Pretreatment with the tumor nerosis factor-alpha blocker etanercept attenuated ischemia-reperfusion renal injury.

INTRODUCTION: Tumor necrosis factor (TNF)-alpha mediates inflammation and apoptosis in ischemia-reperfusion (IR) injury of the kidneys. Etanercept, a soluble TNF-alpha receptor, has shown anti-inflammatory and anti-apoptotic effects in several animal models of renal injury, including chronic insufficiency and unilateral ureteral obstruction. We evaluated the protective effect of etanercept against experimental renal IR injury. METHODS: Male Sprague-Dawley (SD) rats were divided into 4 groups: saline-treated sham rats, etanercept-treated sham rats, saline-treated IR rats, and etanercept-treated IR rats. Renal messenger RNA (mRNA) levels of TNF-alpha and monocyte chemotactic protein-1 (MCP-1) were measured by real-time polymerase chain reaction (PCR) at 24 hours after IR injury. The protein levels of renal Bcl-2 associated X (Bax), B-cell lymphoma 2 (Bcl), extracellular signal-regulated kinase (ERK), and caspase-3 activation were evaluated using Western blot analysis. The degree of apoptosis of renal tubular cells was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. RESULTS: At 24 hours after IR injury, the serum levels of blood urea nitrogen (BUN) and creatinine were significantly lower among etanercept-treated than saline-treated IR rats. Renal mRNA levels of TNF-alpha and MCP-1 in saline-treated IR rats were significantly higher than the levels in saline-treated sham rats, and TNF-alpha and MCP-1 mRNA levels in etanercept-treated IR rats were significantly lower than those in saline-treated IR rats. Etanercept pretreatment of IR-injured rats significantly increased EKR phosphorylation and reduced the renal Bcl-2/Bax ratio, the renal caspase-3 activation, and the number of TUNEL-positive apoptotic cells. CONCLUSION: Etanercept improved resistance to renal injury during IR by enhancing the activation of ERK and increasing the Bcl-2/Bax ratio.

Acute poststreptococcal glomerulonephritis superimposed on IgA nephropathy.

Superimposition of poststreptococcal glomerulonephritis (PSGN) on the course of IgA nephropathy (IgAN) is uncommon. A case of PSGN during IgA nephropathy is presented. A 30-year-old man who had alternating gross and microscopic hematuria for 7 months underwent a renal biopsy. The first renal biopsy revealed IgAN with mesangial deposits of IgA and C3. Two months later, the patient suffered generalized edema, proteinuria, hematuria, an increased ASO titer and a decreased C3 level. A second renal biopsy revealed diffuse endocapillary proliferative glomerulonephritis with epimembranous hump-like electron-dense deposits of C3, but the original mesangial IgA deposits had disappeared. A diagnosis of acute PSGN was indicated. Two months after the onset of acute nephritic syndrome, the patient remained asymptomatic, except for microscopic hematuria and proteinuria. Some cases with persistent proteinuria or hematuria after PSGN are probably related to preexisting IgAN.

Spontaneous bladder rupture in a chronic hemodialysis patient.

Spontaneous bladder rupture is very rare. A 67-year-old woman who was nearly anuric and had been on chronic hemodialysis therapy for diabetic end-stage renal disease for 6 years complained of severe low abdominal pain and fever for 2 days. Abdominal computerized tomography and retrograde cystography revealed the extraperitoneal leakage of contrast medium, confirming bladder perforation. Partial cystectomy around the perforation site and repair of the bladder rupture were performed. Microscopic examination of the excised bladder tissue revealed that the bladder mucosa was ulcerated. Severe suppurative inflammation was observed throughout the bladder wall. Antibiotic treatment was continued for 3 weeks postoperatively, and repeated retrograde cystography showed no evidence of contrast extravasation. She was discharged, with no other complications.

Hypoalbuminemia as a risk factor for progressive left-ventricular hypertrophy in hemodialysis patients.

BACKGROUND: This study was performed to evaluate the changes in left-ventricular (LV) mass in the patients starting maintenance hemodialysis and the risk factors for the progression of LVH. METHODS: From June 1994 to February 1997, baseline echocardiography was obtained within six months after the initiation of hemodialysis in 111 patients with end-stage renal disease. Of the patients who had LVH on baseline echocardiography, 32 patients underwent follow-up echocardiography after 15 months (range: 9-24 months). LVH was defined as a left-ventricular mass index (LVMI) greater than 131 g/m(2) in males and 100 g/m(2) in females. Progressive LVH was defined as a follow-up LVMI greater than 105% of the baseline value. Hemoglobin, blood urea nitrogen, creatinine, cholesterol, albumin, prealbumin, parathyroid hormone, Kt/V, nPCR, fibrinogen, homocysteine and ACE gene polymorphism were also measured. RESULTS: LVH was detected in 91 of 111 (82%) ESRD patients starting maintenance hemodialysis. Of the 32 patients in whom follow-up echocardiography was performed, progressive LVH occurred in 19 patients (M:F = 12:7). Progressive LVH was associated with lower diastolic blood pressure (81 +/- 11 vs. 90 +/- 12 mm Hg, p = 0.036) and lower serum albumin (3.5 +/- 0.4 vs. 3.9 +/- 0.4 g/dl, p = 0. 009). Serum albumin was negatively (r = -0.420, p = 0.017) correlated to Delta LVMI (follow-up LVMI minus baseline LVMI). Hypoalbuminemia was an independent risk factor for progressive LVH in multiple logistic regression analysis (R.R. = 1.29, p = 0.046). The association of progressive LVH with age, gender, diabetes mellitus, smoking history or other laboratory parameters was not significant. CONCLUSION: LVH was highly prevalent in the patients starting maintenance hemodialysis for ESRD. In the follow-up echocardiography, LVH progressed in a substantial portion of the patients, and hypoalbuminemia was a risk factor for progressive LVH.

Intrathymic tolerance in the Lewis-to-F344 chronic cardiac allograft rejection model.

Successful induction of donor-specific unresponsiveness by intrathymic inoculation of alloantigen in several experimental acute rejection models has led us to hypothesize that similar immune manipulations can prevent chronic rejection and development of graft arteriosclerosis in the Lewis-to-F344 rat chronic cardiac allograft rejection model. Recipient F344 rats were treated with donor (Lewis) splenocytes by intrathymic injection (i.t.) alone (10 x 10(6) cells/lobe); with donor splenocytes i.t. plus a one-time dose of ALS (1 mg) by intraperitoneal injection (i.p.); or with ALS i.p. (1 mg) alone 2 and 6 weeks prior to heterotopic Lewis heart transplantation. Control F344 recipients received saline i.t. Allografts were monitored by daily palpation, and long-term surviving grafts were harvested on day 90 for histopathologic analysis. Control allografts had 28.6% long-term survival (> 90 days) with mean graft survival of 46.7 +/- 12.2 days. At day 90 the surviving control allografts were enlarged and fibrotic with barely palpable heartbeat (mean heartbeat grade 0.29 +/- 0.18), and histologically showed diffuse moderate mononuclear cell infiltrates and advanced graft arteriosclerosis (mean vessel score 3.57 +/- 0.10 and 89 +/- 1% vessels diseased). Recipient treatment with intrathymic donor splenocytes alone significantly prolonged graft survival (89% long-term survival; mean 83.8 +/- 6.2 days, P < 0.04), but did not significantly inhibit the development of graft arteriosclerosis (score 2.98 +/- 0.53 and 79 +/- 8% diseased, P = NS). By contrast, treatment with i.t. donor splenocytes plus ALS 2 weeks prior to transplantation prolonged graft survival (100% long-term; mean 90.0 +/- 0.0 days, P < 0.04), and markedly inhibited graft arteriosclerosis (score 0.80 +/- 0.14, P < 0.05; 27 +/- 4% diseased, P < 0.05). ALS alone given two weeks prior to transplantation also prolonged graft survival (100% long-term; mean 90.0 +/- 0.0 days, P < 0.04), and inhibited graft arteriosclerosis (score 0.89 +/- 0.31, P < 0.05; 25 +/- 7% diseased, P < 0.05). However, when ALS was given 6 weeks prior to heart transplantation the beneficial effect of ALS alone was abolished, suggesting that lymphocyte depletion may have been responsible for the observed effects when ALS was administered at 2 weeks. Interestingly, intrathymic donor splenocytes plus ALS 6 weeks prior to transplantation, on the other hand, showed significant prolongation of allograft survival (100% long-term, mean 90.0 +/- 0.0 days, P < 0.04), and inhibited graft arteriosclerosis (score 0.41 +/- 0.02, P < 0.05; 16 +/- 2% diseased, P < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Tc-99m dimercaptosuccinic acid(DMSA) renal scintigraphy in patients with acute pyelonephritis.

OBJECTIVES: Recently, several authors reported that Tc-99m DMSA renal scan frequently showed cortical defects of the involved kidneys even in the patients with acute pyelonephritis who did not show abnormal findings in the ultrasonography and intravenous pyelography (IVP). METHODS: In order to evaluate the utilities of Tc-99m DMSA renal scan and the clinical meaning of cortical defects in the Tc-99m DMSA renal scan of the patients with acute pyelonephritis, ninety two patients with acute pyelonephritis, from March 1991 to February 1994 in Chungnam National University Hospital(CNUH), were included in this study. Patients were subdivided as Group A:Patients showing normal Tc-99m DMSA renal scan (n = 42) and Group B:Patients with definite cortical defects on the Tc-99m DMSA renal scan (n = 50). We compared clinical characteristics such as age and sex, recurrency, duration of fever, bacterial culture study, incidence of renal insufficiency and the results of renal ultrasonography and intravenous pyelography between the two groups. RESULTS: Fifty four percents of 92 patients with acute pyelonephritis showed a significantly longer febrile period after admission, higher positive rates on the urine and blood culture studies and higher incidence of renal insufficiency than those of the Group A patients. Sixty nine percents of Group B patients showed normal results in ultrasonography or IVP study. CONCLUSIONS: Tc-99m DMSA renal scan was a more sensitive imaging test than ultrasonography in kidneys and IVP to detect pyelonephritis lesions and may be useful to predict the patient group with a severe disease course. These patients may need more careful management and further studies to evaluate the possibility of complications.

Effects of temperature and flow rate on regional blood flow and metabolism during cardiopulmonary bypass.

Eleven dogs were subjected to a 150-minute period of cardiopulmonary bypass that consisted of a high-flow, normothermic phase, a high-flow, hypothermic phase, a low-flow, hypothermic phase, and then a high-flow, rewarming phase. Regional blood flow and oxygen consumption to the brain, intestines, kidney, and hind limb were determined at baseline and at 10-minute intervals during cardiopulmonary bypass. Blood flow to the carotid artery, superior mesenteric artery, and renal artery declined significantly with hypothermic cardiopulmonary bypass whereas blood flow to the femoral artery increased significantly. Although total body oxygen consumption returned to baseline values at the end of the rewarming phase, oxygen consumption for these regions differed somewhat from their baseline values. We conclude that blood flow during hypothermic cardiopulmonary bypass is shunted to skeletal muscle, particularly with high pump flows. Additionally, the return of total body oxygen consumption to baseline after rewarming is not necessarily reflected at the regional level.

Isolated coronary artery bypass grafting in one hundred consecutive octogenarian patients. A multivariate analysis.

One hundred consecutive patients aged 80 or older underwent isolated coronary artery bypass grafting for New York Heart Association functional class III (24%) or IV (76%) disease in our institution from 1985 to 1989. The operations were elective in 36 patients, urgent in 52, and emergent in 12. Twenty-eight patients had significant disease of the left main coronary artery, with the remainder having an average of 2.8 diseased coronary vessels. Preoperative left ventricular ejection fraction was considered good (greater than 50%) in 62 patients, fair (30% to 50%) in 24 patients, and poor (less than 30%) in 14 patients. An average of 2.8 grafts were performed per patient, and the internal mammary artery was used in 10 patients. Univariate analysis of 36 perioperative factors followed by multivariate logistic regression analysis of the significant variables (p less than 0.05) revealed that the urgency of the operation and left ventricular ejection fraction were independent predictors of operative mortality. There were 12 in-hospital deaths, and the mortality was significantly lower in the elective cases (2.8%) than in the urgent (13.5%) and emergent cases (33.3%). Major complications occurred in 14% of the elective cases, in 21% of the urgent cases, and in 67% of the emergent cases. The operative mortality rates for good, fair, and poor left ventricular ejection fraction were 4.9%, 12.5%, and 42.9%, respectively. Long-term follow-up averaging 22 months revealed a 77% actuarial probability of survival at 24 months and 51% at 48 months, with only two cardiac-related deaths. We conclude that coronary artery bypass grafting can be performed in octogenarians with a favorable outcome when done electively in patients with normal to moderately depressed left ventricular function.

Myocardial reperfusion injury. Platelet-activating factor stimulates polymorphonuclear leukocyte hydrogen peroxide production during myocardial reperfusion.

To study the roles of platelet-activating factor, polymorphonuclear leukocytes, and oxygen free radicals in myocardial reperfusion injury, we subjected 10 sheep to 90 minutes of mid-left anterior descending coronary artery followed by 6 hours of reperfusion. Stainings with gentian violet and tetratriphenyl ammonium chloride demonstrated 20% +/- 3% of the left ventricular mass at risk for ischemia, of which 75% +/- 10% underwent infarction. Coronary sinus blood was assayed for platelet-activating factor and neutrophil hydrogen peroxide production before and during coronary occlusion and during reperfusion. Platelet-activating factor was isolated by column chromatography and lipid extraction and quantified by radioimmunoassay. Neutrophil hydrogen peroxide production was measured by a 2',7'-dichlorofluorescein flow-cytometric assay. Platelet-activating factor was elevated to 899 +/- 210 pg/ml at 15 minutes of reperfusion, compared with the preocclusion level of 271 +/- 55 pg/ml and coronary occlusion level of 359 +/- 64 pg/ml (p less than 0.05; analysis of variance). Neutrophil hydrogen peroxide production, measured on a relative fluorescence scale, was also elevated to a level of 141 +/- 27 at 1 hour of reperfusion, compared with the preocclusion level of 103 +/- 6 and the coronary occlusion level of 114 +/- 13 (p less than 0.01; analysis of variance). Both of these parameters returned toward baselines at the end of 6 hours of reperfusion. Histologic examination revealed infiltration of polymorphonuclear leukocytes into the interstitium of the reperfused myocardium. Neutrophils isolated from unoperated and healthy sheep demonstrated a graded dose response in hydrogen peroxide production when stimulated by purified platelet-activating factor in vitro. These findings suggest that platelet-activating factor is released in the coronary circulation and is a mediator of oxygen free radical production in polymorphonuclear leukocytes during myocardial reperfusion.