Mizoribine therapy combined with steroids and mizoribine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome.

BACKGROUND: We designed a prospective and randomized trial of mizoribine (MZR) therapy combined with prednisolone (PSL) for idiopathic membranous nephropathy (IMN) with steroid-resistant nephrotic syndrome (SRNS). METHODS: Patients with IMN were divided into 2 groups, and MZR combined with PSL was administered for 2 years. PSL was initially prescribed at 40 mg/day and tapered. MZR was given once-a-day at 150 mg and 3-times-a-day at 50 mg each to groups 1 and 2. Serum MZR concentrations from 0 to 4 h after administration were examined within one month of treatment. The concentration curve and peak serum level (C max) of MZR were estimated by the population pharmacokinetic (PPK) parameters of MZR. RESULTS: At 2 years, 10 of 19 patients (52.6 %) in group 1 and 7 of 18 patients (38.9 %) in group 2 achieved complete remission (CR). The time-to-remission curve using the Kaplan-Meier technique revealed an increase in the cumulative CR rate in group 1, but no significant difference between the groups. Meanwhile, there was a significant difference in C max between groups 1 and 2 (mean ± SD: 1.20 ± 0.52 vs. 0.76 ± 0.39 µg/mL, p = 0.04), and C max levels in CR cases were significantly higher than those in non-CR cases. Receiver operating characteristic analysis showed that C max more than 1.1 µg/mL was necessary for CR in once-a-day administration. CONCLUSION: Administration of MZR once a day is useful when combined with PSL for treatment of IMN with SRNS. In addition, it is important to assay the serum concentration of MZR and to determine C max, and more than 1.1 µg/mL of C max is necessary for CR.

Significance of combined cyclosporine-prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial.

BACKGROUND: Combined treatment with cyclosporine microemulsion preconcentrate (CyA MEPC) and steroids has been widely used for idiopathic membranous nephropathy (IMN) associated with steroid-resistant nephrotic syndrome (SRNS). Recent studies have shown that once-a-day and preprandial administration of CyA MEPC is more advantageous than the conventional twice-a-day administration in achieving the target blood CyA concentration at 2 h post dose (C2). We designed a randomized trial to compare these administrations. METHODS: IMN patients with SRNS (age 16-75 years) were divided prospectively and randomly into 2 groups. In group 1 (n = 23), 2-3 mg/kg body weight (BW) CyA MEPC was given orally once a day before breakfast. In group 2 (n = 25), 1.5 mg/kg BW CyA MEPC was given twice a day before meals. CyA + prednisolone was continued for 48 weeks. RESULTS: Group 1 showed a significantly higher cumulative complete remission (CR) rate (p = 0.0282), but not when incomplete remission 1 (ICR1; urine protein 0.3-1.0 g/day) was added (p = 0.314). Because a C2 of 600 ng/mL was determined as the best cut-off point, groups 1 and 2 were further divided into subgroups A (C2 ≥600 ng/mL) and B (C2 <600 ng/mL). Groups 1A and 2A revealed significantly higher cumulative remission (CR + ICR1) (p = 0.0069) and CR-alone (p = 0.0028) rates. On the other hand, 3 patients with high CyA levels (C2 >900 ng/mL) in Group 1A were withdrawn from the study because of complications. CONCLUSION: CyA + prednisolone treatment is effective for IMN with associated SRNS at a C2 of ≥600 ng/mL. To achieve remission, preprandial once-a-day administration of CyA at 2-3 mg/kg BW may be the most appropriate option. However, we should adjust the dosage of CyA by therapeutic drug monitoring to avoid complications.

[A case of gastric cancer with peritoneal dissemination successfully treated with low-dose S-1 or capecitabine chemotherapy for five years].

We report a case of gastric cancer with peritoneal dissemination that was successfully treated with low-dose S-1 or capecitabine chemotherapy over a 5-year period. In September 2007, distal gastrectomy was performed for treating gastric cancer with synchronous peritoneal dissemination in a 78-year-old man. Combination chemotherapy of S-1 and CDDP was administered after the surgical procedure. Following the completion of 9 courses, this regimen was discontinued owing to adverse events; therefore, S-1 (40-50mg/body/day) or capecitabine (1,800 mg/body/day) chemotherapy was initiated. S-1 or capecitabine were orally administered for 2 weeks, followed by a 2-week or 1-week interval, respectively; this regimen was continued for over 5 years. The patient died in June 2013.

Doubling of serum creatinine: is it appropriate as the endpoint for CKD? Proposal of a new surrogate endpoint based on the reciprocal of serum creatinine.

BACKGROUND: The evaluation of the progression of renal insufficiency, or decline in glomerular filtration rate (GFR), has been approached more simply and precisely by converting measured serum creatinine value into the reciprocal of serum creatinine, estimated GFR, or other parameters. Doubling of serum creatinine (simple doubling) is conveniently used as a surrogate endpoint for progression of renal disease but is thought to be biased unfairly by the initial value of serum creatinine (Scr(Int)). We proposed the definite decline in the reciprocal of serum creatinine (2-4 doubling) as a surrogate endpoint, comparing simple doubling with this new endpoint to verify the effect of Scr(Int) on the endpoint. METHODS: For the purpose of comparison between endpoints, 194 patients in a historical cohort of chronic glomerulonephritis were investigated. Kaplan-Meier survival analysis was performed with the composite endpoint of need for dialysis and either simple doubling or 2-4 doubling. Then, the distribution of Scr(Int) was compared between total patients and patients developing each endpoint. RESULTS: The endpoint value of serum creatinine (Scr(End)) with 2-4 doubling was lower than that with simple doubling at Scr(Int) <2.00 mg/dl, and the difference of Scr(End) between simple doubling and 2-4 doubling was larger, as Scr(Int) became lower. In patients reaching simple doubling, Scr(Int) was higher than that of the total patients (1.66 vs. 1.07 mg/dl in median, respectively; p < 0.001). In patients reaching 2-4 doubling, there was no significant difference in Scr(Int). CONCLUSION: Patients with low serum creatinine concentration at baseline had a tendency of prolonged development into simple doubling. In contrast, with 2-4 doubling, there was no bias of Scr(Int).

Lack of collagen XVIII/endostatin exacerbates immune-mediated glomerulonephritis.

Collagen XVIII is a component of the highly specialized extracellular matrix associated with basement membranes of epithelia and endothelia. In the normal kidney, collagen XVIII is distributed throughout glomerular and tubular basement membranes, mesangial matrix, and Bowman's capsule. Proteolytic cleavage within its C-terminal domain releases the fragment endostatin, which has antiangiogenic properties. Because damage to the glomerular basement membrane (GBM) accompanies immune-mediated renal injury, we investigated the role of collagen XVIII/endostatin in this disorder. We induced anti-GBM glomerulonephritis in collagen XVIII alpha1-null and wild-type mice and compared the resulting matrix accumulation, inflammation, and capillary rarefaction. Anti-GBM disease upregulated collagen XVIII/endostatin expression within the GBM and Bowman's capsule of wild-type mice. Collagen XVIII/endostatin-deficient mice developed more severe glomerular and tubulointerstitial injury than wild-type mice. Collagen XVIII/endostatin deficiency altered matrix remodeling, enhanced the inflammatory response, and promoted capillary rarefaction and vascular endothelial cell damage, but did not affect endothelial proliferation. Supplementing collagen XVIII-deficient mice with exogenous endostatin did not affect the progression of anti-GBM disease. Taken together, these results suggest that collagen XVIII/endostatin preserves the integrity of the extracellular matrix and capillaries in the kidney, protecting against progressive glomerulonephritis.

Public involvement in pharmacogenomics research: a national survey on patients' attitudes towards pharmacogenomics research and the willingness to donate DNA samples to a DNA bank in Japan.

To assess the attitude of Japanese patients towards pharmacogenomics research and a DNA bank for identifying genomic markers associated with adverse drug reactions (ADRs) and their willingness to donate DNA samples, we conducted a survey of 550 male and female patients. The majority of the respondents showed a positive attitude towards pharmacogenomics research (87.6%) and a DNA bank (75.1%). The willingness to donate DNA samples when experiencing severe ADRs (55.8%) was higher than when taking medications (40.4%). Positive attitudes towards a DNA bank and organ donation were significantly associated with an increased willingness to donate. Though the level of positive attitude in the patient population was higher than that in the general public in our former study (81.0 and 70.4%, respectively), the level of the willingness of patients to donate was 40.4% when taking medications and 55.8% when experiencing severe ADRs which was lower than that of the general public in our former study (45.3 and 61.7%). The results suggested that the level of true willingness in the patient population was lower than that of the general public considering the fictitious situation presented to the public (to suppose that they were patients receiving medication). It is important to assess the willingness of patients who are true potential donors, not the general public.

[A case of synchronous multiple liver metastases of rectal cancer successfully treated with tegafur/uracil and oral leucovorin chemotherapy].

We report a case of synchronous multiple liver metastases of rectal cancer successfully treated with tegafur/uracil(UFT) and oral Leucovorin (LV) chemotherapy. Lower anterior resection was carried out on the rectal cancer patient (an 80-year- old man), who had synchronous multiple liver metastases. The UFT (450 mg/day) and oral LV (75 mg/day) were orally administered for 4 weeks, followed by a 1-week interval after the surgical procedure. After completion of 16 courses, CT scan showed no liver metastases, and the patient was judged to have achieved a complete response (CR). The interval of CR was maintained for sixteen months until the age of 82. This chemotherapy is expected to have a potent therapeutic efficacy for older adult patients with advanced rectal cancer, because it is convenient and causes no severe diverse events.

A large gastric rupture due to blunt trauma: a case report and a review of the Japanese literature.

Gastric rupture due to blunt trauma is rare, occurring in only 0.07-1.2% of all abdominal blunt traumas. We reported a case with a 10-cm-long hole and review 25 cases in Japan. A 22-year-old man was involved in a traffic accident, 2 h after eating a lot of food. He had suffered muscular defense in the abdomen. An abdominal computed tomography (CT) scan revealed free air, disruption of the gastric wall and a lot of food residue. The laparotomy showed a burst of 10 cm that ran parallel to the long axis from the cardia to the body. A simple closure was primarily performed and drains were placed in the abdominal cavity. The patient was discharged on the 32nd day. Most cases of gastric rupture are diagnosed intraoperatively, but careful evaluation of CT scans and patient interviews are needed to make an accurate preoperative diagnosis.

Interactions of human organic anion transporters with aristolochic acids.

Aristolochic acids (AAs), contained in Chinese herbal preparations, have been considered to induce nephropathy. In order to elucidate the molecular mechanisms of AA-induced nephrotoxicity, we have elucidated the interaction of human organic anion transporters (hOATs) with AAs using their stable cell lines. AA-I and AA-II inhibited organic anion uptake by hOAT1, hOAT3, and hOAT4 in dose-dependent manners. Treatment of hOAT3 with AA-I resulted in a significant reduction in viability compared with that of mock, which was rescued by the organic anion transport inhibitor probenecid. In conclusion, hOAT3-mediated AA-I uptake may be associated with the induction of nephrotoxicity.

Low-dose darbepoetin alpha attenuates progression of a mouse model of aristolochic acid nephropathy through early tubular protection.

BACKGROUND/AIM: Aristolochic acid (AA) nephropathy, first reported as Chinese herbs nephropathy, is a rapidly progressive tubulointerstitial nephropathy that results in severe anemia, interstitial fibrosis and end-stage renal disease. Tubulointerstitial injury was studied in a mouse model of AA nephropathy to determine whether low-dose darbepoetin alpha (DPO) treatment prevents acute tubular necrosis and interstitial fibrosis. METHODS: AA was administered to C3H/He mice intraperitoneally and some mice were also treated with 0.1 microg/kg of DPO weekly starting on the day of AA administration or on day 28. At 28, 56 or 84 days, blood and urine samples were collected and mice were sacrificed for histological assessment of the kidneys. RESULTS: AA-treated mice developed anemia, elevation of serum creatinine, severe tubular injury similar to acute tubular necrosis and progressive interstitial fibrosis. Although early treatment with low-dose DPO had minimal effects on the hematocrit, it significantly ameliorated acute tubular injury and interstitial inflammation through increasing the survival of tubular cells. As a result, it contributed to preservation of peritubular capillaries and reduction of interstitial fibrosis. CONCLUSION: Low-dose DPO treatment conferred protection against acute tubular damage and attenuated interstitial fibrosis in a mouse model of AA nephropathy. Early administration of low-dose DPO may prevent the progression of acute tubular necrosis and the subsequent renal fibrosis in human AA nephropathy.

Relationship between plasma concentrations of morphine and its metabolites and pain in cancer patients.

OBJECTIVE: This study was undertaken to investigate the relationship between the plasma concentration of morphine, morphine-3-glucuronide and morphine-6-glucuronide and pain in cancer patients receiving oral morphine. METHODS: The trough value of plasma concentrations of morphine and its metabolites were measured by high performance liquid chromatography using an ultraviolet detector. Using this assay system, the plasma concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide in 26 cancer pain patients were measured and compared with pain intensity. The pain intensity was assessed at the time of blood sampling using the visual analog scale. RESULTS: The trough value of morphine and morphine-6-glucuronide did not show a significant correlation with pain intensity by visual analog scale assessment, but morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine showed a significantly positive correlation (r = 0.528, P = 0.006 and r = 0.671, P < 0.001, respectively). By dividing the group according to low (≤ median value) or high (> median value) VAS scores a significant difference was found between the two groups in morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine (P = 0.045 and P = 0.007, respectively). CONCLUSION: These results indicated that the level of morphine-3-glucuronide is related to the patient's perception of morphine effect, and the plasma concentration of morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine indicated potency to assess clinical effect.

[Retardation of hemodialysis by recombinant human erythropoietin in patients with chronic kidney disease].

UNLABELLED: Renal anemia is a serious complication of chronic kidney disease (CKD) and accelerates its progress. Recombinant human erythropoietin (rHuEPO) therapy not only improves anemia but also has a renoprotective effect. This study aimed to determine whether treatment with rHuEPO can retard the initiation of hemodialysis (HD) in patients with CKD. METHODS: Clinical data of CKD patients who had already been treated with HD were analyzed retrospectively. Twenty-one patients who had received rHuEPO therapy constituted the treated group (EPO(+) group), and twenty-one other patients without rHuEPO constituted the non-treated group (EPO(-) group). The study start-point was the day of kidney function deterioration, judged as CKD stage 5. The end-point of the study was the initiation of HD. RESULTS: During the evaluation period, mean values of hemoglobin (Hb) in the EPO(+) group remained lower than those in the EPO(-) group. Survival analysis limited to the two-year period from the beginning of evaluation showed that the renal survival rate of the EPO(+) group was significantly better than that of the EPO(-) group [EPO(+): 42.1% vs. EPO(-): 12.5%, p<0.05]. Duration of renal survival was 29.8 +/- 4.07 months in the EPO(+) group and 19.1 +/- 3.27 months in the EPO(-) group (p<0.05). CONCLUSION: Although the mean values of Hb remained lower in the EPO(+) group than in the EPO(-) group during the observation period, the renal survival rate and duration of renal survival in the EPO(+) group were significantly superior than in the EPO(-) group. The study suggests that rHuEPO exerts a renoprotective effect via a mechanism other than the correction of anemia.

[A case of respiratory bronchiolitis-associated interstitial lung disease].

A 37-year-old man was referred to our hospital with a cough. His blood test result and chest radiography findings were normal. High resolution chest computed tomography (HRCT) showed diffuse ground glass attenuation (GGA) with centrilobular distribution in the bilateral upper lung fields. As diagnosis could not be made using transbronchial lung biopsy and bronchoalveolar lavage, video-assisted lung biopsy was performed. The histological findings were a thickening of the alveolar walls with infiltration of lymphocyte-dominant inflammatory cells, and exudation of pigmented macrophages in the air spaces of the respiratory bronchioles and alveolis. We diagnosed his illness as respiratory bronchiolitis-associated interstitial lung disease. Six months after stopping smoking, his symptoms, and the GGA on chest HRCT improved.

Halofuginone prevents extracellular matrix deposition in diabetic nephropathy.

Transforming growth factor-beta (TGF-beta) is known to promote the accumulation of extracellular matrix (ECM) and the development of diabetic nephropathy. Halofuginone, an analog of febrifugine, has been shown to block TGF-beta(1) signaling and subsequent type I collagen production. Here, the inhibitory effect of halofuginone on diabetic nephropathy was examined. Halofuginone suppressed Smad2 phosphorylation induced by TGF-beta(1) in cultured mesangial cells. In addition, the expression of TGF-beta type 2 receptor decreased by halofuginone. Halofuginone showed an inhibitory effect on type I collagen and fibronectin expression promoted by TGF-beta(1). An in vivo experiment using db/db mice confirmed the ability of halofuginone to suppress mesangial expansion and fibronectin overexpression in the kidneys. Moreover, an analysis of urinary 8-OHdG level and dihydroethidium fluorescence revealed that halofuginone reduced oxidative stress in the glomerulus of db/db mice. These data indicate that halofuginone prevents ECM deposition and decreases oxidative stress, thereby suppressing the progression of diabetic nephropathy.

[A case of recurrent rectal cancer with multiple lung metastases successfully treated with S-1 and CPT-11 combination chemotherapy].

We report a case of recurrent rectal cancer with multiple lung metastases successfully treated with S-1 and CPT-11 combination chemotherapy. Rectal amputation was carried out on the rectal cancer patient, a 63-year-old man. CT scan revealed multiple lung metastases after 20 months of surgery. The patient was treated with S-1 and CPT-11 combination chemotherapy. S-1(100mg/body/day)was orally administered for 2 weeks followed by a 1-week interval, and CPT-11 (120 mg/body on day 1)was simultaneously administered. After completion of 8 courses, CT scan showed no lung metastases, and the patient was judged to have achieved a complete response (CR). The CR interval was maintained for twelve months until 20 courses of chemotherapy had been completed. This chemotherapy was expected to have a potent therapeutic efficacy for recurrent rectal cancer, considering the convenience, cost benefit and no severe adverse event.

[A case of nonspecific interstitial pneumonia with reversed halo sign on chest HRCT].

A 39-year-old man was referred to our hospital with anterior chest discomfort, dry cough and shortness of breath. His blood test revealed mild inflammatory change and high serum KL-6 levels. Chest radiograph and computed tomography (CT) showed ground glass attenuation with volume loss in both lower lung fields, and in particular a reversed halo sign was shown on high-resolution CT (HRCT). As transbronchial lung biopsy and bronchoalveolar lavage did not enable a diagnosis, video-assisted thoracic surgery was performed. The histological findings of the resected specimen showed cellular nonspecific interstitial pneumonia. This suggested the possibility of collagen vascular disorder (CVD) associated with interstitial pneumonitis, but no criteria of CVD were fulfilled. Although the reversed halo sign is relatively specific for cryptogenic organizing pneumonia, we report a case of cellular nonspecific interstitial pneumonia showing this sign on chest HRCT.

Prognostic value of increased plasma levels of brain natriuretic peptide in patients with septic shock.

Our objective was to investigate the plasma levels of brain and atrial natriuretic peptides (BNP and ANP, respectively) in patients with septic shock/severe sepsis and to study the association of BNP and ANP levels with hemodynamic parameters, severity of the disease, and prognosis of those patients. This is a prospective case series study of 22 patients with septic shock, 11 patients with severe sepsis, and 20 healthy volunteers at the Department of Emergency and Critical Care Medicine, Nara Medical University Hospital, Japan. Blood collection was performed on admission and on days 1, 2, and 4. Plasma BNP and ANP levels were measured by radioimmunoassay. Right atrial pressure, mean pulmonary arterial pressure, pulmonary arterial wedge pressure, and left ventricular stroke work index were determined using a thermodilution catheter. Acute Physiological and Chronic Health Evaluation II scores were calculated. Plasma levels of BNP and ANP were markedly elevated in patients with septic shock/severe sepsis compared with controls (BNP, 7 +/- 0.3 pg mL; ANP, 13 +/- 1 pg mL). In patients with septic shock, both BNP and ANP peaked on day 2 (BNP, 987 +/- 160 pg mL; ANP, 103 +/- 17 pg mL). Plasma levels of BNP on day 2 in patients with septic shock significantly correlated with right atrial pressure (r = 0.744, P < 0.01), mean pulmonary arterial pressure (r = 0.670, P < 0.01), pulmonary arterial wedge pressure (r = 0.709, P < 0.01), left ventricular stroke work index (r = -0.552, P < 0.05), Acute Physiological and Chronic Health Evaluation II score (r = 0.581, P < 0.01), and poor prognosis (P < 0.05). The optimal cutoff point for predicting mortality in patients with septic shock was a BNP level of 650 pg mL on day 2, in which sensitivity and specificity were 92% and 80%, respectively. Increased plasma levels of BNP may reflect not only the severity of myocardial depression but also the disease severity and could be of prognostic value in patients with septic shock.