Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model.

BACKGROUND: Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity. METHODS: We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity. RESULTS: DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p < 0.0001; serum creatinine in CsA + DHMEQ vs CsA vs control, 0.75 ± 0.02 vs 0.91 ± 0.02 vs 0.49 ± 0.02 mg/dL, respectively, p < 0.0001), and creatinine clearance was restored in the treatment group (CsA + DHMEQ vs CsA vs control, 2.57 ± 0.09 vs 1.94 ± 0.12 vs 4.61 ± 0.18 ml/min/kg, respectively, p < 0.0001). However, DHMEQ treatment did not alter the inhibitory effect of CsA on urinary protein secretion. The development of renal fibrosis due to chronic CsA nephrotoxicity was significantly inhibited by DHMEQ treatment (CsA + DHMEQ vs CsA vs control, 13.4 ± 7.1 vs 35.6 ± 18.4 vs 9.4 ± 5.4%, respectively, p < 0.0001), and these results reflected the results of renal functional assessment. DHMEQ treatment also had an inhibitory effect on the increased expression of chemokines, monocyte chemoattractant protein-1, and chemokine (c-c motif) ligand 5 due to repeated CsA administration, which inhibited the infiltration of macrophages and neutrophils into the renal tissue. CONCLUSIONS: These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.

Pre-donation BMI and preserved kidney volume can predict the cohort with unfavorable renal functional compensation at 1-year after kidney donation.

BACKGROUND: The magnitude of renal function recovery after kidney donation differs in donors with a heterogeneous background. Preoperative assessment of candidates with potentially unfavorable renal functional compensation is critical when baseline kidney function is marginal. We explored the significance of preserved kidney volume (PKV) and known preoperative risk factors for the prediction of unfavorable renal function compensation. METHODS: We enrolled 101 living donors for whom a 1-mm sliced enhanced computed tomography scan was performed preoperatively and clinical data could be collected up to 1 year after donation. The donors whose estimated glomerular filtration rate (eGFR) at 1 year after donation was 70% or higher of baseline eGFR were assigned to the "favorable renal compensation" group and the others to the "unfavorable renal compensation" group. RESULTS: Age, sex, and preoperative serum uric acid level were not significant predictors for "unfavorable renal compensation." Multivariable logistic regression analysis revealed that body mass index (BMI) and body surface area (BSA)-adjusted PKV were independent preoperative risk factors for "unfavorable renal compensation" (adjusted odds ratio, 1.342 and 0.929, respectively). Hypertension and preoperative eGFR were not independent predictors when adjusted with BMI and BSA-adjusted PKV. Receiver operative characteristic analysis revealed that the predictive equation with the two independent predictors yielded a good accuracy to detect donor candidates with unfavorable renal functional compensation (area under the curve = 0.803), and the optimal cut-off values were identified as 23.4 kg/m2 for BMI and 107.3 cm3/m2 for BSA-adjusted PKV. CONCLUSIONS: BMI and BSA-adjusted PKV may be useful to select candidates with potentially unfavorable renal function compensation before kidney donation.

Obstructive azoospermia caused by low ligation of varicocele: A case report.

Varicocele is commonly observed in male partners of infertile couples. The surgical ligation of varicoceles under microscopy can be safely performed by a skilled andrologist with most patients subsequently experiencing an improvement in semen quality. This is the first case in which obstructive azoospermia occurred after high inguinal varicocelectomy. The vas deferens was disrupted near the internal inguinal ring by fibrous tissue. A vasovasostomy was performed and semen parameters subsequently recovered.

Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review.

Ganciclovir-resistant cytomegalovirus infection is sometimes life-threatening for organ transplant recipients. Foscarnet is an alternative, although it may potentially worsen the preexistent impaired renal function. Here we report the case of a successful low-dose leflunomide treatment in a kidney transplant recipient with very high viral replication, who underwent kidney transplantation 10 years before. Administering 10mg leflunomide daily for 5 months without a loading dose completely cleared the ganciclovir-resistant cytomegalovirus strains.

Dietary intake in Japanese patients with kidney transplantation.

BACKGROUND: Kidney transplantation may release the patient receiving dialysis therapy in their life style, especially in restriction of dietary intake. However, their renal functions are not enough to take daily diet without any restriction. In Japan, we have neither standard of diet intake for them, nor data to build it. METHODS: Dietary intake and its satisfaction were surveyed in 62 outpatients who received kidney transplantation in Keio University Hospital using brief-type self-administered diet history questionnaire. RESULTS: Cross-sectional research was carried out in 2013. Estimated GFR of the object was 42 ± 16 ml/min/1.73 m2. One patient was CKD G1 stage, five in G2, 17 in G3a, 24 in G3b, 14 in G4, and one in G5. Urinary protein was shown in 30 % of patients. Their daily intake was 29 ± 8 kcal/kg of energy, 1.1 ± 0.4 g/kg of protein, 9.9 ± 3.6 g of salt. Protein and salt intakes were over comparing the respective standards for CKD in Japan. The patient who have dissatisfaction for their daily diet was significantly decreased from 79 to 4 % after their kidney transplantation. Attentions to overtake were significantly reduced after kidney transplantation from 56 to 8 % for potassium, 55 to 21 % for salt, 50 to 16 % for protein, 35 to 3 % for calcium/phosphate. CONCLUSIONS: Changes in daily diet of the patients with dialysis and kidney transplantation were recognized. The patients who received kidney transplantation would take daily diet according to their renal function although they do not have specific standards.

A case of paraneoplastic liver dysfunction with elevated serum interleukin-6 in clinically localized renal cell carcinoma.

We report a case of paraneoplastic liver dysfunction associated with a renal cell carcinoma, which disappeared after surgery. A 62-year-old male presented with fatigue and weight loss. The most prominent laboratory abnormality was elevated alkaline phosphatase, C-reactive protein, and interleukin-6 while normal aminotransferases. Computed tomography scan revealed a solid mass in the left kidney. A left radical nephrectomy was performed. After the surgery, biochemical abnormalities returned to normal.

[Clinical characteristics and outcomes of congenital midureteral stricture detected by fetal ultrasonography].

OBJECTIVES: Congenital midureteral stricture (CMS), which develops from obstructive lesion between pyeloureteral junction and ureterovesical junction, is relatively rare and its clinical condition and therapeutic strategy have not yet been established. We analyzed the clinical characteristics and surgical outcomes of CMS. PATIENTS AND METHODS: From November 2006 to December 2012, out of 137 patients presented with congenital hydrohephrosis, we identified 4 pediatric patients diagnosed with CMS at our institutions. We retrospectively investigated clinical characteristics and surgical outcomes in these 4 patients. RESULTS: Three boys and one girl were identified in this study. All patients were detected hydronephrosis by fetal ultrasonography. The median age at the diagnosis of CMS was 1 year and 11 months. Three patients had obstructive lesion in left side and 1 patient in right. CMSs were located at the level of L4 in 2 patients, and at the level of L5 and S1 in each 1. Split renal function was decreased less than 45% in 3 of 4 patients. Ipsilateral pyeloureteral junction obstruction and ipsilateral hypoplastic kidney were identified in 2 and 1 patient, respectively. One patient developed urosepsis and underwent nephrostomy. Partial ureterectomy and ureteroureterostomy, pyeloplasty were performed in 3 and 1 patient, respectively. Extrinsic obstruction was detected in just 1 patient intraoperatively. In all patients, there were no protruded lesion and atrophied, fibrotic and ischemic muscles were not detected in pathological finding. Neither urinary tract infection nor recurrence of obstructive lesion was detected in all patients at the mean follow-up period of 3 years and 1 month. CONCLUSION: We analyzed the clinical characteristics of 4 pediatric patients with CMS. In order to prevent critical infection and maintain renal function, it could be considered that surgical intervention is undertaken just after making the diagnosis of CMS.

Renal arteriolar injury by salt intake contributes to salt memory for the development of hypertension.

The role of salt intake in the development of hypertension is prominent, but its mechanism has not been fully elucidated. Our aim was to examine the effect of transient salt intake during the prehypertensive period in hypertensive model animals. Dahl salt-sensitive rats and spontaneously hypertensive rats were fed from 6 to 14 weeks with low-salt (0.12% NaCl), normal-salt (0.8% NaCl), high-salt (7% NaCl), or high-sodium/normal-chloride diet and returned to normal-salt diet for 3 months. Rats in the high-salt group saw elevations in blood pressure (BP) not only during the treatment period but also for the 3 months after returning to normal-salt diet. We named this phenomenon salt memory. Renal arteriolar injury was found in the high-salt group at the end of experiment. Dahl salt-sensitive rats were fed from 6 to 14 weeks with high-salt diet with angiotensin receptor blocker, vasodilator, calcium channel blocker, and calcium channel blocker+angiotensin receptor blocker and returned to normal-salt diet. Although BP was suppressed to control levels by vasodilator or calcium channel blocker, elevated renal angiotensin II and renal arteriolar injury were observed, and salt memory did not disappear because of sustained renal arteriolar injury. Calcium channel blocker+angiotensin receptor blocker suppressed renal arteriolar injury, resulting in the disappearance of salt memory. Cross-transplantation of kidneys from Dahl salt-sensitive rats on high salt to control rats caused increase of BP, whereas control kidneys caused reduction in BP of hypertensive rats, inducing the central role of the kidney. These results suggest that renal arteriolar injury through BP and renal angiotensin II elevation plays important roles in the development of salt memory for hypertension.

[Copper deficiency anemia morphologically mimicking myelodysplastic syndrome].

A 64-year-old man underwent kidney transplantation for progressive chronic renal failure which had developed 8 years after allogeneic bone marrow transplantation for acute myeloid leukemia. Because of post-operative complications, he had been placed on intravenous hyperalimentation. Three months after the transplantation, anemia rapidly progressed (hemoglobin, 7.9 g/dl). The proportion of reticulocytes was 0.2%, but white blood cell and platelet counts remained within normal ranges. Serum iron, vitamin B12, and folate levels were normal. Bone marrow examination showed the presence of ringed sideroblasts and cytoplasmic vacuoles in a fraction of erythroid cells. Megakaryocytes were adequate in number with normal morphology. Although the findings were consistent with refractory anemia with ringed sideroblasts according to the WHO classification, cytoplasmic vacuolations were also observed in myeloid cells, suggesting copper deficiency. Indeed, serum copper and ceruloplasmin levels were found to be low (33 µg/dl and 11 mg/dl, respectively), and oral copper supplementation at a daily dose of 1 mg was initiated. There was a prompt increase in reticulocytes, and the hemoglobin level was normalized within one month, in response to this regimen. In progressive anemia cases with ringed sideroblasts in the bone marrow, copper deficiency should be considered in the differential diagnosis.

Effect of a novel nuclear factor-κB activation inhibitor on renal ischemia-reperfusion injury.

BACKGROUND: In kidney transplantation, the relationship between prolonged warm or cold ischemic storage of kidneys and a higher incidence of delayed graft function is previously known, and delayed graft function has been known to aggravate poor long-term graft survival. We investigated the effect of a novel nuclear factor-κB activation inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on renal ischemia-reperfusion (I/R) injury. METHODS: DHMEQ was administered to Lewis rats once just before renal artery clamping (DHMEQ pretreatment group), and the effect on I/R injury was investigated. RESULTS: In the DHMEQ pretreatment group, the 24-hr urine volume on days 1 to 3 after I/R was significantly larger, and the protein concentration of the urine on days 2 to 7 was significantly smaller than in the untreated group. The serum creatinine level was significantly improved, and significantly lower levels of the inflammatory cells and inflammatory cytokines were present in the kidneys on day 1. The relative ratio of nuclear to cytoplasmic nuclear factor-κB and oxidative stress of kidney tissue on day 1 were significantly decreased. CONCLUSIONS: Treatment with DHMEQ before renal artery clamping may therefore be useful for renal I/R injury and application to renal transplantation is expected.

Regulation of human dendritic cells by a novel specific nuclear factor-kappaB inhibitor, dehydroxymethylepoxyquinomicin.

Regulation of antigen-presenting cells (APC) is crucial in controlling allograft rejection. Dendritic cells (DC) are the most potent APC and must mature to present antigens to T-cell receptors. During DC maturation, nuclear factor-kappaB (NF-kappaB) is a key transcriptional factor. We synthesized dehydroxymethylepoxyquinomicin (DHMEQ), which specifically inhibits the final step of nuclear translocation of activated NF-kappaB proteins and examined its immunoregulatory effects on human monocyte-derived DC (Mo-DC). Regulatory Mo-DC were generated by pretreatment with DHMEQ before LPS stimulation, which were termed dl-DC. DHMEQ pretreatment (5 microg/ml) completely inhibited nuclear translocation of activated NF-kappaB. DHMEQ significantly inhibited DC production of proinflammatory cytokines (IL-6, TNF-alpha, and IL-12 p70) in a dose-dependent manner. IL-12 was most potently inhibited. However, IL-10 production by dl-DC was only moderately affected by DHMEQ. Although CD40 and the expression of HLA-DR (HLA-DR) expression on dl-DC was downregulated, CD80 and CD86 expression was moderately upregulated. Induction of T helper 1 cell responses was efficiently impaired by dl-DC. This confirmed that DHMEQ-treated Mo-DC exhibited immunoregulatory effects. These findings suggest that DHMEQ has potential as an immunosuppressive drug for human immune cells.

Contrast-enhanced ultrasonography of the prostate with Sonazoid.

OBJECTIVE: The diagnosis of prostate cancer is based on the results of ultrasonography-guided needle biopsy of the prostate, but cancer foci are often not visible in conventional transrectal ultrasonography. Sonazoid is a new microbubble contrast agent. The purpose of our study was to compare areas of contrast material enhancement in the prostate at ultrasonography with whole-mount radical prostatectomy specimens to determine if the use of Sonazoid improves the detection rate of prostate cancer. METHODS: Fifty patients with biopsy-proven cancer of the prostate who were scheduled to undergo radical prostatectomy were recruited for this study. The day before the operation, each patient was evaluated with ultrasonography at baseline and again during intravenous infusion of Sonazoid. A map of ultrasonography findings was created prospectively at the time of imaging. Following radical prostatectomy, independent mapping of the pathologic results was performed and the maps were compared. RESULTS: Ultrasonography evaluation at baseline demonstrated that at least one focus of cancer was identified in 20 of the 50 subjects (40.0%). Meanwhile at least one cancer focus was enhanced in 31 of the 50 patients (62.0%) when Sonazoid was used. The combination of baseline grayscale imaging and contrast-enhanced imaging allowed identification of at least one focus of cancer in 40 patients (80.0%). Contrast-enhanced ultrasonography can improve sensitivity, especially for the detection of large cancer, peripheral zone cancer and highly malignant cancer. CONCLUSIONS: Our study has demonstrated significantly improved detection of prostate cancer with the combination of baseline grayscale imaging and contrast-enhanced imaging compared with conventional ultrasonography techniques only, and this technique may be applicable to targeted biopsy.

Prognostic stratification in patients who received hormonal therapy for prostate-specific antigen recurrence after radical prostatectomy.

The present study was undertaken to investigate the predictors in patients who received hormonal therapy (HT) for prostate-specific antigen recurrence (PSAR) after surgery. Predictors for the progression-free survival were assessed in 55 patients who received HT for PSAR after surgery. In multivariate analysis, primary Gleason grade > or =4 and PSA doubling time (PSA-DT) <6 months were independent predictors. The patients were stratified into low-risk group (Gleason grade <4 and PSA-DT > or =6), high-risk group (Gleason grade > or =4 and PSA-DT <6) and intermediate-risk group (all others). In the intermediate- and high-risk groups, progression-free survival rate was significantly higher in patients with PSA level <2 than in those with PSA level > or =2 at the initiation of HT. Primary Gleason grade > or =4 and PSA-DT <6 months are independent predictors. Patients in the intermediate- and high-risk groups may benefit from early HT for PSAR after surgery.

Docetaxel in combination with prednisolone for hormone refractory prostate cancer.

OBJECTIVE: The objective of this study was to evaluate the efficacy and toxicity of docetaxel in combination with prednisolone in Japanese patients with hormone refractory prostate cancer. METHODS: Twenty patients with hormone refractory prostate cancer (HRPC) were administered a treatment regimen consisting of docetaxel 75 mg/m(2) once every 3 or 4 weeks and prednisolone 5 mg twice daily at our institution between 2006 and 2008. RESULTS: The patients received a median of 5.5 cycles of treatment (range, 2-12 cycles). Nine of the 20 patients (45%) had a >or=50% decrease in serum prostate-specific antigen (PSA). The median duration of response was 4 months (range, 1-11 months). The number of cycles performed, the presence of bone metastasis and the extent of disease had statistically significant associations with the response. Three patients had a transient PSA rise among the patients who ultimately had a response. Grade 3/4 leukopenia and neutropenia occurred in 80.0% and 85.0% of the patients, respectively. Interstitial pneumonia occurred in only one patient; however, the patient recovered. Finally, no treatment-related deaths were seen during the observation period. CONCLUSIONS: The combination of docetaxel 75 mg/m(2) every 3 weeks and prednisolone 10 mg daily was effective and well tolerated in Japanese patients with HRPC. The results of this study suggest that a decision concerning discontinuation of this treatment should be carefully considered because a transient PSA rise was observed. Although interstitial pneumonia was rare, the potential risk of its development should be taken into consideration.

Primary intratesticular leiomyosarcoma.

This report presents a case of primary intratesticular leiomyosarcoma. A 73-year-old male presented with a 6-year history of left scrotal swelling. A radiological examination revealed a left testicular tumour with multiple metastases in the lung, para-aortic lymph node and other organs. A radical orchiectomy was carried out and the pathology revealed an intratesticular leiomyosarcoma. The patient received additional chemotherapy. Cases of primary intratesticular leiomyosarcoma are rare. This is, to the best of our knowledge, only the tenth case of leiomyisaocoma in an adult reported in the literature, and the first case involving multiple metastases.