Yoshiyuki Furumatsu

Effect of Renin-Angiotensin-Aldosterone System Triple Blockade on Non-Diabetic Renal Disease: Addition of an Aldosterone Blocker, Spironolactone, to Combination Treatment with an Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker

Although dual blockade of the renin-angiotensin-aldosterone system (RAAS) with the combination of an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) is generally well-established as a treatment for nephropathy, this treatment is not fully effective in some patients. Based on the recent evidence implicating aldosterone in renal disease progression, this study was conducted to examine the efficacy of blockade with three different mechanisms by adding an aldosterone blocker in patients who do not respond adequately to the dual blockade. A 1-year randomized, open-label, multicenter, prospective controlled study was conducted, in which 32 non-diabetic nephropathy patients with proteinuria exceeding 0.5 g/day were enrolled after more than 12 weeks of ACE-I (5 mg enalapril) and ARB (50 mg losartan) combination treatment. These patients were allocated into two groups of 16 patients each: a triple blockade group in which 25 mg of spironolactone daily was added to the ACE-I and ARB combination treatment, and a control group in which 1 mg of trichlormethiazide or 20 mg of furosemide was added to the combination treatment instead of spironolactone depending upon the creatinine level. After 1 year of treatment, the urinary protein level decreased by 58% (p<0.05) with the triple blockade but was unchanged in the controls. Furthermore, urinary type IV collagen level decreased by 40% (p<0.05) with the triple blockade but was unchanged in the controls. The decreases in urinary protein and urinary type IV collagen were not accompanied by a decrease in blood pressure. Mean serum creatinine, potassium and blood pressure did not change significantly by either treatment. In conclusion, triple blockade of the RAAS was effective for the treatment of proteinuria in patients with non-diabetic nephropathy whose increased urinary protein had not responded sufficiently to a dual blockade. (Hypertens Res 2008; 31: 59−67)

Prospective Randomized Study Evaluating the Efficacy of the Spherical Adsorptive Carbon AST-120 in Chronic Kidney Disease Patients with Moderate Decrease in Renal Function

Aims: We studied whether adding the spherical adsorptive carbon AST-120 to conventional treatments is effective in inhibiting progression of chronic kidney disease (CKD) at the stage of moderate decrease in renal function. Methods: 43 CKD patients with moderately impaired renal function indicated by glomerular filtration rate (GFR) of 20–70 ml/min as measured by non-radiolabeled iothalamate clearance method were enrolled in the study. 26 patients showing a decrease of GFR by 5 ml/min during a 1-year observation period were randomized to receive ongoing treatments only (control group, 12 cases) or with AST-120 co-administered with ongoing treatment (AST-120 group, 14 cases). The intervention period was 1 year and the change in GFR was the primary evaluation variable. Results: The mean changes of GFR per month (ΔGFR) in the intervention period were not significantly different between both groups. However, when comparing the ΔGFR in the observation and intervention periods for each group, the rate of decline in GFR was significantly retarded (p < 0.001) in the AST-120 group while no significant difference was observed in the control group. Conclusion: These results suggest that co-administration of AST-120 with conventional treatments retards decline in renal function in CKD patients with moderate decrease in renal function.

Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs

The antipyretic and analgesic actions of nonsteroidal anti-inflammatory drugs (NSAIDs) are caused by the inhibition of prostaglandin E2 (PGE2), thromboxane A2 and prostacyclin (PGI2) production. Accumulating evidence suggests that the inhibition of PGE2 production can cause adverse side-effects of NSAIDs on fluid and blood pressure regulation, such as hypertension and edema formation. Since both cyclooxygenase (COX)-1 and COX-2 isoforms contribute to the production of PGE2, selective COX-2 inhibitors are not free of these adverse side-effects although they may be less severe. Four subtypes of PGE2 receptors have been identified. The antipyretic action of blunted PGE2 production is mediated predominantly by a reduced input to the prostaglandin E receptor 3 (EP3) pathway, whereas the analgesic action is mediated predominantly by a reduced input to the EP1 pathway and perhaps by contributions from the other EP receptors. Accordingly, some of the adverse side-effects might be moderated by combined use of NSAIDs with selective EP2 or EP4 agonists that do not block the antipyretic or analgesic actions of NSAIDs that are mediated by reduced activation of EP1 or EP3 receptors. Moreover, EP2 receptor-deficient mice had salt-sensitive hypertension and EP4 receptor blockade moderated salt and water excretion and both EP2 and EP4 agonists had renoprotective effects. This suggests that strategies to maintain activation of EP2 and EP4 receptors during NSAID administration may not only reduce adverse effects but might confer additional benefits. In conclusion, enhancing EP2 and EP4 receptor activity by administration of selective agonists during the administration of NSAIDs has the potential to permit treating fever, inflammation and pain but with marginal adverse effects on fluid or blood pressure regulation.

Microarray analysis of tonsils in immunoglobulin A nephropathy patients.

BACKGROUND Recently, combination of tonsillectomy and steroid pulse therapy was reported to be effective as the treatment of the immunoglobulin A nephropathy (IgAN). However, the gene expression difference between the tonsils in patients with IgAN and those in control patients is not established. METHODS We performed tonsillectomy combined with steroid pulse as a treatment to IgAN, analyzed the gene expression in the tonsils (N=23) using microarray, compared with those with patients suffering from chronic tonsillitis (N=22). From some candidate genes related with IgAN, we confirmed the apolipoprotein B messenger RNA-editing enzyme catalytic polypeptides 2 (APOBEC2) gene expression in the tonsil and we also analyzed its expression levels and clinical features. RESULTS Up-regulated genes seem to be categorized into two groups. One group belongs to the muscle related genes which might be caused by structural differences. The other group includes the immune system-related genes, such as APOBEC2, CALB2, DUSP27, and CXCL11. APOBEC2 was positively stained in the epithelium and the peripheral region of the germinal center in both tonsils. APOBEC2 expression level was negatively related with serum igg level, but did not correlate with clinical course after tonsillectomy. CONCLUSION We confirmed gene expression differences related with immune system and muscle structure. The APOBEC2 was confirmed to be elevated in the tonsils with IgAN patients, and the gene expression level was negatively related with serum igg level in overall patients. These results might be helpful to reveal the mechanism of IgAN.

Urinary type IV collagen in nondiabetic kidney disease.

Background: Type IV collagen is one of the major components of basement membrane. In diabetic nephropathy, it is already known that urinary excretion of type IV collagen increases with the disease progression. However, in nondiabetic kidney disease, urinary type IV collagen (u-IVc) levels have not been extensively investigated. The aim of this study was to evaluate u-IVc levels in various nephropathies except diabetic nephropathy. Methods: u-IVc levels were measured cross-sectionally from 527 biopsy-proven nondiabetic renal disease patients at tertiary care hospitals by one-step sandwich enzyme immunoassay. Results: On simple regression analyses, u-IVc levels had positive correlation with age, blood pressure, urinary protein (u-Prot), urinary β2 microglobulin, urinary N-acetyl-β-D-glucosaminidase, HbA1c, and selectivity index (SI), while u-IVc had negative correlation with eGFR and serum albumin. Multiple regression analyses revealed that u-IVc was positively correlated with u-Prot, HbA1c and SI. Among biopsy-proven nondiabetic nephropathies, elevation of u-IVc was distinctively observed in membranous nephropathy and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. Conclusion: u-IVc levels were elevated with the increase in u-Prot, HbA1c and SI. In addition, among nondiabetic kidney disease, elevation of u-IVc was observed in patients with membranous nephropathy and ANCA, which might reflect the thickening of basement membrane or severe kidney damage.

Early plasma exchange for progressive liver failure in recipients of adult-to-adult living-related liver transplants.

Background/Aims: Little information is available concerning the effectiveness of plasma exchange for progressive liver failure in liver transplant recipients. The aims of the present study were to evaluate the effectiveness of plasma exchange and discuss its indication. Methods: Forty-six ABO-compatible recipients of living-related liver transplants operated on in Osaka University hospital were retrospectively studied. Results: Total bilirubin was identified as the most accurate predictor of the short-term prognosis of 46 recipients (optimal cut-off point: 13.3 mg/dl). Eleven patients received 14 plasma exchange sessions. Elevation of total bilirubin was significantly suppressed after plasma exchange in the patients with total bilirubin below the median (24 mg/dl), whereas total bilirubin significantly increased even after plasma exchange in those with total bilirubin above the median. Conclusion: Plasma exchange improved liver function in recipients with progressive liver failure and appears to be indicated in patients with total bilirubin levels ranging between 13 and 24 mg/dl.

Specialist care and improved long-term survival of dialysis patients

BACKGROUND The quality of dialysis care provided by specialists is expected to be superior to that by nonspecialists. However, little is known about the actual effect of specialist care on long-term prognosis in dialysis patients. We sought to determine whether specialist care can actually be associated with better survival rates in a nationwide Japanese dialysis cohort. METHODS The Japanese Society for Dialysis Therapy (JSDT) has annually reported clinical and demographic variables of dialysis patients for each prefecture in Japan since 1983. We analysed the data for the 47 prefectures from 1983 to 2006 to evaluate the relationship between the proportion of specialists and the cumulative survival rates for 5-year periods. RESULTS Trend analyses revealed that a higher quintile of specialists was associated with a better cumulative survival rate at 5-, 10-, 15- and 20-year periods. Univariate analyses for the 47 prefectures showed a higher proportion of specialists to be correlated with a better cumulative survival at 10-, 15- and 20-year periods. Multivariate analyses revealed that the proportion of specialists persisted as an independent contributor for better survival at 10-, 15- and 20-year periods even after adjustment for age, sex, diabetes mellitus and socioeconomical status, while the survival rate at 5 years was at a nonsignificant level. CONCLUSIONS While our study should be confirmed using data for individuals, this was not possible due to privacy issues. Therefore, based on our current findings, we conclude that for patients on maintenance dialysis, specialist care can be associated with better survival rates, particularly with longer follow-up.

Acute renal failure with severe loin pain after anaerobic exercise (ALPE): detection of patchy renal ischaemia by contrast-enhanced colour Doppler

An 18-year-old Japanese boy developed a severe loin pain 6 h after performing a 200 m dash three times in a baseball training, and was admitted to our hospital. He had a history of acute renal failure with severe loin pain after anaerobic exercise (ALPE) following the same kind of exercise 2 years before. On admission, his serum creatinine (Cr) level was 292 μmol/l (3.3 mg/dl) without accompanying findings of rhabdomyolysis-like elevation of creatine phosphokinase or myoglobinuria. Renal stones were not detected either by plain abdominal X-ray or by sonography. Accordingly, a diagnosis of ALPE was made. We started hydration and pain control by pentazocine without using non-steroidal anti-inflammatory drugs (NSAIDs). ALPE [1] is an uncommon syndrome, which mainly occurs in Asians possibly because of the relatively high prevalence (0.15–0.6%) of renal hypouricaemia [2,3,4]. The pathogenesis of ALPE is not clearly understood, but is considered to be a severe arterial vasoconstriction in the kidney. ALPE is known to demonstrate patchy wedge-shaped defects by contrast media-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) in delayed phase, which are considered to reflect renal ischaemia caused by vasospasm [5]. 99mTc-methylene diphosphonate (MDP) bone scintigraphy is also helpful to diagnose ALPE and to detect its ischaemic regions [6]. However, it requires time to start and to perform these imaging tests, and besides, contrast media for CT or MRI may cause harm, especially to patients with impaired renal function. Thus, we attempted to detect ischaemic regions caused by ALPE with colour Doppler imaging, which is non-invasive and can be implemented at any time and at the patients’ bedside. The use of micro-bubble contrast agent

Severe adverse effects of 5-fluorouracil in S-1 were lessened by haemodialysis due to elimination of the drug

S-1 and cisplatin are used as one of the first-line chemotherapies for gastric cancer in Japan. The plasma concentration of 5-fluorouracil (5-FU) is increased in patients with renal dysfunction because gimeracil in S-1 inhibits the degradation of 5-FU and about 50% of gimeracil is excreted in the urine. We describe a 35-year-old man with acute kidney injury while taking S-1 and cisplatin for advanced gastric cancer and who presented severe adverse effects of 5-FU. This case report describes the evolution of the plasma concentrations of 5-FU with haemodialysis along with a decrease in the adverse drug effects.

Investigation of small intestinal lesions in dialysis patients using capsule endoscopy: Capsule endoscopy in dialysis patients

Introduction: Although gastrointestinal hemorrhage is an important complication for dialysis patients, the details of many points remain unclear with regard to small intestinal lesions.