MMP-2, -3, and -9 (zymogen and activity); MMP-1, -2, -3, -7, -9, -11, -12, and -14; and TIMP-1 (messenger ribonucleic acid [mRNA]) were measured in the aneurysm wall. No differences were found between the treatment and placebo groups in zymogen levels of MMP-2, -3, or -9 or in the free or total activities of MMP-2 and -9. Treatment with doxycycline also had no effect on the concentration of any mRNA measured. No relationship was found between the number of tablets taken and MMP or TIMP protein, mRNA, or activity levels in the aneurysm wall. Low-dose doxycycline treatment does not alter the expression or activity of metalloproteinases or their inhibitor, TIMP-1, in the aneurysm wall.     

Modulation of matrix gelatinases and metalloproteinase-activating process in acute kidney rejection

Changes in matrix metalloproteinase (MMP) activities would contribute to the accumulation of extracellular matrix during acute kidney allograft rejection. MMP-2 and MMP-9 and other gelatinolytic activities were examined in the rejected graft and the urine of a rat model of acute kidney rejection (orthotopic allotransplantation from a Buffalo donor to a Wistar-Furth recipient) by either zymography or fluorescence assay. MMP-2, membrane type 1 (MT1)-MMP, and tissue inhibitor of metalloproteinase (TIMP)-2 were also examined by immunodetection. The proMMP-2 activity and protein level increased in the graft during rejection when compared with normal Buffalo kidney, whereas activated MMP-2 decreased. TIMP-2 protein levels were markedly decreased and MT1-MMP proteolytic fragments (44-40 kDa) were undetectable. This suggests an altered MT1-MMP-dependent processing of proMMP-2 into active MMP-2 due to a diminished TIMP-2 level in acute kidney rejection. In the urine the overall gelatinolytic activity decreased considerably, although activity associated with an as yet unidentified 78-kDa protein appeared 6 days after transplantation.