A Polymorphism rs6726395 in Nrf2 Contributes to the Development of Emphysema-Associated Age in Smokers Without COPD.

INTRODUCTION: Several studies have reported that single nucleotide polymorphisms (SNPs) in the gene encoding NF-E2-related factor 2 (Nrf2) contribute to airflow limitations in smokers without COPD. Although small airway lesions and emphysema contribute cooperatively to airflow limitation, the relationship between Nrf2 SNPs and the development of emphysema in smokers without COPD is not well understood. METHODS: Healthy subjects who underwent an annual health checkup with computed tomography (CT) of the chest at Osaka City University Hospital were prospectively recruited. The percentage of low-attenuation area (%LAA) on chest CT was quantified, and correlations between %LAA, Nrf2 SNP [rs6726395 (G/A)] genotypes, and clinical characteristics were examined. RESULTS: A total of 245 subjects without COPD [non-/light-smoker: 153 (62.4%) and smoker: 92 (37.6%)] were enrolled. The %LAA in the upper lung field was higher than that in the lower lung field (p < 0.001). The %LAA in smokers was significantly higher than that in non-/light-smokers (p = 0.021). The %LAA showed significant but weak correlation with age in all subjects (r = 0.141, p = 0.028). Divided by genotype, the %LAA of the upper lung field was significantly correlated with age in smokers with genotype GG (wild type) (r = 0.333, p = 0.022), but was not significantly correlated with age in smokers with genotype AG/AA. These correlations were not observed in non-/light smokers. CONCLUSION: A polymorphism rs6726395 in Nrf2 can contribute to the development of emphysema-associated aging in smokers. The Nrf2 SNP may be a predictive factor for smoking-induced emphysema, and genotyping of Nrf2 SNP may serve as biomarker for emphysema prevention.

Safety and efficacy of guselkumab in Japanese patients with moderate-to-severe plaque psoriasis: a randomized, placebo-controlled, ascending-dose study.

BACKGROUND: The interleukin (IL)-23/IL-17 pathway is central in the pathogenesis of psoriasis. The favourable efficacy and safety of guselkumab, an IL-23-specific monoclonal antibody, has been demonstrated in global phase III studies of plaque psoriasis. OBJECTIVES: To evaluate the safety, efficacy and pharmacokinetics of single-dose subcutaneous guselkumab in Japanese patients with moderate-to-severe plaque psoriasis. METHODS: Patients with ≥ 10% of total body surface area involvement and a Psoriasis Area and Severity Index (PASI) ≥ 12 were randomized (5 : 1) to receive guselkumab or placebo in four cohorts of this double-blind, placebo-controlled, single ascending-dose, single-centre study. Safety, pharmacokinetics and clinical response were monitored at baseline and specific time points over a 24-week follow-up period. RESULTS: To week 24, 55% (11/20) of patients in the guselkumab group and 50% (2/4) in the placebo group experienced ≥1 adverse event (AE). No deaths, serious AEs or AEs leading to treatment discontinuation were reported. Maximum clinical response was seen at week 16 with PASI 75 (≥ 75% improvement from baseline PASI) response in two of five (10 mg), four of five (30 mg and 300 mg) and three of five (100 mg) patients; and PASI 90 (≥ 90% improvement from baseline PASI) in zero of five (10 mg), three of five (30 mg), two of five (100 mg) and three of five (300 mg) patients. Mean maximum serum concentration (Cmax ) and area under the curve from time zero to infinity values increased in a dose-proportional manner with a mean terminal half-life of 15·6-17·6 days and median time to reach Cmax of 4-6 days. CONCLUSIONS: Guselkumab was generally well-tolerated and exhibited sustained high levels of clinical response in Japanese patients with moderate-to-severe psoriasis.

Longitudinal monitoring of CYP3A activity in patients receiving 3 cycles of itraconazole pulse therapy for onychomycosis.

WHAT IS KNOWN AND OBJECTIVE: Itraconazole, a CYP3A inhibitor, is used for the treatment for onychomycosis with a three-cycle pulse therapy over 3 months, but its effects on in vivo CYP3A activity during the entire course remain unknown. METHODS: Urinary 6ß-hydroxycortisol/cortisol ratios were determined in 19 patients with onychomycosis, before therapy, during three cycles of itraconazole pulse therapy (200 mg twice daily for a week in each monthly cycle) and at 3 month after completion of therapy. RESULTS AND DISCUSSION: The mean 6ß-hydroxycortisol/cortisol ratio was reduced by 68% from baseline (P < 0·05) after the 1st pulse dosing, but the inhibitory effect appeared to be resolved before the next pulse dosing and at 3 months post-treatment. The magnitude of inhibition appeared in proportion to the baseline CYP3A activity. WHAT IS NEW AND CONCLUSION: The inhibitory effect of itraconazole pulse therapy on the in vivo CYP3A activity appears clinically relevant at the end of each cycle, but the inhibition resolves, on average, within 3 weeks.

Surfactant protein C G100S mutation causes familial pulmonary fibrosis in Japanese kindred.

Several mutations in the surfactant protein C (SP-C) gene (SFTPC) have been reported as causing familial pulmonary fibrosis (FPF). However, the genetic background and clinical features of FPF are still not fully understood. We identified one Japanese kindred, in which at least six individuals over three generations were diagnosed with pulmonary fibrosis. We examined the patients radiologically and histopathologically and sequenced their SFTPC and ABCA3 genes. We also established a cell line stably expressing the mutant gene. All the patients had similar radiological and histopathological characteristics. Their histopathological pattern was that of usual interstitial pneumonia, showing numerous fibroblastic foci even in areas without abnormal radiological findings on chest high-resolution computed tomography. No child had respiratory symptoms in the kindred. Sequencing of SFTPC showed a novel heterozygous mutation, c.298G>A (G100S), in the BRICHOS domain of proSP-C, which co-segregated with the disease. However, in the ABCA3 gene, no mutation was found. In vitro expression of the mutant gene revealed that several endoplasmic reticulum stress-related proteins were strongly expressed. The mutation increases endoplasmic reticulum stress and induces apoptotic cell death compared with wild-type SP-C in alveolar type II cells, supporting the significance of this mutation in the pathogenesis of pulmonary fibrosis.

VEGF-D promotes the metastatic spread of tumor cells via the lymphatics.

Metastasis to local lymph nodes via the lymphatic vessels is a common step in the spread of solid tumors. To investigate the molecular mechanisms underlying the spread of cancer by the lymphatics, we examined the ability of vascular endothelial growth factor (VEGF)-D, a ligand for the lymphatic growth factor receptor VEGFR-3/Flt-4, to induce formation of lymphatics in a mouse tumor model. Staining with markers specific for lymphatic endothelium demonstrated that VEGF-D induced the formation of lymphatics within tumors. Moreover, expression of VEGF-D in tumor cells led to spread of the tumor to lymph nodes, whereas expression of VEGF, an angiogenic growth factor which activates VEGFR-2 but not VEGFR-3, did not. VEGF-D also promoted tumor angiogenesis and growth. Lymphatic spread induced by VEGF-D could be blocked with an antibody specific for VEGF-D. This study demonstrates that lymphatics can be established in solid tumors and implicates VEGF family members in determining the route of metastatic spread.

Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3.

The lymphatic vasculature transports extravasated tissue fluid, macromolecules and cells back into the blood circulation. Recent reports have focused on the molecular mechanisms regulating the lymphatic vessels. Vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to stimulate lymphangiogenesis and their receptor, VEGFR-3, has been linked to human hereditary lymphedema. Here we show that a soluble form of VEGFR-3 is a potent inhibitor of VEGF-C/VEGF-D signaling, and when expressed in the skin of transgenic mice, it inhibits fetal lymphangiogenesis and induces a regression of already formed lymphatic vessels, though the blood vasculature remains normal. Transgenic mice develop a lymphedema-like phenotype characterized by swelling of feet, edema and dermal fibrosis. They survive the neonatal period in spite of a virtually complete lack of lymphatic vessels in several tissues, and later show regeneration of the lymphatic vasculature, indicating that induction of lymphatic regeneration may also be possible in humans.

Neutrophil emigration in the skin, lungs, and peritoneum: different requirements for CD11/CD18 revealed by CD18-deficient mice.

To determine the role of CD11/CD18 complexes in neutrophil emigration, inflammation was induced in the skin, lungs, or peritoneum of mutant mice deficient in CD18 (CD18-/- mutants). Peripheral blood of CD18-/- mutants contained 11-fold more neutrophils than did blood of wild-type (WT) mice. During irritant dermatitis induced by topical application of croton oil, the number of emigrated neutrophils in histological sections of dermis was 98% less in CD18-/- mutants than in WT mice. During Streptococcus pneumoniae pneumonia, neutrophil emigration in CD18-/- mutants was not reduced. These data are consistent with expectations based on studies using blocking antibodies to inhibit CD11/CD18 complexes, and on observations of humans lacking CD11/CD18 complexes. The number of emigrated neutrophils in lung sections during Escherichia coli pneumonia, or in peritoneal lavage fluid after 4 h of S. pneumoniae peritonitis, was not reduced in CD18-/- mutants, but rather was greater than the WT values (240 +/- 30 and 220 +/- 30% WT, respectively). Also, there was no inhibition of neutrophil emigration during sterile peritonitis induced by intraperitoneal injection of thioglycollate (90 +/- 20% WT). These data contrast with expectations. Whereas CD11/CD18 complexes are essential to the dermal emigration of neutrophils during acute dermatitis, CD18-/- mutant mice demonstrate surprising alternative pathways for neutrophil emigration during pneumonia or peritonitis.

Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E-selectin and P-selectin double mutant mice.

During the initial phase of the inflammatory response, leukocytes marginate and roll along the endothelial surface, a process mediated largely by the selectins and their ligands. Mice with mutations in individual selectins show no spontaneous disease and have mild or negligible deficiencies of inflammatory responses. In contrast, we find that mice with null mutations in both endothelial selectins (P and E) develop a phenotype of leukocyte adhesion deficiency characterized by mucocutaneous infections, plasma cell proliferation, hypergammaglobulinemia, severe deficiencies of leukocyte rolling in cremaster venules with or without addition of TNF-alpha, and an absence of neutrophil emigration at 4 h in response to intraperitoneal Streptococcus pneumoniae peritonitis. These mice provide strong evidence for the functional importance of selectins in vivo.

Differential diagnosis of cystic tumors of the pancreas by endoscopic ultrasonography.

BACKGROUND AND STUDY AIMS: Generally, cystic tumors are divided into two categories: neoplastic cystic tumors and non-neoplastic cystic (NNC) tumors. Neoplastic cystic tumors include mucinous cystic neoplasm (MCN), intraductal papillary-mucinous neoplasm (IPMN), and serous cystic neoplasm (SCN). MCNs and IPMNs have the potential to progress to a malignant state, whereas SCNs are known for their almost benign behavior. Thus, in order to make management decisions, it is important to distinguish between potentially malignant (MCN and IPMN), and benign (SCN and NNC) tumors. The aim of this study was to retrospectively investigate the value of endoscopic ultrasonography (EUS) for the differential diagnosis of cystic tumors of the pancreas. PATIENTS AND METHODS: A total of 76 patients with cystic tumors of the pancreas were preoperatively examined by EUS. Eight cases were MCNs, 45 were IPMNs, 13 were SCNs, and 10 were NNC tumors. The EUS findings relevant to distinguishing between potentially malignant and benign were analyzed statistically. RESULTS: All patients with MCNs were female and all these tumors were located in the pancreatic body/tail. IPMN, however, occurred predominantly in men, and in the pancreatic head. Eight of 11 monolocular cystic tumors were NNC in nature. Eleven of 13 SCNs included microcystic areas within the tumors. All MCNs were round in appearance, whereas 93 % of IPMNs were not round in appearance. Mural nodules were present in 25 % of MCN and 38 % of IPMN cases. In univariate analysis, age, tumor size, locularity, the number of cystic formation, cystic component, and appearance were significant variables. In multivariate analysis, locularity and cystic component were important for differential diagnosis of potentially malignant cystic tumors. CONCLUSIONS: The characteristics of cystic tumors of the pancreas revealed by EUS are useful for their differential diagnosis.

Multiple intravascular papillary endothelial hyperplasia affecting skin and bone.

We report a 75-year-old man with multiple recurrent black papules involving his entire body. In the course of 3 years, 20 lesions were resected, which were histologically confirmed as intravascular papillary endothelial hyperplasia (IPEH). A similar vascular lesion was found on his tibia. The occurrence of multiple IPEH affecting skin and bone is extremely rare. The patient's medical history included hepatitis C, hepatoma and associated coagulopathy. We suggest that this patient's multiple lesions were induced by microthrombus formation due to liver dysfunction.

Radiological outcome after treatment of juvenile flatfeet with subtalar arthroereisis: a matched pair analysis of 38 cases comparing neurogenic and non-neurogenic patients.

PURPOSE: Therapy of juvenile neurogenic flatfoot (JNF) with subtalar arthroereisis (SA) is currently under critical clinical investigation. In this retrospective matched pair analysis, the radiological outcome after arthroereisis in paediatric patients with infantile cerebral palsy and JNF was compared with children with juvenile flatfeet (JF) without neurological diseases. METHODS: From October 2007 to April 2018 80 patients with 149 flatfeet underwent surgery with SA. Inclusion criteria were: 1) JNF or JF with age at surgery ≤ 13 years; 2) treatment with SA; 3) presence of three sets of biplane radiographs (preoperative, postoperative and follow-up (FU)). The radiographs were analyzed for: 1) navicular-cuboidal-index (NCI); 2) talocalcaneal angle anteroposterior; 3) talocalcaneal angle lateral; 4) calcaneal-pitch (CP); and 5) talometatarsal-index (TMTI). Following this, 25 patients with 38 flatfeet could be included. RESULTS: The mean age at SA of the JNF group was 9.2 years (JF group: 9.3 years) and the mean time of FU was 35.2 months (JF group: 39.4 months). In comparison with preoperatively, a significant decrease of the NCI was seen in both groups (p = ≤ 0.05 and p = ≤ 0.001) in the FU radiographs. The analysis of CP and TMTI in the JF group also resulted in a significant improvement (p = ≤ 0.001 and p = ≤ 0.05). Overall, the comparison between the JNF and JF group showed no significant differences in regard to the analyzed postoperative parameters. CONCLUSION: Based on this data, treatment of flatfeet by SA in patient with neurological disorders shows an improvement of radiological parameters comparable with neurologically unimpaired patients and might be considered as additional treatment option. LEVEL OF EVIDENCE: IV.

Continued inhalation of lidocaine suppresses antigen-induced airway hyperreactivity and airway inflammation in ovalbumin-sensitized guinea pigs.

It is unclear whether inhaled lidocaine is effective against airway hyperreactivity and inflammation in asthma. The aim of this study was to investigate the effects of inhaled lidocaine on airway hyperreactivity and inflammation. Airway reactivity to inhaled histamine, cellular composition of bronchoalveolar lavage (BAL) fluid, plasma substance P (SP), and isolated lung tissue were evaluated in ovalbumin (OVA)-sensitized guinea pigs 7 days after OVA challenge. The effects of inhaled lidocaine on this model were also evaluated. Treatment with lidocaine was administered in two fashions: as single inhalation or inhalation bid for 7 consecutive days, for comparison with a saline-inhaled control group. Airway hyperreactivity to histamine, increase in number of total cells and increased proportion of eosinophils in BAL fluid, and marked eosinophil infiltration in airway walls were noted even 7 days after OVA challenge in the control group. Plasma SP level was also significantly increased. Although treatment with single lidocaine inhalation did not affect airway hyperreactivity, continued inhalation (bid for 7 days) attenuated airway hyperreactivity. Continued, but not single, inhalation of lidocaine also suppressed infiltration of eosinophils in BAL fluid and in airway walls. In addition, plasma SP levels were significantly reduced by continued but not by single inhalation. It appears possible that lidocaine when inhaled suppresses eosinophilic inflammation of the airway and SP-induced neurogenic inflammation, leading to alleviation of airway hyperreactivity.

Diffusion-weighted magnetic resonance imaging of urinary epithelial cancer with upper urinary tract obstruction: preliminary results.

BACKGROUND: Various malignant tumors of the body show high signal intensity on diffusion-weighted magnetic resonance imaging (DWI). In the genitourinary region, DWI is expected to have a role in detecting urinary epithelial cancer noninvasively. PURPOSE: To demonstrate the feasibility of DWI for the diagnosis of urinary epithelial cancer with upper urinary tract obstruction. MATERIAL AND METHODS: Twenty upper urinary tract cancers in 16 patients were evaluated by high-b-value DWI (b=800 s/mm(2)). The signal intensity was visually evaluated, and the apparent diffusion coefficients (ADCs) were measured. RESULTS: All urinary epithelial cancers showed high signal intensity on DWI. The ADC in cancerous lesions was 1.31+/-0.27 x 10(-3) mm(2)/s, which was significantly lower than that of the lumens of the ureter or renal pelvis (3.32+/-0.44 x 10(-3) mm(2)/s; P<0.001). Maximum intensity projection images of DWI in combination with static-fluid MR urography provided three-dimensional entire urinary tract imaging with the extension of tumors. CONCLUSION: DWI is useful in the tumor detection and in evaluating the tumor extension of urinary epithelial cancer in patients with upper urinary tract obstruction.

High-b-value diffusion-weighted magnetic resonance imaging of pancreatic cancer and mass-forming chronic pancreatitis: preliminary results.

BACKGROUND: Mass-forming chronic pancreatitis may mimic a pancreatic cancer on dynamic computed tomography (CT) and magnetic resonance (MR) imaging, and preoperative differential diagnosis is often difficult. Recently, the usefulness of diffusion-weighted MR imaging (DWI) in the diagnosis of pancreatic cancer has been reported in several studies. PURPOSE: To determine whether high-b-value DWI can distinguish pancreatic cancer from benign mass-forming chronic pancreatitis. MATERIAL AND METHODS: Twenty pancreatic cancers and four cases of mass-forming chronic pancreatitis were evaluated by high-b-value DWI (b=800 s/mm(2)). The signal intensity on DWI was visually evaluated, and the isotropic apparent diffusion coefficients (ADCs) were measured. RESULTS: All twenty pancreatic cancers showed high signal intensity (18 showed very high, two showed slightly high) on DWI. None of the mass-forming chronic pancreatitis cases showed very high intensity (three showed iso to low, one showed slightly high) on DWI. The ADCs in the pancreatic cancer and mass-forming chronic pancreatitis were 1.38 +/- 0.32 x 10(-3) mm(2)/s and 1.00 +/- 0.18 x 10(-3) mm(2)/s, respectively (P < 0.05). CONCLUSION: On high-b-value DWI, most pancreatic cancers showed very high signal intensity, and may hence be distinguished from benign mass-forming chronic pancreatitis based on our preliminary results.

Apnoea-hypopnoea index during rapid eye movement and non-rapid eye movement sleep in obstructive sleep apnoea.

This study investigated the differences in apnoea-hypopnoea index (AHI) during rapid eye movement (REM) sleep (AHI-REM) and AHI during non-REM (NREM) sleep (AHI-NREM) in patients with obstructive sleep apnoea (OSA). Nocturnal polysomnography was performed in 102 Japanese OSA patients and their AHI along with a variety of other factors were retrospectively evaluated. Regardless of the severity of AHI, mean apnoea duration was longer and patients' lowest recorded oxygen saturation measured by pulse oximetry was lower during REM sleep than during NREM sleep. Approximately half of the patients (n = 50) had a higher AHI-NREM than AHI-REM. In subjects with AHI >or= 60 events/h, AHI-NREM was significantly higher than AHI-REM. On multivariate logistic regression, severe AHI >or= 30 events/h was the only predictor of a higher AHI-NREM than AHI-REM. This may indicate that important, but unknown, factors related to the mechanism responsible for the severity of OSA are operative during NREM sleep.

The six-year results of a combined surgical and endovascular repair for thoracoabdominal aortic aneurysm involving the visceral arteries.

The authors report a case of a combined endovascular and open repair (hybrid procedure) for a mycotic thoracoabdominal aneurysm (TAAA) including its 6-year result. A 72-year-old man with diabetes mellitus, old brain infarction and moderate aortic stenosis was transferred to the hospital because of obstinate fever and back pain, The initial computed tomography (CT) scan revealed giant (TAAA), and from the laboratory findings, the white blood cell and C-reactive protein (CRP) were significantly elevated 12,400/mm3 and 23.9 mg/dL respectively. Based on the CT and laboratory findings, a mycotic TAAA was highly suspected. After the remission of inflammation, graft replacement with reconstruction of celiac trunk (CA) and superior mesenteric artery (SMA) was performed via spiral incision under extracorporeal circulation. two months after the first operation, the patient complained about his back pain again. CT showed a pseudoaneurysm which formed at the distal anastomotic site. A hybrid procedure was deemed to be the most appropriate for such patient who needs a second operation. First bilateral renal artery bypass (ilio-renal artery bypass) were done using the saphenous vein grafts (SVGs). Following bypass grafting to renal arteries, endovascular aneurysm repair was performed with handmade stent-graft which was fabricated using a self-expanding "Z" stent and woven Dacron graft. The postoperative course was uneventful, and follow-up CT showed the aneurysm to have shrunk with no endoleaks. At six months after hybrid procedure, the shrinkage of the aneurysm sac and the patency of the graft to renal arteries were confirmed by a CT scan. A hybrid procedure is considered to be useful and feasible for the poor surgical candidate with severe comorbidities, hostile abdomen and a complex anatomy. The long-term results of this hybrid procedure is considered to be promising.

Poorer radiological outcome after delayed diagnosis and treatment in human position in Fettweis plaster cast in 93 unstable hip joints type D, III and IV according to Graf.

PURPOSE: In this study the course of unstable hips after successful treatment with Fettweis plaster of Paris (POP) is examined. Special focus will be given to age at beginning of treatment and initial hip type. METHODS: The development of 93 unstable hips treated between November 2001 and April 2015 was examined. Inclusion criteria were: 1) unstable hips with successful treatment with Fettweis POP; 2) presence of two pelvic radiographs (12 to 24 months and 24 to 48 months). We analyzed: 1) the initial ultrasound hip type according to Graf; 2) the average age at first and second radiograph; 3) the Tönnis classification: normal findings (< 1 SD), slightly (1 SD to 2 SD) and severely dysplastic hips (> 2 SD). RESULTS: In all, there were 14 hips type D, 41 hips type III and 38 hips type IV. Mean age of the first radiograph was 13.9 months and of the second 28.5 months. The first radiograph showed: (< 1 SD): 36, (1 SD to 2 SD): 34, (> 2 SD): 23 hips, the second radiograph: (< 1 SD): 33, (1 SD to 2 SD): 19, (> 2 SD): 30 hips. With subdivision at the start of treatment at age eight or fewer weeks 2/16 hips (12.5%) and with initiation of the treatment more than eight weeks 22/77 (26.0%) deteriorated. During the course between first and second radiograph a total of 35.7% of initial hip type D, 19.5% of type III and 23.7% of type IV deteriorated. CONCLUSION: Radiograph controls after treatment with Fettweis POP show poorer outcome after delaying the start of treatment more than 8 weeks. These findings were independent of the initial ultrasound hip type. Regular radiograph controls of all hip types treated for unstable hips are justified to detect residual dysplasia. LEVEL OF EVIDENCE: IV.

Preservation of complement-induced lung injury in mice with deficiency of NADPH oxidase.

Mice with chronic granulomatous disease (X-CGD mice) generated by mutating the X-linked gene for a subunit of NADPH oxidase have been analyzed for their ability to respond to intravenous injection of purified cobra venom factor (CVF). This agent in wild-type mice produces a neutrophil-dependent and catalase-sensitive form of lung injury. Lung injury was evaluated by measuring the accumulation of extravascular albumin. Quite unexpectedly, the lungs of X-CGD mice showed no difference in the increased accumulation of extravascular albumin after injection of CVF when compared to wild-type mice. In both X-CGD and wild-type mice, full development of injury required neutrophils. While catalase was highly protective in wild-type mice, its protective effects were completely lost in the X-CGD mice. Furthermore, a competitive antagonist of L-arginine, N(G)-methyl-L-arginine, was protective in X-CGD mice but not in wild-type mice. Allopurinol was protective in both types of mice. Both the basal and the CVF-inducible lung mRNA for inducible nitric oxide synthase and IL-1beta was similar in X-CGD and wild-type mice. These data indicate that oxygen radical production and lung injury in response to injection of CVF occurs through alternative pathways in mice with genetic deletion of NADPH oxidase.

Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy.

Studies conducted over the last decade demonstrated variable therapeutic efficacy of angiotensin converting enzyme (ACE) inhibitor on the progression of glomerular diseases, including IgA nephropathy. In this study, among patients with biopsy-proven IgA nephropathy, 53 patients in whom creatinine clearance had been monitored over 5 yr were recruited for study. These patients were classified into two groups according to whether or not renal function had declined as determined by the slope of creatinine clearance against time: group 1 had stable renal function; group 2 had declining renal function (average: -6.7 +/- 1.3 ml/min/yr). 21 of 53 patients were treated with ACE inhibitor and followed for 48 wk. Gene polymorphism consisting of insertion (I) or deletion (D) of a 287-bp DNA fragment (presumed to be a silencer element) of the ACE gene was determined by PCR. 46 age-matched individuals without history of proteinuria were analyzed as controls. The DD genotype was significantly more frequent in group 2 (43%) than in controls (7%) or group 1 patients with stable renal function (16%). 48 wk after ACE inhibitor administration, proteinuria significantly decreased in patients with DD genotype but not in those with ID or II genotypes. The results indicate that deletion polymorphism in the ACE gene, particularly the homozygote DD, is a risk factor for progression to chronic renal failure in IgA nephropathy. Moreover, this deletion polymorphism predicts the therapeutic efficacy of ACE inhibition on proteinuria and, potentially, on progressive deterioration of renal function.