A case of immunoglobulin G4-related retroperitoneal fibrosis and hypophysitis with antecedent respiratory disease followed by spontaneous remission and recurrence.

A 65-year-old man presented with apparent bronchopneumonia. After treatment with antibiotics, he showed eosinophilia. Computed tomography (CT) imaging revealed bilateral consolidation, ground-glass opacities with nodular consolidations, and pleural effusion. Lung biopsy showed organising pneumonia with lymphoplasmacytic infiltration in the alveolar septa and in the thickened pleura and interlobular septa. All pulmonary abnormalities spontaneously went into remission within 12 months. At 73 years old, a follow-up CT scan revealed small nodules in both lungs and the review of the head CT scan showed thickening of the pituitary stalk in studying prolonged headache. Two years later, he visited the hospital complaining of severe oedema on the lower extremities with high serum immunoglobulin (Ig)G4 186 mg/dl. A whole-body CT scan showed retroperitoneal mass surrounding aortic bifurcation and compressing inferior vena cava, pituitary stalk thickening and gland swelling, and enlarged pulmonary nodules. Anterior pituitary stimulation tests showed central hypothyroidism, central hypogonadism, and adult growth hormone deficiency with partial primary hypoadrenocorticism. Retroperitoneal mass biopsy showed storiform fibrosis and obliterative phlebitis with marked lymphoplasmacytic infiltration with moderate IgG4-positivity. Immunostaining of the former lung specimen revealed dense interstitial infiltration of IgG4-positive cells. These findings indicated metachronous development of IgG4-related disease in lung, hypophysis, and retroperitoneum, according to the recent comprehensive diagnostic criteria of IgG4-related disease. Glucocorticoid therapy ameliorated oedema, on the other hand, unmasked partial diabetes insipidus at the initial dose of the treatment. Hypothyroidism and retroperitoneal mass regressed at 6 months of the treatment. This case warns us that long-term follow-up from prodromal to remission is necessary for the treatment of IgG4-related disease.

Development of Myeloperoxidase Anti-neutrophil Cytoplasmic Antibody-positive Necrotizing Crescentic Glomerulonephritis in an Elderly Patient with Immunological Kidney Disease.

A 78-year-old man presented with hypercalcemia and renal disease with high serum IgG4 and positive myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), exhibiting sarcoidosis-like chest findings. A renal biopsy revealed tubulointerstitial nephritis, membranous nephropathy (MN), and sub-capsular lymphoid aggregates without fulfilling the diagnostic criteria of IgG4-related disease or sarcoidosis. Steroid therapy ameliorated the serological and renal abnormalities. After 5 years, following gradual increases in the neutrophil count and upper respiratory infection (URI), necrotizing crescentic glomerulonephritis (NCGN) developed with an increased serum MPO-ANCA level. These results suggest that in the presence of MPO-ANCA in immune senescence, the persistent neutrophil increase with URI may lead to the development of NCGN.

Chronic hypoxia exacerbates diabetic glomerulosclerosis through mesangiolysis and podocyte injury in db/db mice.

BACKGROUND: Chronic hypoxia may play a pivotal role in the development of diabetic nephropathy (DN). However, the precise mechanisms underlying progressive hypoxia-induced glomerular injury remain unclear. METHODS: We housed db/db mice in a hypoxia chamber (12% O2) for up to 16 weeks beginning at 8 weeks of age. Various urine, serum and kidney abnormalities and glomerular messenger RNA (mRNA) expression were compared with those in age-matched db/db mice housed under normoxia. RESULTS: Levels of urinary albumin and podocalyxin (PCX) were significantly higher in hypoxic mice early during hypoxia. Ultracentrifugation of urine samples revealed that podocytes in the hypoxic mice shed PCX-positive microparticles into the urine. After 16 weeks of hypoxia, the mice also had higher hematocrits with lower serum glucose and various degrees of mesangiolytic glomerulosclerosis with microaneurysms and the infrequent occurrence of nodular lesions. Immunohistologically, hypoxic mice showed significantly decreased endothelial cell densities early during hypoxia and decreased podocyte densities later. In both hypoxic and normoxic mice, glomerular macrophage and transforming growth factor-ß1 (TGF-ß1) staining significantly increased with aging, without changes in vascular endothelial growth factor or endothelial nitric oxide synthase (eNOS). Glomerular mRNA expression of monocyte chemoattractant protein-1, eNOS and TGF-ß1 was significantly enhanced in the hypoxic mice. CONCLUSIONS: These results indicate that chronic hypoxia induces advanced glomerulosclerosis with accelerated albuminuria triggered by mesangiolysis and podocyte injury in a murine model of DN.

Analytical and clinical validation of rapid chemiluminescence enzyme immunoassay for urinary thioredoxin, an oxidative stress-dependent early biomarker of acute kidney injury.

BACKGROUND: Oxidative stress is now recognized to be an important therapeutic target in kidney diseases. However, there are currently no biomarkers that can be used clinically to diagnose renal oxidative stress. METHODS: A rapid assay system for urinary thioredoxin 1, an oxidative stress-dependent biomarker of acute kidney injury (AKI), was developed as a chemiluminescence enzyme immunoassay and validated analytically and clinically. RESULTS: Analytic evaluation revealed that hemolytic hemoglobin caused measurements to be abnormally high, above the detectable range. However, urine sediment containing red blood cells did not affect the measurements. Assays using our proposed chemiluminescence enzyme immunoassay were completed within as little as 6 min, whereas a conventional ELISA > 4 h. Aciduria

Tubulointerstitial Nephritis with IgM-Positive Plasma Cells.

Infiltration by IgG-positive plasma cells is a common finding in tubulointerstitial nephritis. Indeed, it has been thought that CD138-positive mature plasma cells secrete mainly IgG, and the occurrence of tubulointerstitial nephritis with CD138-positive plasma cells secreting IgM has rarely been reported. Routine immunofluorescence of fresh frozen sections is considered the gold standard for detection of immune deposits. However, the immunoenzyme method with formalin-fixed, paraffin-embedded sections is superior for detecting IgM- or IgG-positive cells within the renal interstitium, thus histologic variants may often go undetected. We recently discovered a case of tubulointerstitial nephritis showing IgM-positive plasma cell accumulation within the interstitium. To further explore the morphologic and clinical features of such cases, we performed a nationwide search for patients with biopsy-proven tubulointerstitial nephritis and high serum IgM levels. We identified 13 patients with tubulointerstitial nephritis and IgM-positive plasma cell infiltration confirmed with the immunoenzyme method. The clinical findings for these patients included a high prevalence of distal renal tubular acidosis (100%), Fanconi syndrome (92%), and anti-mitochondrial antibodies (82%). The pathologic findings were interstitial nephritis with diffusely distributed CD3-positive T lymphocytes and colocalized IgM-positive plasma cells, as well as tubulitis with CD3-positive T lymphocytes in the proximal tubules and collecting ducts. Additionally, levels of H+-ATPase, H+, K+-ATPase, and the HCO3--Cl- anion exchanger were markedly decreased in the collecting ducts. We propose to designate this group of cases, which have a common histologic and clinical form, as IgM-positive plasma cell-tubulointerstitial nephritis.

Serum CETP status is independently associated with reduction rates in LDL-C in pitavastatin-treated diabetic patients and possible involvement of LXR in its association.

BACKGROUND: Statins decrease cholesteryl ester transfer protein (CETP) levels, which have been positively associated with hepatic lipid content as well as serum low density lipoproteins-cholesterol (LDL-C) levels. However, the relationship between the CETP status and statin-induced reductions in LDL-C levels has not yet been elucidated in detail. We herein examined the influence of the CETP status on the lipid-reducing effects of pitavastatin in hypercholesterolemic patients with type 2 diabetes mellitus as well as the molecular mechanism underlying pitavastatin-induced modifications in CETP levels. METHODS: Fifty-three patients were treated with 2 mg of pitavastatin for 3 months. Serum levels of LDL-C, small dense (sd) LDL-C, and CETP were measured before and after the pitavastatin treatment. The effects of pitavastatin, T0901317, a specific agonist for liver X receptor (LXR) that reflects hepatic cholesterol contents, and LXR silencing on CETP mRNA expression in HepG2 cells were also examined by a real-time PCR assay. RESULTS: The pitavastatin treatment decreased LDL-C, sdLDL-C, and CETP levels by 39, 42, and 23%, respectively. Despite the absence of a significant association between CETP and LDL-C levels at baseline, baseline CETP levels and its percentage change were an independent positive determinant for the changes observed in LDL-C and sdLDL-C levels. The LXR activation with T0901317 (0.5 µM), an in vitro condition analogous to hepatic cholesterol accumulation, increased CETP mRNA levels in HepG2 cells by approximately 220%, while LXR silencing markedly diminished the increased expression of CETP. Pitavastatin (5 µM) decreased basal CETP mRNA levels by 21%, and this was completely reversed by T0901317. CONCLUSION: Baseline CETP levels may predict the lipid-reducing effects of pitavastatin. Pitavastatin-induced CETP reductions may be partially attributed to decreased LXR activity, predictable by the ensuing decline in hepatic cholesterol synthesis. TRIAL REGISTRATION: UMIN Clinical Trials Registry ID UMIN000019020.

[Kidney Disease and Laboratory Examinations--Opening Remarks: For Better Understanding of CKD].

Chronic kidney diseases (CKD) have been cited as major risk factors not only for endstage renal failure, but also for the development of cardiovascular diseases and death. In the former criteria for CKD diagnosis (NKF K/DOQI, 2002), estimation of the severity of CKD was simply based on GFR, in order for it to be widely and easily understood by general physicians and patients. Therefore, the use of the CKD guideline without information on the causes and grades of albuminuria was limited for estimation of the prognosis. The revised guideline for CKD diagnosis (KDIGO CKD guideline 2012), with the disease category specified for diabetes mellitus and the different scoring system of microalbuminuria, is presently being effectively utilized by nephrologists as well as general physicians. In this symposium, to advice understanding of the causes and evaluation methods of CKD, speakers were invited to discuss topics in kidney pathology, urine sample examination, urinary biomarkers, and GFR.

Renal resistive index correlates with peritubular capillary loss and arteriosclerosis in biopsy tissues from patients with chronic kidney disease.

BACKGROUND: The renal resistive index (RI) is a Doppler-derived measure that reportedly correlates with renal histological changes and renal disease severity and outcome. The aim of this study was to investigate the factors related to the RI elevation in chronic kidney disease (CKD). METHODS: Using Doppler ultrasonography, RIs were determined in 30 patients with CKD, after which they were correlated with interstitial fibrosis, arteriosclerosis, arteriolosclerosis and peritubular capillary (PTC) density. PTC-positive areas were determined based on CD34 immunostaining. Interstitial fibrosis was detected with Masson trichrome staining. All histological markers were assessed using quantitative and semi-quantitative analyses and evaluated statistically using Pearson correlation tests, unpaired t tests and stepwise multiple regression analysis. RESULTS: RI correlated positively with age (r = 0.603, p = 0.0004), systolic blood pressure (r = 0.775, p < 0.0001), diastolic blood pressure (r = 0.575, p = 0.001), interstitial fibrosis (r = 0.381, p = 0.038) and arteriosclerosis (r = 0.520, p = 0.003), and negatively with creatinine clearance (r = -0.471, p = 0.009) and CD34+ (PTC) areas (r = -0.437, p = 0.016). Patients with hypertension or diabetes mellitus showed higher RIs (p < 0.05) than those without the ailments. Multivariate analysis showed PTC and arteriosclerosis to be independent variables correlating with RI (r (2) = 0.321, p < 0.05). CONCLUSIONS: To our knowledge, this is the first report of using RI measurements to evaluate peritubular capillary loss. Our findings indicate that increases in RI are associated with both arteriosclerosis and loss of PTCs.

Telmisartan, a possible PPAR-δ agonist, reduces TNF-α-stimulated VEGF-C production by inhibiting the p38MAPK/HSP27 pathway in human proximal renal tubular cells.

Vascular endothelial growth factor-C (VEGF-C) is a main inducer of inflammation-associated lymphangiogenesis in various inflammatory disorders including chronic progressive kidney diseases, for which angiotensin II receptor type 1 blockers (ARBs) are widely used as the main treatment. Although proximal renal tubular cells may affect the formation of lymphatic vessels in the interstitial area by producing VEGF-C, the molecular mechanisms of VEGF-C production and its manipulation by ARB have not yet been examined in human proximal renal tubular epithelial cells (HPTECs). In the present study, TNF-α dose-dependently induced the production of VEGF-C in HPTECs. The TNF-α-induced production of VEGF-C was mediated by the phosphorylation of p38MAPK and HSP27, but not by that of ERK or NFkB. Telmisartan, an ARB that can activate the peroxisome proliferator-activated receptor (PPAR), served as a PPAR-δ activator and reduced the TNF-α-stimulated production of VEGF-C. This reduction was partially attributed to a PPAR-δ-dependent decrease in p38MAPK phosphorylation. Our results indicate that TNF-α induced the production of VEGF-C in HPTECs by activating p38MAPK/HSP27, and this was partially inhibited by telmisartan in a PPAR-δ dependent manner. These results provide a novel insight into inflammation-associated lymphangiogenesis.

Renal redox dysregulation in AKI: application for oxidative stress marker of AKI.

Oxidative stress is a major determinant of acute kidney injury (AKI); however, the effects of an AKI on renal redox system are unclear, and few existing AKI markers are suitable for evaluating oxidative stress. We measured urinary levels of the redox-regulatory protein thioredoxin 1 (TRX1) in patients with various kinds of kidney disease and in mice with renal ischemia-reperfusion injury. Urinary TRX1 levels were markedly higher in patients with AKI than in those with chronic kidney disease or in healthy subjects. In a receiver operating characteristic curve analysis to differentiate between AKI and other renal diseases, the area under the curve for urinary TRX1 was 0.94 (95% confidence interval, 0.90-0.98), and the sensitivity and specificity were 0.88 and 0.88, respectively, at the optimal cutoff value of 43.0 µg/g creatinine. Immunostaining revealed TRX1 to be diffusely distributed in the tubules of normal kidneys, but to be shifted to the brush borders or urinary lumen in injured tubules in both mice and humans with AKI. Urinary TRX1 in AKI was predominantly in the oxidized form. In cultured human proximal tubular epithelial cells, hydrogen peroxide specifically and dose dependently increased TRX1 levels in the culture supernatant, while reducing intracellular levels. These findings suggest that urinary TRX1 is an oxidative stress-specific biomarker useful for distinguishing AKI from chronic kidney disease and healthy kidneys.

Telmisartan activates endogenous peroxisome proliferator-activated receptor-δ and may have anti-fibrotic effects in human mesangial cells.

Telmisartan, an angiotensin II receptor type 1 blocker (ARB), was recently reported to promote lipolysis in mice by acting as a peroxisome proliferator-activated receptor (PPAR)-δ activator, although in clinical studies, it has also been recognized to activate PPAR-γ as a major cause of its pleiotropic actions. The aim of this study was to investigate whether telmisartan activates endogenous PPAR-δ and thereby exerts anti-fibrotic effects in human mesangial cells (HMC). Immunohistochemical analysis of human renal biopsy specimens revealed that PPAR-δ protein was detected in the HMC of glomeruli with moderately proliferative changes. In the HMC, both GW0742, an authentic PPAR-δ agonist, and telmisartan enhanced PPAR response element (PPRE)-luciferase activity dose dependently, and these increases were blunted by GSK0660, a specific PPAR-δ antagonist, but not by GW9662, a PPAR-γ antagonist. Telmisartan also upregulated the expression of PPAR-δ target genes related to fatty acid oxidation; that is, heart type-fatty acid-binding protein and uncoupling protein-2. These effects were inhibited by both PPAR-δ antagonism and PPAR-δ gene silencing. Transforming growth factor-ß1 (TGF-ß1) increased the expression of plasminogen activator inhibitor-1 (PAI-1), TGF-ß1 and collagen IV. The PAI-1 expression was mediated, at least in part by the phosphorylation of extracellular signal-regulated kinases (ERKs). Telmisartan suppressed TGF-ß1-stimulated PAI-1 and collagen IV expression and ERK phosphorylation, and these effects were weakened by PPAR-δ antagonism, whereas eprosartan, a non-PPAR activating ARB, did not affect TGF-ß1-stimulated PAI-1 expression. These results indicate that in HMC telmisartan activates endogenous PPAR-δ and may prevent TGF-ß1-induced fibrotic changes by reducing ERK phosphorylation in a PPAR-δ-dependent manner, and thus, might be useful for treating hypertensive patients with renal and metabolic disorders.

Renal disease in the elderly and the very elderly Japanese: analysis of the Japan Renal Biopsy Registry (J-RBR).

BACKGROUND AND OBJECTIVES: Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed. RESULTS: The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P < 0.001), and IgAN was less common (P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life. CONCLUSIONS: Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.

Rapid detection of the Mycobacterium tuberculosis complex by use of quenching probe PCR (geneCube).

Early detection of tuberculosis (TB) is essential for infection control. The geneCube (Toyobo) is a novel fully automated gene analyzer that can amplify target DNAs within 60 min. In this study, we evaluated the ability of the geneCube to directly detect Mycobacterium tuberculosis complex (MTBC) and Mycobacterium avium complex (MAC) in clinical specimens. The results were then compared with those obtained using conventional culture, microscopy, and the Cobas Amplicor assay (Roche). We examined a total of 516 frozen samples from 69 patients who showed culture-positive infection (73 samples; 39 MTBC, 32 MAC, and 2 mixed infections) and from 354 patients who were culture negative (443 samples). Assays using the geneCube had a sensitivity of 85.4% and a specificity of 99.8% for detection of MTBC and a sensitivity of 85.3% and a specificity of 99.8% for detection of MAC. These results are similar to those obtained using the Amplicor system but were obtained much more rapidly (1 h with the geneCube versus 5.5 h with the Amplicor system). The geneCube thus enables a significant shortening of the assay time with no loss of sensitivity or specificity.

[Clinicopathological study of chronic kidney diseases (CKD)].

I started my life as a medical doctor at Amagasaki Prefectural Hospital after graduation from the Faculty of Medicine, Kyoto University in September 1971. I joined the newly established section of nephrology in the second year. The chief was Dr. Kazuro Kanatsu who had just moved from Kyoto University at the time of the campus disturbances. Dr. Kanatsu not only oriented me in clinical nephrology, but also guided me in medical research. I used to go to the laboratory of Dr. Tadao Tamura, Kyoto University once a week to learn renal biopsy study. In 1977, I entered the Department of Pathology, Postgraduate School of my university to learn immunopathology from Prof. Yoshihiro Hamashima. In the second year, I was willingly involved in the research group on murine SLE organized by the newly invited associate professor, Dr. Toshikazu Shirai, who taught young researchers such as myself how to consider, practice and enjoy experiments. In 1982, I went abroad to Prof. Peter Miescher, University of Geneva, who was a friend of Prof. Hamashima and organized immunopathology research groups. In the laboratory of Prof. Shozo Izui, I performed an isoelectric focused study on anti-DNA antibodies in lupus-prone mice and identified the pathogenetic role of the clonal expansion of autoantibodies. After 3 years, I came back to the 3rd Division of Internal Medicine of my university. Meanwhile, Prof. Chuichi Kawai guided me to go back to Prof. Hamashima's Pathology Department, where I helped young doctors publish a series of papers, including studies on SLE and a murine model of IgA glomerulonephritis. Later, I was obliged to leave the Pathology Department, and moved to Himeji National Hospital in 1992 as a clinical nephrologist by the invitation of the Director, Dr. Tamura. At that time I was very much encouraged by Prof. Shirai at Juntendo University, who gave me a letter with an old saying "Jinkan itarutokoro seizan ari". After 3 years, I moved to Kitano Hospital, Osaka, where I learned up-to-date information and techniques in clinical nephrology. From this hospital, I published a paper in Kidney International entitled, "Mesangiolytic glomerulopathy in severe congestive heart failure", based on the autopsy cases collected at the Pathology Department. This paper became a milestone in starting to study the role of chronic hypoxia in CKD. In 1999, I was elected as a professor of the Department of Clinical Laboratories, Faculty of Medicine, University of Fukui. In Fukui, I could extend my hypoxia study to cellular levels and diabetic mouse experiments in collaboration with Dr. Kimura, Dr. Li, Dr. Takahashi and many other doctors and technicians. When overviewing my research history, I realize that I was fortunate to be involved at the starting point of every laboratory with energetic mood and that I was supported and helped by many people.

Severe intraglomerular detachment of podocytes in a Gitelman syndrome patient.

We report the case of a 38-year-old woman diagnosed with Gitelman syndrome. A kidney biopsy showed abundant floating cells in the Bowman's space of the mildly cystic glomeruli, moderate tubulointerstitial changes and apparent intimal thickening of small arteries. These floating cells were immunohistologically identified as podocytes, by the expression of podocalyxin, vimentin, Wilms' tumor 1, synaptopodin and nephrin with positivities of 100%, 88.4%, 80.4%, 74.7% and 22.6%, respectively. In these phenotypes, nephrin expression was notably decreased in both detached and capillary-attached podocytes in comparison with normal control podocytes. Immunostaining of both detached and capillary-attached podocytes for Bax, Bcl-2, desmin, fibroblast-specific protein-1, α-smooth muscle actin and Ki-67 was negative, as were TUNEL assays. These results suggest that apoptosis and epithelial-mesenchymal transition were not the main cause of podocyte detachment in this patient. In addition, levels of urinary podocalyxin were not elevated, suggesting the detached podocytes were not excreted in the urine. To the best of our knowledge, this is the first report of severe intraglomerular non-apoptotic detachment of podocytes in Gitelman syndrome. This podocyte detachment may be associated with nephron obstruction and reduced nephrin expression.

[Clinical application of urinary redox regulating protein, thioredoxin].

Thioredoxin (TRX) is a redox-regulating protein, induced in response to oxidative stress. The function of TRX in the urine is unknown. We show here that urinary TRX begin to increase within one hour and peaks within two hours after ischemia reperfusion of mice. Serum levels of TRX are not changed by the ischemia/reperfusion. In a time-dependent study of immunohistochemistry, TRX appears diffusely in the tubular cytosol in sham-operated mice. On the other hand, immediately after renal ischemia/reperfusion, TRX become to eccentrically-locate in the apical side of the tubular cytosol, and then TRX is detected only in the urinary lumen. In contrast, when we examine the immunolocalization of glutaredoxin, which is a member of the TRX superfamily, we find that the immunoreactivity is unchanged after renal ischemia/reperfusion. Northern blotting and in situ hybridization show that epithelial cells constitutively express TRX mRNA but neither expression levels nor distribution are altered by ischemia-reperfusion. An overexpression of hTRX in transgenic mice attenuates the reperfusion injury. These data suggests that TRX is produced in tubular cells in a steady state. The increase in the urine after ischemia-reperfusion is not mediated by a de novo induction of TRX mRNA but by a discharge of TRX protein from tubular epithelial cells. TRX is useful for the diagnosis of AKI in association with oxidative stress.

Smaller low-density lipoprotein size as a possible risk factor for the prevalence of coronary artery diseases in haemodialysis patients: associations of cholesteryl ester transfer protein and the hepatic lipase gene polymorphism with low-density lipoprotein size.

AIM: Smaller low-density lipoprotein (LDL) size has recently been reported as a non-traditional lipid risk factor for coronary artery disease (CAD). Cholesteryl ester transfer protein (CETP) and the C/T hepatic lipase (HL) gene polymorphism may promote LDL size reduction via the CETP-mediated exchange of CE for triglyceride (TG) and subsequent HL-mediated TG hydrolysis in LDL. However, little is known about LDL size status and its relationship with CAD prevalence in haemodialysis (HD) patients who are at high risk for atherosclerosis. METHODS: CETP levels, HL genotypes and LDL size were determined, and the determinants of LDL size and its association with CAD prevalence in HD patients (n = 236) aged over 30 years were investigated. RESULTS: The HD patients had a similar LDL size to the healthy subjects. In the HD group, high-density lipoprotein cholesterol was an independent positive determinant of LDL size, while log(10) (TG) was an independent negative determinant in the high (≥2.1 µg/mL) but not low (<2.1 µg/mL) CETP group. In the patients with hypertriglyceridemia, the high CETP group had a significantly smaller LDL size than the low CETP group. Among the patients with above-median TG levels, the CC genotype and CETP were independent negative determinants of LDL size. In the whole group and the high CETP group, the patients with CAD had a significantly smaller LDL size than those without CAD. Finally, DM and smaller LDL size were identified as independent risk factors for CAD prevalence. CONCLUSION: These suggest that a smaller LDL size, which is associated with higher levels of TG and CETP and the HL/CC genotype, may serve as a risk factor for CAD in HD patients.

Glucocorticoid enhances hypoxia- and/or transforming growth factor-ß-induced plasminogen activator inhibitor-1 production in human proximal renal tubular cells.

BACKGROUND: Glucocorticoid (GC) treatment reportedly exaggerates renal fibrosis in progressive kidney diseases during which hypoxia occurs as an unavoidable consequence in renal tubular cells. Two major fibrotic factors, hypoxia and transforming growth factor-ß (TGF-ß), upregulate the production of plasminogen activator inhibitor-1 (PAI-1), a fibrosis enhancer. Most recently, we reported that GC increases PAI-1 production in human proximal tubular epithelial cells (HPTEC). However, the detailed interactions that occur between these PAI-1 inducers in HPTEC remain to be clarified. METHODS: Confluent HPTECs were treated with GC and/or TGF-ß for 24 h under normoxia or hypoxia. The mRNA and protein amounts of PAI-1 and GC receptor (GR) were determined by TaqMan quantitative PCR and immunoassays, respectively. GC and hypoxia response element (GRE and HRE) activities were measured by transient transfection of GRE- and HRE-luciferase expression vector. RESULTS: Hypoxia had no influence on dexamethasone (DXA)-enhanced GRE activity, as DXA had no influence on hypoxia-enhanced HRE activity. Hypoxia induced PAI-1 expression. TGF-ß increased basal and hypoxia-stimulated PAI-1 production. Hydrocortisone (HC) and DXA increased hypoxia- or TGF-ß-stimulated production of PAI-1 mRNA and protein. Moreover, DXA enhanced hypoxia plus TGF-ß-stimulated PAI-1 production. The PAI-1-increasing effect of HC under hypoxia was abolished completely by RU-486, a specific inhibitor of the GR, and largely by PP2, a specific inhibitor of the Src family of protein tyrosine kinases. CONCLUSION: Glucocorticoid induces hypoxia- and hypoxia plus TGF-ß-stimulated PAI-1 production via the GR and tyrosine kinase pathways. These actions of GC may partially explain the renal fibrotic changes seen in progressive inflammatory kidney diseases during GC treatment.