Serum Uromodulin Is a Possible Auxiliary Diagnostic Tool for Acute Tubular Injury and Acute Interstitial Nephritis: A Case Series.

Recently, the usefulness of serum uromodulin (sUmod) as a novel renal biomarker has been attracting attention. Clinical evidence regarding sUmod measurements has been accumulated by analyzing cross-sectional data. However, little is known about the longitudinal data on sUmod. Therefore, we decided to investigate the variability of sUmod in patients with acute kidney injury due to different causes. High concentrations of sUmod have been observed in patients with acute tubular injury (ATI) and/or acute interstitial nephritis (AIN). sUmod could be used as an auxiliary diagnostic tool for ATI and AIN.

Serum uromodulin is a novel renal function marker in the Japanese population.

BACKGROUND: Uromodulin, also known as Tamm-Horsfall protein, is the most abundant protein in urine. It has recently been reported that uromodulin exists in a small amount in blood and that its concentration correlates with the estimated glomerular filtration rate (eGFR). METHODS: First, we generated anti-human uromodulin mouse monoclonal antibodies (mAb(s)) and established a specific enzyme-linked immunosorbent assay (ELISA) for uromodulin. We then performed an observational clinical study to determine if there was a correlation between serum uromodulin concentration and estimates of kidney function and whether the serum uromodulin value could be a biomarker in clinical nephrology. The clinical study included 308 patients with and without chronic kidney disease and healthy volunteers. Serum concentrations of creatinine, cystatin C, and uromodulin were measured and correlations were sought between the eGFR calculated from the creatinine and cystatin C levels and the serum uromodulin concentration. RESULTS: There was a good correlation between the serum uromodulin concentration and the eGFR value calculated from the creatinine (r = 0.76) and cystatin C (r = 0.79) levels. The mean serum uromodulin level in the group with an eGFR > 90 mL/min/1.73 m2 calculated using cystatin C was significantly higher than that in the group with an eGFR of 80-89 mL/min/1.73 m2. CONCLUSIONS: The serum uromodulin measurement could be a useful biomarker for identification of patients with early deterioration of kidney function.

Efficacy of Semiannual Single Fixed Low-Dose Rituximab Therapy in Steroid-Dependent Minimal Change Nephrotic Syndrome: A Case Series.

The frequency of using rituximab to treat refractory nephrotic syndrome has recently been increasing, and the conventional dose of rituximab used to treat it, 375 mg/m2 body surface area once weekly for 4 weeks, has been modelled on the chemotherapy regimen for B-cell non-Hodgkin's lymphoma. The dose and intervals of rituximab in refractory nephrotic syndrome remain controversial. Clear lymphoma cell hyperplasia is seen in lymphoma patients, but not in nephrotic syndrome patients. Since we thought that it might be possible to reduce the dose of rituximab if only used for the purpose of depleting CD20-positive B cells in nephrotic patients' peripheral blood, we tried semiannually with a single fixed rituximab dose of 100 mg/body, and a complete remission was attained in 3 cases without treatment with prednisolone or cyclosporine. Our report strongly suggests considering appropriate dose and interval of rituximab therapy in the treatment of steroid-dependent nephrotic syndrome.

A case of acetaminophen-induced acute tubulointerstitial nephritis in adult.

We report a case of allergic acute tubulointerstitial nephritis (TIN) induced by acetaminophen in a 48-year-old Japanese man with no past medical history. Two days after receiving the non-steroidal anti-inflammatory drug (NSAID) loxoprofen for left shoulder pain, he developed cold symptoms such as fever and sore throat. He then took a 300 mg dose of acetaminophen three times a day and a 100 mg dose of minocycline hydrochloride twice a day for 7 days. Because there was no improvement in his symptoms, he consulted a local clinic again, where blood tests revealed renal insufficiency, and he was, then, referred to our hospital for evaluation of kidney function. Renal biopsy revealed acute TIN, and Ga-67 scintigraphy showed diffuse uptake in bilateral kidneys. A drug-induced lymphocyte stimulation test (DLST) was positive for acetaminophen and negative for loxoprofen and minocycline. Based on these findings, we made a diagnosis of acetaminophen-induced TIN. We treated the patient with three courses of semi-pulse steroid therapy, after which his fever went down, and his serum creatinine level recovered from 2.09 to 1.43 mg/dL. Although we medical doctors think that therapeutic dose of acetaminophen retains high safety, it is important to keep in mind that acetaminophen can cause allergic acute TIN.

The Improvement of the Outcome of Osmotic Demyelination Syndrome by Plasma Exchange.

A 71-year-old Japanese woman presented with progressive fatigue, lethargy, dysarthria and a gait disorder. Her laboratory data revealed hyponatremia (Na 101 mEq/L), and we started correcting her serum sodium level. Within a few days, she became comatose, bedridden, and was intubated. We diagnosed osmotic demyelination syndrome (ODS) and started performing plasma exchange (PE) on the 39th day of hospitalization. She fully recovered after starting PE, and was discharged on foot unassisted. PE can be a beneficial treatment in patients with chronic ODS.

A case of posterior reversible leukoencephalopathy syndrome caused by fibromuscular dysplasia.

A 23-year-old woman presented with disturbance of consciousness and seizure. Her blood pressure was remarkably high, and brain magnetic resonance imaging (MRI) showed high-intensity T2 signals in the bilateral basal ganglia, corpus callosum, cerebral white matter, and cortex. With the administration of angiotensin II receptor blocker, the symptoms and MRI findings improved, along with normalization of blood pressure, and a diagnosis of posterior reversible leukoencephalopathy syndrome (PRES) was made. Plasma renin activity was high, and the right kidney was severely atrophic. Results from renal and adrenal vein sampling revealed renal vascular hypertension derived from the right renal artery stenosis. The right kidney was then removed by laparoscopic nephrectomy. Pathological examination of the kidney confirmed the diagnosis of fibromuscular dysplasia (FMD). In juvenile-onset encephalitis/encephalopathy, PRES due to FMD should be included in the differential diagnosis.

Five-year follow-up of a case of lipoprotein glomerulopathy with APOE Kyoto mutation.

We report the case of a 34-year-old Japanese male with lipoprotein glomerulopathy (LPG). Renal biopsy showed LPG, and followed by a genetic analysis revealed a mutation in apolipoprotein E gene (APOE Kyoto; Arg25Cys). We started treatment with probucol, bezafibrate, losartan, and allopurinol. Urinary protein decreased in response to treatment but has remained at about 1.27 ± 0.71 g/gCr, and a repeat biopsy which was performed 1 year after the first biopsy showed no clear evidence of pathological remission and complication of other glomerular disease. After 5 years of follow-up after the start of treatment, renal function has almost maintained without apparent deterioration. Interestingly, the course of the urinary protein level closely paralleled his triglyceride and cholesterol levels in a long-term. This observation suggests the importance of tight control of lipid profiles as a means of renoprotection in LPG patient.

[Treatment of hypertriglyceridemia: plasma exchange].

Severe hypertriglyceridemia ( >1,000 -2,000 mg/dL) is known to cause acute pancreatitis (AP). If standard treatment regimen including absolute diet restriction regarding fats, use of lipid -lowering agents and combination of low molecular weight heparin with insulin is not effective, plasma exchange (PE) has emerged as an effective modality in rapidly lowering serum triglyceride levels and helping to treat and prevent hypertriglyceridemia-induced AEP. It has been shown to reduce triglyceride levels by an average of 61% after 1 session and provide rapid resolution of AP symptoms. However, the timing of PE in managing hypertriglyceridemia remains unevaluated. Randomized controlled trials on this specific topic are needed to be performed in the future.

A case of TSH-producing adenoma treated with octreotide in combination with thiamazole for the control of TSH and thyroid hormones after trans-sphenoidal neurosurgery.

While TSH-producing adenoma (TSHoma) is rare, the diagnosis is often delayed because the clinical features are heterogeneous. The patient was a 69-year-old woman who had been referred to the Yachiyo Medical Center in August 2008, because of dyspnea, loss of appetite, weight loss of 10 kg, and diarrhea that lasted 4 years. We diagnosed this patient with pituitary TSH-producing macroadenoma. Thyroid hormone concentration was increasing although the serum TSH level was within a normal range after trans-sphenoidal surgery. We considered that because of enlargement of the thyroid gland due to long-term stimulation by TSH, a low concentration of TSH could stimulate the thyroid gland to produce excess T3 or T4. The somatostatin analogue, octreotide was used to control the TSHoma and serum TSH concentration but not thyroid hormone. The octreotide in combination with thiamazole treatment for 14 months controlled thyroid hormone concentration and decreased the thyroid mass, and ultimately, the thiamazole could be stopped. To date, the use of combination therapy of octreotide with thiamazole in patients with remaining TSH-producing adenoma without Basedow's disease is rare, and we suggest that this treatment is one of the therapeutic means to treat recurrence of TSH-producing adenoma after surgery with progressive complications or large thyroid gland.

[Chronic kidney disease and atherosclerosis].

Atherosclerosis is common in patients with chronic kidney disease (CKD), and cardiovascular disease (CVD) represents a major cause of death in these patients, especially, in patients with end-stage renal disease(ESRD). The pathological features in ESRD patients are intimal atherosclerosis and medial calcific sclerosis. The important risk factors for CVD in ESRD patients are hypertension, dyslipidemia and CKD bone and mineral disorder (CKD-MBD). Atherosclerosis has been evaluated by measurements of intima-media thickness and pulse-wave velocity. Although the target blood pressure still undetermined, hypertension would be treated with renin-angiotensin system inhibitors. In addition, treatment of dyslipidemia with statins may lead to favorable CVD outcome. Finally, inhibition of vascular calcification should be important by treatment with active vitamin D and sevelamer.

Inhibitory effects of whisky congeners on IgE-mediated degranulation in rat basophilic leukemia RBL-2H3 cells and passive cutaneous anaphylaxis reaction in mice.

Whisky is matured in oak casks. Many nonvolatile substances (whisky congeners, WC) seep from the oak cask during the maturing process. In this study, three antiallergic agents (syringaldehyde, SA; lyoniresinol, Lyo; and ellagic acid, EA) were isolated from WC. Treatment with SA, Lyo, and EA reduced the elevation of intracellular free Ca(2+) concentration ([Ca(2+)]i) and intracellular ROS production caused by FcepsilonRI activation. The inhibitions of the elevation of [Ca(2+)]i and intracellular ROS production by SA and Lyo were mainly due to the suppression of the NADPH oxidase activity and scavenging of the produced radical, respectively. On the other hand, EA inactivated spleen tyrosine kinase and led to the inhibition of the elevation of [Ca(2+)]i and intracellular ROS production. Furthermore, it was found that WC strongly inhibited IgE binding to the FcepsilonRIalpha chain, whereas SA, Lyo, and EA did not indicate this inhibitory effect. These results suggest that WC inhibits allergic reactions through multiple mechanisms. To disclose the in vivo effects of WC, SA, Lyo, and EA, these compounds were administered to type I allergic model mice, and the passive cutaneous anaphylaxis (PCA) reaction was measured. These compounds remarkably suppressed the PCA reaction. Taken together, these findings suggest that WC seemed to be beneficial to ameliorate allergic reactions.

Frequency of renal disease in Japan: an analysis of 2,404 renal biopsies at a single center.

BACKGROUND: Evaluating the frequency of renal disease according to sex, age, time period and ethnicity is of considerable importance. METHODS: Disease frequency was evaluated in a total of 2,404 cases that had undergone a renal biopsy at Tokyo Women's Medical University between 1979 and 2008. RESULTS: The overall frequencies of primary glomerulonephritis (GN) and secondary GN were 77.8 and 14.4%, respectively. Primary GN and nephrosclerosis occurred more frequently among men, while secondary GN was more frequent among women. Primary GN decreased and secondary GN increased with advancing age. Immunoglobulin A nephropathy was the most common form of primary GN during each time period and also gradually increased over time (44.4-57.4%). The most common form of secondary GN was lupus nephritis (59.0%); this disease was commonly observed in women (79.3%) but not as frequently among men (27.9%). Our data regarding the frequencies of each form of primary GN were almost the same as data from other regions of Japan and East Asia but were quite different from data originating in West Asia and South America. CONCLUSIONS: Our epidemiological results may be useful for analyzing the morbidity of renal disease.

Structure-activity relationship study on alpha1 adrenergic receptor antagonists from beer.

Hordatine A and aperidine have been previously isolated from beer as active ingredients, which bind to muscarinic M3 receptor. In addition, these compounds have exhibited antagonist activity against the alpha1A adrenoceptor. Although the relative structures of these two molecules have previously been determined, the absolute stereochemistry was unclear. Hence, to elucidate the absolute stereochemistry of natural hordatine A, we synthesized each enantiomer of hordatine A and aperidine from optically pure dehydrodi-p-coumaric acid. Several additional related compounds were also synthesized for structure-activity relationship studies. Chiral column HPLC analysis demonstrated that the absolute stereochemistry of natural hordatine A is (2S,3S), while based on the isomerization mechanism, the stereochemistry of aperidine is (2R,3S). The alpha1A adrenoceptor binding activity of (2R,3R)-hordatine A is the most potent among the enantiomeric pairs of hordatines and aperidines. Furthermore, the related, synthetic compound, (2R,3R)-methyl benzofurancarboxylate exhibits antagonist activity against the alpha1A adrenoceptor at a lower concentration than that of hordatine A.

Inhibitory effects of whisky congeners on melanogenesis in mouse B16 melanoma cells.

We examined the effect of whisky congeners, substances other than ethanol in whisky, on melanogenesis in mouse B16 melanoma cells. Treatment with whisky congeners significantly blocked melanogenesis. Our results indicate that the inhibitory effects of whisky congeners on melanogenesis is due to direct inhibition of tyrosinase activity and to suppression of tyrosinase protein levels.

Clinical assessment of low-dose steroid therapy for patients with IgA nephropathy: a prospective study in a single center.

BACKGROUND/AIM: No accepted therapy has been established for progressive IgA nephropathy (IgAN). The purpose of the present study was to assess low-dose steroid therapy in the treatment of patients with IgAN. METHODS: A prospective trial of low-dose steroid therapy was performed in patients with IgAN with mild histological activities. Twenty-four patients in the steroid group and 24 patients in the control group were included in this study. The initial dose of prednisolone was 0.4 mg/kgBW/day (20-30 mg/day), gradually tapered to 5-10 mg/day over 24 months. The patients with mild active inflammatory lesions were treated with prednisolone. The patients assigned to the control group were treated with dipyridamole or zilazep hydrochloride in a dose of 150 or 300 mg/day. RESULTS: In all of the patients studied, serum creatinine levels did not significantly change over 24 months. However, daily proteinuria significantly reduced after 24 months of steroid therapy (0.97 +/- 0.75 vs. 0.31 +/- 0.51 g/day, P = 0.0012), even if did not change after 24 months of anti-platelet drugs (0.89 +/- 0.49 vs. 0.68 +/- 0.69 g/day, P = 0.2289), respectively. In addition, the grade of hematuria significantly reduced after 24 months of steroid therapy (35.6 +/- 36.3 RBC/HPF vs. 13.7 +/- 28.4 RBC/HPF, P = 0.0249) and 24 months of anti-platelet drugs (30.1 +/- 37.1 RBC/HPF vs. 12.4 +/- 20.3 RBC/HPF, P = 0.0465), respectively. Systolic and diastolic blood pressures did not significantly change during treatment with steroid or anti-platelet drugs. Vascular changes (0.63 +/- 0.73) in the steroid group were lower than those (1.08 +/- 0.88) in the control group (P = 0.008). CONCLUSION: Our data suggested that low-dose steroid therapy for IgAN patients with mild inflammatory lesions could reduce the amount of urinary protein excretion and prevent deterioration of renal function, provided the histological findings in the renal biopsies showed mild vascular lesions.

Fatal diffuse pulmonary arterial thrombosis as a complication of nephrotic syndrome.

A 21-year-old man was admitted to our hospital because of leg edema. Because laboratory findings revealed massive proteinuria and hypoproteinemia, he was diagnosed as having nephritic syndrome caused by minimal change disease. He was given a continuous heparin infusion and intravenous steroid therapy, at a prednisolone dose of 1 mg/kg per day, and his condition gradually improved. Five months after discharge, the patient's proteinuria relapsed. He was readmitted to our hospital and we restarted anticoagulant treatment with intravenous heparin and 60 mg prednisolone. On the third hospital day, he complained of chest pain with sudden onset and dyspnea. He quickly developed shock and died. The findings of an autopsy confirmed the presence of diffuse fibrin thrombi in bilateral pulmonary arteries, and we diagnosed the cause of death as diffuse pulmonary artery thrombosis. A coagulation test for activated partial thromboplastin time (aPTT) had already shown that aPTT was prolonged before the initiation of treatment. There may have been a deficit of antithrombin III (ATIII) - a cofactor of heparin - because of the proteinuria; thus, the continuous heparin treatment might not have been effective for the prevention of thrombosis. Alternatives to heparin treatment that do not suppress AT III, such as nafamostat mesilate or argatroban, which do not require the presence of AT III for their anticoagulant action, should be considered in cases similar to the that in the patient reported here. In patients with nephrotic syndrome who exhibit altered coagulation test results, the choice of anticoagulation therapy for treatment of the hypercoagulabilty status associated with nephrotic syndrome should be carefully considered.

Wegener's granulomatosis complicated by intestinal ulcer due to cytomegalovirus infection and by thrombotic thrombocytopenic purpura.

A 61-year-old woman was admitted to our hospital because of acute kidney injury. She complained of general fatigue, appetite loss, and a high fever. Nodular lesions were observed on chest X-rays and there were >100 erythrocytes per high power field in her urinary sediment. A renal biopsy revealed necrotizing granulomatous glomerulonephritis, and her serum proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) titer was elevated (55 EU). Based on these findings we made a diagnosis of Wegener's granulomatosis (WG). Hemodialysis was started immediately after admission. Steroid therapy was administered and her symptoms were relieved, but her renal function did not improve. On the 50th hospital day her condition suddenly became complicated by hemoperitoneum and massive intestinal bleeding, and the descending, transverse, ascending colon and part of the ileum were surgically resected. The cytomegalovirus (CMV) antigen titer was elevated, and histologic examination of the bowel specimen showed positive staining for CMV in the ulcer lesion, suggesting that CMV infection had caused the bowel hemorrhage. After treatment with ganciclovir, the bleeding was resolved and the CMV antigens became negative. We considered that this patient was further complicated by thrombotic thrombocytopenic purpura (TTP) because of thrombocytopenia, hemolytic anemia and neurologic symptoms. She was treated by plasma exchange. We report here a case of WG complicated by acute intestinal ulcer due to CMV infection and by TTP.

The characteristics of relapse in adult-onset minimal-change nephrotic syndrome.

BACKGROUND: Although minimal-change nephrotic syndrome (MCNS) is highly steroid-responsive, the frequency of relapses in some patients is high, necessitating the administration of repeated courses of prednisolone in high doses. It is, therefore, necessary to identify factors that can predict this increased risk of relapse in some patients in order to establish useful treatment methods to reduce the risk. METHODS: To clarify the factors that might increase the risk of relapses, the data of 82 Japanese adult patients with MCNS receiving treatment at our department were analyzed retrospectively. Of the total, 55 patients (67.1%) experienced relapse after showing an initial response. We divided the patients into two groups; namely, the nonrelapse group (n = 27) and the relapse group (n = 55), and compared the clinico-pathophysiological characteristics between the two groups. RESULTS: Significantly increased serum immunoglobulin E (IgE) levels (P = 0.0002) and increased frequency of steroid side effects were observed in the relapse group as compared to the nonrelapse group. CONCLUSIONS: To develop effective therapeutic modalities, it is important to have a thorough understanding of the clinico-pathophysiological characteristics of MCNS patients showing relapse.

Structural determination of two active compounds that bind to the muscarinic M3 receptor in beer.

BACKGROUND: It is known that beer accelerates gastrointestinal motility in humans. Our previous studies showed that beer congener stimulates gastrointestinal motility by directly stimulating the muscarinic M3 receptor. Further, we isolated 2 active compounds (compounds A and B) from beer by liquid chromatography. The objective of the present study was to identify the 2 active compounds that bind to the muscarinic M3 receptor in beer. METHODS: Structural analyses of the active compounds were performed by fast atom bombardment mass spectra, 1H-nuclear magnetic resonance (NMR), and 13C-NMR spectroscopy. Active compounds were chemically synthesized from p-coumaric acid and agmatine as starting materials. Binding activity to the muscarinic M3 receptor was used to confirm the activity of the synthetic compounds. RESULTS: It was identified that 2 active compounds had the same structural characteristics: stereoisomers (cis-isomer and trans-isomer), molecular weight=550 and molecular formula=C28H38N8O4. Trans-isomer (compound B) was identified as the known substance hordatine A, a kind of phytoalexin in barley, and cis-isomer (compound A) was found to be a novel compound (tentatively referred to as aperidine). Both naturally present and chemically synthesized aperidine (compound A) and hordatine A (compound B) were demonstrated to have potent binding activities to the muscarinic M3 receptor. CONCLUSIONS: The 2 active compounds isolated from beer, namely aperidine (compound A) and hordatine A (compound B), have structurally and functionally been identified as active entities of binding to the muscarinic M3 receptor.