Kazuhiko Tsuruya

Predominance of Th1 Immune Response in Diffuse Proliferative Lupus Nephritis

OBJECTIVE Lupus nephritis, which shows various histologic patterns, is a serious complication of systemic lupus erythematosus (SLE). We previously demonstrated the importance of Thl cell-mediated immune response in patients with diffuse proliferative lupus nephritis (DPLN). The aim of this study was to examine the relationship between the peripheral blood Th1/Th2 balance and the intrarenal immune response. METHODS The Th1:Th2 ratio in peripheral blood was measured by intracellular staining for cytokines with flow cytometry. Immunohistochemical analysis of renal biopsy specimens was performed to clarify the characterization of local infiltrating cells in 3 groups of subjects: SLE patients with World Health Organization (WHO) class IV nephritis (DPLN) (group I; n = 13), SLE patients with WHO class V nephritis (group II; n = 9), and patients with minor glomerular lesions (group III; n = 7). In addition, the histologic activity index and chronicity index were evaluated and correlated with the Th1:Th2 ratio. RESULTS Immunohistochemical studies showed higher numbers of CD68+ macrophages, CD3 + T cells, and interferon-gamma-positive cells in group I than in groups II or III. Renal tissues from patients in group I also showed up-regulation of expression of osteopontin and CD40, with a small number of infiltrating T cells expressing interleukin-4. Overall, the Thl:Th2 ratio in group I patients (SLE with DPLN) was high and correlated significantly with the histologic activity index, but not with the chronicity index. CONCLUSION We have identified a predominance of Thl-type response in both peripheral and renal tissues of patients with DPLN, suggesting that the peripheral blood Thl:Th2 ratio directly reflects the local histopathologic findings. In patients with lupus nephritis, the peripheral blood Th1:Th2 ratio could be useful as a parameter that reflects the renal histologic activity or the strength of the local Thl response.

Association of Kidney Function With Coronary Atherosclerosis and Calcification in Autopsy Samples From Japanese Elders: The Hisayama Study

BACKGROUND Chronic kidney disease (CKD) is associated with increased risk of coronary heart disease. However, information regarding the histopathologic characteristics of coronary atherosclerosis in individuals with CKD is scarce. This study investigated the relationship between CKD and severity of coronary atherosclerosis in population-based autopsy samples. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS 126 individuals randomly selected from 844 consecutive population-based autopsy samples. PREDICTOR Estimated glomerular filtration rate (eGFR) calculated using the 6-variable Modification of Diet in Renal Disease (MDRD) Study equation. OUTCOMES Severity of atherosclerosis in 3 main coronary arteries, including atherosclerotic lesion types defined using the American Heart Association classification; stenosis rates; and coronary calcified lesions. MEASUREMENTS The relationship between CKD and severity of coronary atherosclerosis was evaluated using generalized estimating equation methods. RESULTS Frequencies of advanced atherosclerotic lesions increased gradually as eGFR decreased (33.6%, 41.7%, 52.3%, and 52.8% for eGFRs > or = 60, 45-59, 30-44, and <30 mL/min/1.73 m(2), respectively; P for trend = 0.006). This relationship was substantially unchanged even after adjustment for potential confounding factors (ORs, 1.40 [95% CI, 0.76-2.55], 2.02 [95% CI, 0.99-4.15], and 3.02 [95% CI, 1.22-7.49] for eGFRs of 45-59, 30-44, and <30 mL/min/1.73 m(2), respectively). Frequencies of calcified lesions of coronary arteries also increased gradually with lower eGFRs (P for trend = 0.02). Hypertension and diabetes were associated with increased risk of advanced coronary atherosclerosis and calcification of coronary arteries in individuals with decreased eGFR. LIMITATIONS Cross-sectional study, absence of data for proteinuria, and extremely high proportion of aged people. CONCLUSIONS The autopsy findings presented here suggest that CKD is associated significantly with severity of coronary atherosclerosis. Patients with CKD should be considered a high-risk population for advanced coronary atherosclerosis.

Increased renal resistive index in atherosclerosis and diabetic nephropathy assessed by Doppler sonography

Objective The renal resistive index (RI) and pulsatility index (PI), measured using Doppler ultrasonography, reflect intrarenal vascular resistance. We evaluated the relationship between these indices and pulse wave velocity (PWV), a measure of arterial stiffness, which reflects atherosclerosis, and determined whether renal RI and PI differ depending on the underlying renal disease. Methods A total of 245 inpatients with or without renal impairment who underwent ultrasonographic assessment of the renal artery were enrolled in the study. Patients with renal artery stenosis or severe renal failure (serum creatinine ≥ 6 mg/dl) were excluded from the study. Results In univariate analysis, the RI and PI of the main renal arteries and the interlobar arteries were significantly correlated with PWV. Multivariate analyses showed that PWV was independently associated with the RI of the main renal arteries (P < 0.01, R2 = 0.256). Patients with a creatinine level less than 3 mg/dl were divided into a control group without renal diseases and three groups with different underlying renal diseases: diabetic nephropathy, chronic glomerulonephritis, and nephrosclerosis. The RI and PI of the main renal arteries and the interlobar arteries were significantly higher in patients with diabetic nephropathy than in the other three groups, even after adjusting for multiple variables, including creatinine clearance. Conclusion These results suggest that the increased RI of the renal arteries is associated with the severity of systemic atherosclerosis. Furthermore, the intrarenal vascular resistance differs depending on the underlying renal disease, and appears to increase to a greater extent in diabetic nephropathy.

Protection by a radical scavenger edaravone against cisplatin-induced nephrotoxicity in rats

Acute renal failure is a dose-limiting factor of cisplatin chemotherapy. Here, we show the protective effect of edaravone, a recently developed radical scavenger for clinical use, against cisplatin-induced renal dysfunction in rats. A marked increase in blood urea nitrogen and creatinine in serum, and histological changes including vacuolation, necrosis and protein casts were observed in proximal renal tubules at the fourth day after cisplatin injection (5-10 mg/kg). Repeated injection of edaravone (1-10 mg/kg, i.v. twice a day for 3 days) reversed the cisplatin-induced elevation of blood urea nitrogen and creatinine, and morphological changes in a dose-dependent manner. In particular, the protective effect of edaravone was almost complete at 10 mg/kg. Moreover, the compound was still fully effective, when it was administered only at the second day after cisplatin injection. On the other hand, the glutathione content in renal tissues lowered at the fourth day after cisplatin injection, which was reversed by the late treatment with edaravone. These findings suggest that the clinically available radical scavenger edaravone is potentially useful for the prevention of cisplatin-induced renal toxicity.

Trends in the prevalence of chronic kidney disease and its risk factors in a general Japanese population: The Hisayama Study

BACKGROUND Chronic kidney disease (CKD) is increasingly recognized as a leading public health issue. However, there are limited data assessing secular trends in the prevalence of CKD in general Asian communities. METHODS We performed three repeated cross-sectional surveys of residents aged >or=40 years in 1974 [2118 subjects (participation rate, 81.2%)], 1988 [2741 subjects (80.9%)] and 2002 [3297 subjects (77.6%)] in a Japanese community. We compared the prevalence of CKD [one or both of proteinuria and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2)] and potential risk factors among the three surveys. RESULTS The prevalence of CKD increased significantly with time in men (13.8% [95% confidence interval (95% CI), 11.4-16.2%] in 1974, 15.9% [95% CI, 13.6-18.2%] in 1988 and 22.1% [95% CI, 19.6-24.6%] in 2002; P for trend < 0.001), but not in women (14.3% [95% CI, 12.2-16.4%], 12.6% [95% CI, 10.9-14.3%] and 15.3% [95% CI, 13.4-17.2%]; P for trend = 0.97). The frequencies of individuals with CKD Stages 3-5 (eGFR < 60 mL/min/1.73 m(2)) increased over the three decades in both sexes. Despite the widespread use of antihypertensive agents, the proportions of individuals with CKD who reached blood pressure of <130/80 mmHg were only 27.0% in men and 47.5% in women. The frequency of metabolic disorders including diabetes, hypercholesterolaemia and obesity increased over the three decades in both sexes. CONCLUSIONS The prevalence of CKD increased significantly in men, but not in women over the last three decades in a general Japanese population. Our findings support the requirement for a comprehensive treatment for hypertension and metabolic disorders to reduce the burden of CKD.

Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia

Hyperphosphatemia contributes to increased cardiovascular mortality through vascular calcification (VC) in patients with chronic kidney disease (CKD). Malnutrition and inflammation are also closely linked to an increased risk of cardiovascular death in CKD. However, the effects of Pi overload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary Pi loading on the interactions among inflammation, malnutrition, and VC in CKD. We used control rats fed normal diets and adenine-induced CKD rats fed diets with different Pi concentrations ranging from 0.3% to 1.2% for 8 wk. CKD rats showed dietary Pi concentration-dependent increases in serum and tissue levels of TNF-α and urinary and tissue levels of oxidative stress markers and developed malnutrition (decrease in body weight, serum albumin, and urinary creatinine excretion), VC, and premature death without affecting kidney function. Treatment with 6% lanthanum carbonate blunted almost all changes induced by Pi overload. Regression analysis showed that serum Pi levels closely correlated with the extent of inflammation, malnutrition, and VC. Also, in cultured human vascular smooth muscle cells, high-Pi medium directly increased the expression of TNF-α in advance of the increase in osteochondrogenic markers. Our data suggest that dietary Pi overload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and that inhibition of Pi loading through dietary or pharmacological interventions or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome.

Japan renal biopsy registry: The first nationwide, web-based, and prospective registry system of renal biopsies in Japan

BackgroundThe Committee for the Standardization of Renal Pathological Diagnosis and the Working Group for Renal Biopsy Database of the Japanese Society of Nephrology started the first nationwide, web-based, and prospective registry system, the Japan Renal Biopsy Registry (J-RBR), to record the pathological, clinical, and laboratory data of renal biopsies in 2007.MethodsThe patient data including age, gender, laboratory data, and clinical and pathological diagnoses were recorded on the web page of the J-RBR, which utilizes the system of the Internet Data and Information Center for Medical Research in the University Hospital Medical Information Network. We analyzed the clinical and pathological diagnoses registered on the J-RBR in 2007 and 2008.ResultsData were collected from 818 patients from 18 centers in 2007 and 1582 patients from 23 centers in 2008, including the affiliated hospitals. Renal biopsies were obtained from 726 native kidneys (88.8%) and 92 renal grafts (11.2%) in 2007, and 1400 native kidneys (88.5%) and 182 renal grafts (11.5%) in 2008. The most common clinical diagnosis was chronic nephritic syndrome (47.4%), followed by nephrotic syndrome (16.8%) and renal transplantation (11.2%) in 2007. A similar frequency of the clinical diagnoses was recognized in 2008. Of the native kidneys, the most frequent pathological diagnosis as classified by pathogenesis was immunoglobulin (Ig) A nephropathy (IgAN) both in 2007 (32.9%) and 2008 (30.2%). Among the primary glomerular diseases (except IgAN), membranous nephropathy (MN) was the most common disease both in 2007 (31.4%) and 2008 (25.7%).ConclusionsIn a cross-sectional study, the J-RBR has shown IgAN to be the most common disease in renal biopsies in 2007 and 2008, consistent with previous Japanese studies. MN predominated in the primary glomerular diseases (except for IgAN). The frequency of the disease and the clinical and demographic correlations should be investigated in further analyses by the J-RBR.

Japanese Society for Dialysis Therapy Guidelines for Management of Cardiovascular Diseases in Patients on Chronic Hemodialysis

Hideki Hirakata, Kosaku Nitta, Masaaki Inaba, Tetsuo Shoji, Hideki Fujii, Shuzo Kobayashi, Kaoru Tabei, Nobuhiko Joki, Hiroki Hase, Masato Nishimura, Shigeyuki Ozaki, Yuji Ikari, Yoshitaka Kumada, Kazuhiko Tsuruya, Shouichi Fujimoto, Tohru Inoue, Hiroyoshi Yokoi, Sumio Hirata, Kazuaki Shimamoto, Kiyotaka Kugiyama, Takashi Akiba, Kunitoshi Iseki, Yoshiharu Tsubakihara, Tadashi Tomo, and Tadao Akizawa

The antioxidant tempol ameliorates arterial medial calcification in uremic rats: Important role of oxidative stress in the pathogenesis of vascular calcification in chronic kidney disease

Vascular calcification is closely related to cardiovascular morbidity and mortality. Accumulating data indicate that oxidative stress is associated with dysfunction of various organs, including cardiovascular diseases in chronic kidney disease (CKD). However, it remains undetermined if oxidative stress induced by uremia promotes arterial medial calcification. The present study investigated the role of oxidative stress in the pathogenesis of arterial medial calcification in uremic rats. Rats with uremia induced by adenine‐rich diet progressively developed arterial medial calcification, which was accompanied by time‐dependent increases in both aortic and systemic oxidative stress. Immunohistochemical and biochemical analyses showed that the arterial medial calcification progressed in a time‐dependent manner that is parallel to the osteogenic transdifferentiation of vascular smooth muscle cells. Accumulation of oxidative stress was also identified in the calcified regions. Time‐course studies indicated that both oxidative stress and hyperphosphatemia correlated with arterial medial calcification. Tempol, an antioxidant, ameliorated osteogenic transdifferentiation of vascular smooth muscle cells and arterial medial calcification in uremic rats, together with reduction in aortic and systemic oxidative stress levels, without affecting serum biochemical parameters. Our data suggest that oxidative stress induced by uremia can play a role in the pathogenesis of vascular calcification in CKD, and that antioxidants such as tempol are potentially useful in preventing the progression of vascular calcification in CKD.

Spironolactone suppresses inflammation and prevents L-NAME-induced renal injury in rats

Chronic inhibition of nitric oxide synthase by N(omega)-nitro- L-arginine methyl ester (L-NAME) causes progressive renal injury with systemic hypertension and interstitial macrophage infiltration. We have previously shown that there is local activation of the renin-angiotensin-aldosterone system in the renal cortex as a major pathogenic feature of macrophage infiltration. In this study, we measured the effects of the aldosterone antagonist, spironolactone, on renal injury in L-NAME-treated male Wistar rats. After 12 weeks of L-NAME-treatment, rats had increased systolic blood pressure, urinary protein excretion, and serum creatinine and histological analysis showed glomerulosclerosis, interstitial fibrosis, and macrophage infiltration. Treatment with spironolactone significantly prevented these renal changes, whereas treatment with hydralazine had no effect. The cortical expression of osteopontin was significantly elevated in L-NAME-treated rats, and expression of its mRNA significantly correlated with the number of infiltrating macrophages and degree of interstitial fibrosis. Spironolactone treatment markedly suppressed osteopontin expression. Our results suggest that reduced nitric oxide bioavailability caused renal inflammation and fibrosis through an aldosterone receptor-dependent mechanism associated with osteopontin expression independent of its systemic hemodynamic effects.