The real-world data of lipid-lowering treatment in patients with peripheral artery disease and its association with severity of disease.

BACKGROUND: The risk of coronary artery disease in peripheral arterial disease (PAD) is high, life prognosis is poor, and lipid-lowering treatment with statins has been reported to improve prognosis. In clinical practice, however, hypolipidemia is more common in patients with severe PAD and statin prescription rates appear to be low, but specific data are scarce in Japan. Therefore, we conducted this cross-sectional study in collaboration with other centers of vascular surgery to determine the rate of statin prescriptions for PAD patients in real-world practice, the rate of achievement of low-density lipoprotein (LDL) cholesterol control targets, and whether statin non-use is a determinant factor of critical limb ischemia (CLI). METHODS: A total of 246 PAD patients (97 with CLI) from 5 sites were included in this study. Medical history and blood test data were obtained from medical records and interviews with patients, and were compared between CLI and non-CLI patients. RESULTS: Statin prescription rate was only 34 %. The overall LDL cholesterol control target rate was 46 % of CLI cases and 51 % of non-CLI cases, according to the lipid management criteria of the Japanese Society for Atherosclerosis 2022 guidelines. Patients in the CLI group had a lower mean body mass index and lower LDL cholesterol levels than those in the non-CLI group, suggesting that these factors were responsible for the lower statin prescription rate. However, multivariate analysis revealed that statin non-use was one of the determinants of CLI. CONCLUSIONS: Statin prescription rates for PAD patients were low in real-world practice settings in the field of vascular surgery. Since statin non-use is a determinant of CLI, there is a need to educate physicians engaged in treatment regarding lipid-lowering treatment with statins.

Novel combination therapy of pedal arch angioplasty and dual distal bypass as an alternative treatment option for vasculitis in patients with chronic limb-threatening ischemia.

A 68-year-old man with chronic limb-threatening ischemia caused by atypical vasculitis was successfully treated by the combination of pedal arch angioplasty and dual distal bypass. Angioplasty alone failed; therefore, we performed pedal arch angioplasty followed by distal bypass revascularized to the newly created dorsalis pedis artery and posterior tibial artery anastomosis sites. Restenosis occurred twice, and both cases were successfully treated by immediate angioplasty. Both branches of the graft remained patent for >2.5 years, and the wound healed completely. This unique combination of techniques can provide favorable results for selected patients with chronic limb-threatening ischemia.

Evaluation of Perfusion Index as a Screening Tool for Developing Critical Limb Ischemia.

Objective: The perfusion index (PI) is a physiological marker for evaluating the peripheral circulation. We explored the possibility of using PI as a screening tool for development of critical limb ischemia in peripheral artery disease (PAD). Method: We measured the PI in 79 limbs of 70 PAD patients. Data were analyzed to find a correlation between the PI and PAD severity. Result: The PI tended to be lower as PAD became severer. Especially, there were significant differences between the Fontaine 1 and Fontaine 4 groups in average PI and minimum PI, and between Fontaine 1 and two other groups (Fontaine 2 and Fontaine 4 groups) in maximum PI. A mild correlation was found between PI and the ankle brachial index. These data were used to calculate an average PI of 0.27 as a cut-off value for critical limb ischemia (CLI). In 65 asymptomatic PAD patients and claudication, significantly more patients with a PI value greater than the cut-off value developed CLI than those with a PI lower than the cut-off. Conclusion: The PI can be a useful tool for evaluating the development of CLI in mild PAD patients, and patients tended not to progress to CLI when their average PI was higher than 0.27. (This is a translation of Jpn J Vasc Surg 2020; 29: 103-108.).

Long-Term Results of Crossover Bypass for Iliac Atherosclerotic Lesions in the Era of Endovascular Treatment: The Re-ACTION Study (Retrospective Assessment of Crossover Bypass as a Treatment for Iliac LesiONs).

Objective: The aim of this study was to elucidate the long-term results of crossover bypass (CB) for iliac atherosclerotic lesions in the era of endovascular treatment (EVT). Methods: A retrospective multicenter cohort study was performed. CB was performed in 242 patients between 2003 and 2014 by vascular surgeons at multiple medical centers in Japan. Results: Perioperative mortality was 1.7%. Primary patency rates were 86% at 5 years and 82% at 8 years. Univariate analysis showed that critical limb ischemia (Rutherford class 4-6), vein graft, and superficial femoral artery occlusion were significantly associated with low primary patency. In multivariate analysis, only critical limb ischemia influenced primary patency. The secondary patency rate was 87% at both 5 and 8 years. The limb salvage rate was 98% at both 5 and 8 years. The overall survival rates were 71% at 5 years and 49% at 8 years. Conclusion: The long-term results of CB were good in our study, compared with previous reports. Our results suggest that CB remains an option for the arterial reconstruction in unilateral iliac occlusive disease after EVT failed.

A case of blunt thoracic aortic injury requiring ECMO for acute malperfusion before TEVAR.

BACKGROUND: Blunt thoracic aortic injury (BTAI) is associated with a high mortality rate and the paradigm of treating patients with BTAI currently favours thoracic endovascular aneurysm repair (TEVAR) if possible. In BTAI, lethal malperfusion caused by a pseudoaneurysm has rarely been reported. We present the first report of a successful case in which a pseudoaneurysm causing the infrequent occurrence of lethal malperfusion and subsequent acute severe ischaemia in the distal portion of the thoracic descending aorta was overcome by veno-arterial extracorporeal membrane oxygenation (VA ECMO) as a bridging therapy until the initiation of TEVAR. CASE PRESENTATION: An adult woman was transferred to our emergency room after injuries sustained by falling from height. Her vital signs were unstable on admission. CT examination revealed the multiple injuries: traumatic subarachnoid haemorrhage, severe unstable pelvic fracture, and a grade III injury of the thoracic aorta. We made the decision to perform TEVAR after external fixation and transcatheter arterial embolization (TAE) for the pelvic injury. During preparations for TEVAR, her lower limbs rapidly felt cold, and her blood lactate level and serum potassium rapidly increased. By the clinical data and ultrasonography and lower extremity Doppler, we diagnosed severe ischaemia in distal portion of the descending aorta caused by a pseudoaneurysm proximal to the descending thoracic aorta. Because we still had not prepared for TEVAR, we immediately started VA ECMO until TEVAR could begin. After the initiation of VA ECMO, her lactate and potassium levels could be controlled. Under VA ECMO support, she underwent TEVAR. After inpatient rehabilitation, she was discharged home without neurologic sequelae. CONCLUSIONS: VA ECMO could be an important, less-invasive treatment as a bridging therapy for acute severe malperfusion syndrome until TEVAR is initiated for BTAI.

Oral Steroid Use and Abdominal Aortic Aneurysm Expansion　- Positive Association.

BACKGROUND: The maximum axial diameter (MAD) of a fusiform abdominal aortic aneurysm (AAA) is an indicator of the risk of expansion or rupture. Apart from smoking and MAD itself, few expansion risk factors have been reported. In this study, we investigated expansion risk factors for AAA.Methods and Results:This retrospective cohort study included 176 patients who attended Tohoku University Hospital with infrarenal fusiform AAA. AAA expansion rate was determined on multidetector computed tomography, and the correlations between expansion rate and the clinical data were analyzed. The median expansion rate was 2.405 mm/year. On univariate analysis, a significant positive correlation with expansion rate was observed for the initial MAD (P<0.001) and significant negative correlations for oral angiotensin receptor blocker usage (P=0.025), height (P=0.005), body weight (P=0.017), total cholesterol (P=0.007), low-density lipoprotein cholesterol (P=0.004), and HbA1c (P=0.037). On logistic regression analysis, significant positive associations with expansion rate were observed for initial MAD (P<0.001) and oral steroid usage (P=0.029) and a negative association for height (P=0.041). CONCLUSIONS: Oral steroid usage is an important risk factor for AAA expansion, independent of other risk factors of atherosclerosis and MAD.

Surgical resection and inferior vena cava reconstruction for treatment of the malignant tumor: technical success and outcomes.

OBJECTIVE: The purpose of this study was to review patients who underwent inferior vena cava (IVC) resection with concomitant malignant tumor resection and to consider the operative procedures and the outcomes. MATERIALS AND METHODS: Between 2000 and 2012, 41 patients underwent resection of malignant tumors concomitant with surgical resection of the IVC at our institute. The records of these patients were retrospectively reviewed. RESULTS: Primary tumor resections included nephrectomy, hepatectomy, retroperitoneal tumor extirpation, lymph node dissection, and pancreaticoduodenectomy. The IVC interventions were partial resection in 23 patients and total resection in 18 patients. Four patients underwent IVC replacement. Operation-related complications included pulmonary embolism, acute myocardial infarction, deep vein thrombosis, leg edema and temporary hemodialysis. There were no operative deaths. The mean follow-up period was 24.9 months (range: 2-98 months). The prognosis depended on the type and stage of the tumor. CONCLUSION: Resection and reconstruction of the IVC can be performed safely if the preoperative evaluations and surgical procedures are performed properly. The IVC resection without reconstruction was permissive if the IVC was completely obstructed preoperatively, but it may also be considered in cases where the IVC is not completely obstructed.

Bioluminescence and magnetic resonance imaging of macrophage homing to experimental abdominal aortic aneurysms.

Macrophage infiltration is a prominent feature of abdominal aortic aneurysm (AAA) progression. We used a combined imaging approach with bioluminescence (BLI) and magnetic resonance imaging (MRI) to study macrophage homing and accumulation in experimental AAA disease. Murine AAAs were created via intra-aortic infusion of porcine pancreatic elastase. Mice were imaged over 14 days after injection of prepared peritoneal macrophages. For BLI, macrophages were from transgenic mice expressing luciferase. For MRI, macrophages were labeled with iron oxide particles. Macrophage accumulation during aneurysm progression was observed by in situ BLI and by in vivo 7T MRI. Mice were sacrificed after imaging for histologic analysis. In situ BLI (n  =  32) demonstrated high signal in the AAA by days 7 and 14, which correlated significantly with macrophage number and aortic diameter. In vivo 7T MRI (n  =  13) at day 14 demonstrated T2* signal loss in the AAA and not in sham mice. Immunohistochemistry and Prussian blue staining confirmed the presence of injected macrophages in the AAA. BLI and MRI provide complementary approaches to track macrophage homing and accumulation in experimental AAAs. Similar dual imaging strategies may aid the study of AAA biology and the evaluation of novel therapies.

Hyperglycemia limits experimental aortic aneurysm progression.

OBJECTIVE: Diabetes mellitus (DM) is associated with reduced progression of abdominal aortic aneurysm (AAA) disease. Mechanisms responsible for this negative association remain unknown. We created AAAs in hyperglycemic mice to examine the influence of serum glucose concentration on experimental aneurysm progression. METHODS: Aortic aneurysms were induced in hyperglycemic (DM) and normoglycemic models by using intra-aortic porcine pancreatic elastase (PPE) infusion in C57BL/6 mice or by systemic infusion of angiotensin II (ANG) in apolipoprotein E-deficient (ApoE(-/-)) mice, respectively. In an additional DM cohort, insulin therapy was initiated after aneurysm induction. Aneurysmal aortic enlargement progression was monitored with serial transabdominal ultrasound measurements. At sacrifice, AAA cellularity and proteolytic activity were evaluated by immunohistochemistry and substrate zymography, respectively. Influences of serum glucose levels on macrophage migration were examined in separate models of thioglycollate-induced murine peritonitis. RESULTS: At 14 days after PPE infusion, AAA enlargement in hyperglycemic mice (serum glucose ≥ 300 mg/dL) was less than that in euglycemic mice (PPE-DM: 54% ± 19% vs PPE: 84% ± 24%, P < .0001). PPE-DM mice also demonstrated reduced aortic mural macrophage infiltration (145 ± 87 vs 253 ± 119 cells/cross-sectional area, P = .0325), elastolysis (% residual elastin: 20% ± 7% vs 12% ± 6%, P = .0209), and neovascularization (12 ± 8 vs 20 ± 6 vessels/high powered field, P = .0229) compared with PPE mice. Hyperglycemia limited AAA enlargement after ANG infusion in ApoE(-/-) mice (ANG-DM: 38% ± 12% vs ANG: 61% ± 37% at day 28). Peritoneal macrophage production was reduced in response to thioglycollate stimulation in hyperglycemic mice, with limited augmentation noted in response to vascular endothelial growth factor administration. Insulin therapy reduced serum glucose levels and was associated with AAA enlargement rates intermediate between euglycemic and hyperglycemic mice (PPE: 1.21 ± 0.14 mm vs PPE-DM: 1.00 ± 0.04 mm vs PPE-DM + insulin: 1.14 ± 0.05 mm). CONCLUSIONS: Hyperglycemia reduces progression of experimental AAA disease; lowering of serum glucose levels with insulin treatment diminishes this protective effect. Identifying mechanisms of hyperglycemic aneurysm inhibition may accelerate development of novel clinical therapies for AAA disease.

Hyperglycemia modulates plasminogen activator inhibitor-1 expression and aortic diameter in experimental aortic aneurysm disease.

BACKGROUND: Extracellular matrix degradation is a sentinel pathologic feature of abdominal aortic aneurysm (AAA) disease. Diabetes mellitus, a negative risk factor for AAA, may impair aneurysm progression through its influence on the fibrinolytic system. We hypothesize that hyperglycemia limits AAA progression through effects on endogenous plasminogen activator inhibitor-1 (PAI-1) levels and subsequent reductions in plasmin generation. METHODS: Experimental AAAs were induced in diabetic and control mice via the intra-aortic elastase infusion method. Serial transabdominal high-frequency ultrasound examinations were performed to monitor aortic diameter following elastase infusion. Circulating PAI-1 and plasmin alpha2-antiplasmin (PAP) complex concentrations were determined by ELISA and local expression of PAI-1 levels was examined by RT-PCR and immunohistochemistry. RESULTS: Hyperglycemia was associated with reduced AAA diameter, increased plasma PAI-1 concentration and reduced plasmin generation. Aneurysmal aortic PAI-1 gene expression increased in parallel with plasma concentration, with peak expression occurring early after aneurysm initiation. CONCLUSION: Hyperglycemia increases PAI-1 expression and attenuates AAA diameter in experimental AAA disease. These results emphasize the role of the fibrinolytic pathway in AAA pathophysiology, and suggest a candidate mechanism for hyperglycemic inhibition of AAA disease.

Inhibitory effects of a biodegradable gelatin hydrogel sponge sheet on the progression of experimental abdominal aortic aneurysms.

We investigated the effects of a biodegradable gelatin hydrogel sponge sheet (GHSS) or GHSS incorporating basic fibroblast growth factor (GHSS + bFGF), which could prolong the effects of bFGF, on the progression of experimental abdominal aortic aneurysms (AAAs). Experimental AAAs were induced in male Sprague-Dawley rats by intra-aortic elastase infusion. The rats were divided according to the following treatments: (1) untreated, (2) GHSS alone, (3) GHSS incorporating 100 ng, 1 microg, and 10 microg of bFGF. GHSSs were placed over the elastase-infused aortas. After 14 days, the GHSS alone group and the three groups with GHSS + bFGF demonstrated significantly smaller aortic diameters than the untreated group, and these groups significantly attenuated a reduction of the elastic fibers and smooth muscle cells in the pathological findings. However, no additional therapeutic effect was noted between the GHSS alone and GHSS + bFGF groups. Immunohistochemical analysis revealed an increase of positive cells for endogenous bFGF in the media and adventitia of both the GHSS alone and GHSS + bFGF groups in comparison to the untreated group. In conclusion, GHSS itself possessed significant therapeutic effects on AAA progression by inducing the production of endogenous bFGF, leading to the preservation of elastic fibers and smooth muscle cells.

Investigation of major genetic polymorphisms in the Renin-Angiotensin-aldosterone system in subjects with young-onset hypertension selected by a targeted-screening system at university.

Although polymorphisms in renin-angiotensin-aldosterone (RAA) system genes for angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE I/D), angiotensin II type 1 receptor (AT1 A/C1166), and aldosterone synthase (CYP11B2-344T/C) have been major targets for genetic investigation in association with essential hypertension (EH), the influence of these genetic factors is still to be determined. Because patients with young-onset EH are thought to possess a stronger genetic background than EH patients who show elevated BP relatively late in life, the targeted screening of hypertensive students in Tohoku University was completed for the selection of subjects for genetic investigation. Out of 16,434 students (12,794 males and 3,670 females) younger than 30, 22 students showed a high blood pressure (BP) (systolic and diastolic BP of 140 and/or 90 mmHg or greater, respectively, on two occasions and more than 135 and/or 85 mmHg, respectively, at a third measurement during casual BP measurements at the Tohoku University Health Center. These 22 students were asked to measure their BP at home (HBP). Six of the students had a systolic HBP of more than 135 mmHg and/or a diastolic HBP of more than 85 mmHg, and these students subsequently received medical examinations at Tohoku University Hospital and were diagnosed with EH. Genotyping for the four major genetic polymorphisms mentioned above was performed on the six students with EH and on 12 of the remaining 16 students whose HBP was within the normal range (white coat hypertension: WCH). Neither the EH nor the WCH students showed a different distribution of genotypes and allelic frequencies, compared to those found in the general Japanese population. Hence, the present study suggests that none of the major genetic polymorphisms in the RAA system strongly influence the onset of EH.

Lithium effectively complements vasopressin V2 receptor antagonist in the treatment of hyponatraemia of SIADH rats.

BACKGROUND: Although, pharmacological intervention with a selective arginine vasopressin (AVP) V(2) receptor antagonist has been demonstrated to be effective for syndrome of inappropriate secretion of antidiuretic hormone (SIADH), its long-term administration has some therapeutic limitations. Lithium, a drug for bipolar disorders, has been known to cause nephrogenic diabetes insipidus by reducing kidney-specific apical water channel, aquaporin 2 (AQP2) expression in the collecting ducts. However, its pharmacological efficacy for SIADH still remains to be elucidated. METHODS: Hyponatraemia was induced in male Sprague-Dawley rats by water loading and subcutaneous infusion of 1-deamino-8-D-arginine vasopressin. For the treatment, lithium chloride (LiCl) was administered singly or in combination with OPC-31260 and/or furosemide for 7 days. Protein expression of AQP2 was examined by western blotting at the end of the observation period. RESULTS: The LiCl administration elevated serum sodium levels in a dose-dependent manner. The therapeutic effect started 3 days after the initial administration and gradually increased. Western blot analysis at the end of the treatment demonstrated dose-dependent reduction of AQP2 protein expression. Additional administration of LiCl (100 mg/kg/day, the dose demonstrated to maintain serum lithium concentration within therapeutic range) to low dose OPC-31260 maintained well the initial elevation of serum sodium level during the treatment. Western blot analysis after combination therapy demonstrated the absence of re-increase in AQP2 expression noted at the end of OPC-31260 treatment. However, further additive effect could not be obtained even when both LiCl and furosemide were added together to low dose OPC-31260. CONCLUSIONS: Although the single effect of therapeutic dose of lithium was weak, it effectively and safely compensated for the therapeutic limitations of a low dose of AVP V(2) receptor antagonist for SIADH by reducing AQP2 expression.

The elevated level of circulating matrix metalloproteinase-9 in patients with abdominal aortic aneurysms decreased to levels equal to those of healthy controls after an aortic repair.

Matrix metalloproteinase-9 (MMP-9) is abundantly expressed in abdominal aortic aneurysms (AAAs), and it is considered to play a pivotal role in aneurysmal formation. Elevated circulating concentrations of MMP-9 have been reported in patients with AAA, but the influence of an operation on circulating MMP-9 is unclear. Therefore, to clarify the influence of an operation on circulating MMP-9 levels and to determine the role of MMP-9 in the progression of AAA, we measured serum MMP-9 levels in patients before and after AAA repair. Blood samples were obtained from 53 patients with AAA; 22 patients underwent AAA operations, including 17 patients with arterial occlusive disease (AOD), and nine normal control subjects. Serum MMP-9 levels were determined by an enzyme-linked immunosorbent assay. The serum MMP-9 concentration was significantly higher in AAA patients (622.0 +/- 400.2 ng/mL) than in either AOD patients (284.3 +/- 151.4 ng/mL) or healthy controls (280.8 +/- 165.5 ng/mL) (p < 0.001). The mean serum MMP-9 levels in patients undergoing surgery for AAA (268.1 +/- 215.9 ng/mL) was significantly lower than that in AAA patients (p < 0.01). Among the 10 patients whose sera were obtained preoperatively and postoperatively, the serum MMP-9 concentration fell significantly after the patients underwent the operation (p = 0.004). No significant difference was identified in serum MMP-9 concentrations among AOD patients, controls, and postoperative patients. These studies suggest that MMP-9 plays a pivotal role in aneurysm formation, and the circulating MMP-9 level is thus considered to reflect the biological behavior of the aneurysm.

Characteristics of young-onset hypertension identified by targeted screening performed at a university health check-up.

Since the prevalence and clinical characteristics of young-onset hypertension are still to be elucidated, we performed targeted-screening at an annual university health check-up for two consecutive years. Out of 16,464 subjects in 2003 and 17,032 in 2004 that were aged less than 30 years, 22 and 26 students (all males) exhibited high blood pressure (BP), respectively, on three occasions during casual BP measurements at the Tohoku University Health Center (systolic and diastolic BP of 140 and/or 90 mmHg or greater, respectively). These students were asked to measure their BP at home, and 9 subjects in total were diagnosed as having essential hypertension (EH). The remaining students were diagnosed as having white coat hypertension (WCH). In 8 out of 9 EH students, their father and/or mother had also been treated with antihypertensive medication. Adjustment by attendance ratio for each BP measurement suggested that the incidence of EH was around 0.1% and that of hypertension (EH and WCH) was around 0.5% in university students aged less than 25 years, since most of the subjects and hypertensive students were between 18 and 24 years old. Body mass index of the EH, which was more than 25 kg/m2 (overweight), was significantly higher than that with WCH. In conclusion, the combination of repeated casual BP measurements and home BP effectively identified young-onset EH. The clinical parameters indicated that male gender, genetic background, and excessive weight were risk factors for young-onset hypertension.

Transient body fluid accumulation and enhanced NKCC2 expression in gerbils with brain infarction.

BACKGROUND: Enhanced expression of a kidney-specific sodium co-transporter (NKCC2: Na-K-2Cl co-transporter) in the thick ascending limb of Henle has been identified in rat models of congestive heart failure and liver cirrhosis, suggesting that high NKCC2 expression underlies edema formation. An increased abundance of NKCC2, however, has also been noted in rats with the syndrome of inappropriate secretion of antidiuretic hormone; hyponatremia without edema. In the present study, we examined NKCC2 expression in non-edematous disease, such as a brain infarction, and investigated the physiological and/or pathological characterization of NKCC2 expression. METHODS: We initially examined NKCC2 expression in an animal model of brain infarction. Mongolian gerbils (around 60 g body weight) underwent bilateral clamping of the common carotid arteries for 5 min for the induction of brain infarction. NKCC2 and apical water channel (AQP2) protein levels in the collecting duct were examined by Western blotting in kidney tissues 2, 7, and 14 days after the brain infarction. Gerbils with brain infarction were then fed either a normal low-sodium diet (0.3 g/kg/day) or a high-sodium diet (3.0 g/kg/day), and body weight, urine volume and urinary osmolality were examined daily. Blood parameters were measured on day 14 after the brain infarction. RESULTS: Histochemical examination of the brain confirmed the presence of brain infarction, as manifested by altered cresyl violet staining in the hippocampus. Protein levels of NKCC2 were significantly increased in gerbils with brain infarction on days 2 and 7 after brain infarction, whereas AQP2 protein signals remained unaltered. However, the increased NKCC2 intensity disappeared on day 14. Body weight gain was slightly, but significantly greater in gerbils with brain infarction than in sham-operated gerbils up to 7 days after the brain infarction. The high-sodium diet resulted in significant urinary concentration and enhanced weight gain in infarcted gerbils. CONCLUSION: We noted increased NKCC2 abundance in non-edematous disease, which enhanced body fluid accumulation, likely via the sodium loading-dependent concentration of the urine. These results suggest that the physiological process of edema formation is based on specific NKCC2 expression. The transient duration of these findings in the present animal model suggests two different characteristics of specific NKCC2 expression, an immediate, transient appearance as a common response in serious conditions and more chronic expression that leads to edema formation.

BSC1 inhibition complements effects of vasopressin V2 receptor antagonist on hyponatremia in SIADH rats.

BACKGROUND: Severe hyponatremia is most frequently caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Although the expressional alteration of the kidney-specific apical water channel, aquaporin 2 (AQP2), in the collecting duct has been demonstrated to be involved in the development of hyponatremia and the subsequent physiologic reaction that is resistant to arginine vasopressin (AVP; vasopressin escape) in SIADH, the complete pathogenesis of and the appropriate medical treatment for hyponatremia have yet to be elucidated. METHODS: Hyponatremia was induced in male Sprague-Dawley rats by water loading and subcutaneous infusion of 1-deamino-8-D-arginine vasopressin (dDAVP). For the treatment, a selective AVP V(2) receptor antagonist (OPC-31260) and/or a loop diuretic (furosemide) were administered orally. Protein expression of AQP2 and rat bumetanide-sensitive cotransporter (rBSC1) was examined by Western blotting during the hyponatremia and the subsequent treatment. RESULTS: We noted a markedly high expression of rBSC1 during the development of hyponatremia, and a relatively low expression during vasopressin escape. OPC-31260 administration elevated serum sodium level in a dose-dependent manner. The therapeutic effect, however, declined with increasing number of treatment days, and doses higher than 15 mg/kg/day induced severe toxicity. The physiologic parameters and the alterations of AQP2 and rBSC1 expression during the treatment demonstrated reactions that were completely opposite to those of vasopressin escape. Combination of a furosemide (100 mg/kg/day) and a low dose of OPC-31260 (5 mg/kg/day) additively elevated serum sodium level and sustained the elevated serum sodium level by significantly reducing sodium accumulation in the renal medulla. CONCLUSION: AVP-induced alterations of rBSC1 expression, as well as those of AQP2, are involved in the pathogenesis of SIADH. The pharmacologic blockade of AVP stimulus in SIADH limits its therapeutic efficacy by discontinuing the vasopressin escape, and the selective inhibition of rBSC1 complements this limitation.

Steroid resistance in prolonged type I membranoproliferative glomerulonephritis and accelerated disease remission after steroid withdrawal.

Two cases of severe proteinuria and hypocomplementemia were referred to our out patient clinic for continuous follow-up. Initial onset of clinical symptoms was at the age of 15 years in both cases. They had already been diagnosed as type I membranoproliferative glomerulonephritis (type I MPGN) by renal biopsy when oral prednisolone administration had been initiated. Several courses of steroid pulse therapy were performed for the flares of the disease, resulting in only temporary amelioration of renal symptoms. Percutaneous renal biopsy was performed during admission on both cases, showing severe glomerular and tubulointerstitial damages, in addition to typical type I MPGN findings such as mesangial cells and matrix interposition and subendothelial deposits. Because the continuous administration of steroid for more than 10 years did not ameliorate the clinical symptoms, steroid was markedly reduced or stopped in these cases. Such withdrawal from steroid therapy accelerated the amelioration of renal symptoms, including decrease in proteinuria, elevation of plasma protein and complement levels, and disappearance of generalized edema. The clinical courses of these cases indicate clinical choice of withdrawal from steroid therapy as one of the treatments in prolonged type I MPGN, which presents in childhood and shows steroid resistance.

Residual urinary concentrating ability and AQP2 expression in a rat model for chronic renal failure.

BACKGROUND: In chronic renal failure (CRF), a defect in urinary concentrating ability develops gradually as the renal failure progresses. Although several molecular mechanisms associated with renal urinary concentration are reported to be impaired in a rat model for renal failure, the mechanisms underlying residual urinary concentration ability in CRF remain to be elucidated. METHODS: Rats that underwent an 8-week recovery period after 5/6 nephrectomy were used as the model for CRF. Urinary concentration was induced by 24-hour water restriction. Plasma osmolality and arginine vasopressin (AVP) were measured from blood sampled by inserting a catheter into the femoral artery before and after the water restriction. AQP2 mRNA expression in the inner medulla was examined by competitive PCR and in situ hybridization, and protein expression, by Western blotting. Rats that underwent sham operation were used as control. RESULTS: Water restriction significantly reduced urine volume and increased urine osmolality in CRF rats, although such changes were much less than those in sham-operated rats. Plasma AVP was elevated at the basal condition, and further elevation was noted after water restriction. AQP2 mRNA signals were significantly intensified by water restriction even in CRF rats, although the increase was limited as in the case of urine osmolality. Western blotting also showed a small but significant enhancement of protein signals in response to water restriction in CRF rats. CONCLUSIONS: We noted a weak but significant response of AQP2 expression to dehydration in CRF rats. This response in the collecting duct may be one of the factors contributing to residual urinary concentrating ability in CRF.