Experience of Quatro-Therapy With Everolimus to Minimize Calcineurin Inhibitor for Kidney Transplant Recipients.

BACKGROUND: This study was divided into three phases, on the occasion of the introduction of everolimus (EVR) in our hospital. METHODS: In the first phase, a study group of six maintenance patients (three living related donors, three deceased donors) who had a history of malignant disease with less than 500 mg/day of proteinuria were enrolled; a high serum creatinine and upper limit of duration after kidney transplant operation was not considered. EVR was discontinued in four of the six patients because of side effects or worsening renal function. The second phase comprised a study group of 12 maintenance patients (12 living related donors) who were more than 5 years after kidney transplant operation with serum creatinine <3 ng/mL and proteinuria <500 mg/day. In two patients, EVR was discontinued because of a skin rash or general fatigue, but EVR was continued in 10 cases. Calcineurin inhibitor (CNI) dosage was reduced and renal function improved, and mean estimated glomerular filtration rate recovered from 42.3 mL/min to 44.8 mL/min, with no rejections occurring. In the third phase, a study group of eight de novo transplant patients who were 2 to 3 weeks after transplant operation were examined. In one case, EVR was discontinued because of proteinuria but was restarted with a stepwise increasing method after 4 months and was continued without any side effects. RESULTS: Our study indicates that EVR was a useful drug for the maintenance of kidney transplant recipients for the optimal patients. CONCLUSIONS: In de novo cases, EVR plus a high dose of mizoribine and low CNI protocol was a useful regimen without serious adverse effects.

Lower thigh muscle mass is associated with all-cause and cardiovascular mortality in elderly hemodialysis patients.

BACKGROUND/OBJECTIVES: Higher body mass index appears protective in hemodialysis patients, although it remains to be determined which component of muscle or fat mass is primarily associated with this survival advantage. SUBJECTS/METHODS: Eighty-one hemodialysis patients in our institution were prospectively followed from July 2011 to August 2015. Muscle and fat mass were evaluated by measuring the cross-sectional areas of the thigh and abdomen using computed tomography. The relationship between muscle and fat mass, and all-cause and cardiovascular mortality was studied using the Kaplan-Meier analyses and multivariate Cox proportional hazard models. RESULTS: During more than 4 years of follow-up, 26 patients (32%) died. In the Kaplan-Meier curve analyses, lower thigh muscle mass was significantly associated with all-cause and cardiovascular mortality (log-rank test, P<0.01 and P<0.001, respectively), but there was no such association with thigh fat, abdominal muscle and fat mass levels. In multivariate Cox proportional hazard models, each 0.1 cm2/kg increase in the thigh muscle area adjusted by dry weight was associated with an estimated 22% lower risk of all-cause mortality (95% confidence interval (95% CI), 0.64-0.95, P<0.05) and a 30% lower risk of cardiovascular mortality (95% CI, 0.54-0.90, P<0.01). CONCLUSIONS: Lower thigh muscle mass is significantly associated with all-cause and cardiovascular mortality in hemodialysis patients. Our findings indicate the importance of focusing on the muscle mass of lower extremities to predict the clinical outcomes of hemodialysis patients.

A novel class of cardiotonics. Synthesis and pharmacological properties of [4-(substituted-amino)phenyl]pyridazinones and related derivatives.

A series of [4-(substituted-amino)phenyl]pyridazinones and [4-(substituted-methyl)amino]phenyl]pyridazinones was synthesized and evaluated for inotropic activity in vitro and for cardiohemodynamic effects in vivo. Above all, 6-[4-(4-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (4, MCI-154) and 6-[4-(4-pyridylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone hydrochloride (5) showed extremely potent positive inotropic activity along with vasodilating activity. Regarding dP/dtmax (an indicator for cardiac contractility), ED30's (doses that increased dP/dtmax by 30%) of compounds 4 and 5 were 8.5 +/- 1.9 and 4.4 +/- 0.6 micrograms/kg, respectively, where that of amrinone was 471.9 +/- 94.1 micrograms/kg. Structure-activity relationships of these series are presented, and a plausible model of receptor binding is discussed.

Association of the serum leptin concentration with weight loss in chronic hemodialysis patients.

Circulating leptin, which is partly cleared by the kidney, has been reported to increase with chronic renal failure and thus may play a role in the weight loss of patients with chronic renal failure. We investigated the association of body weight loss with the serum leptin concentration in Japanese hemodialysis patients. The relationship between serum leptin and the body mass index (BMI) or body fat mass was compared among 181 patients undergoing hemodialysis and 185 control subjects. There was no difference in the serum leptin concentration between the hemodialysis patients (HD) and controls (C) for either the men (3.9 +/- 0.2 ng/mL for HD, n=117; 3.9 +/- 0.3 ng/mL for C, n=89; NS) or women (8.9 +/- 1.2 ng/mL for HD, n=64; 7.4 +/- 0.5 ng/mL for C, n=96; NS), whereas BMI of the hemodialysis patients was significantly lower than that of the controls for both the men (20.1 +/- 0.2 kg/m2 for HD, 22.4 +/- 0.3 kg/m2 for C, P < 0.001) and women (19.2 +/- 0.3 kg/m2 for HD, 22.0 +/- 0.4 kg/m2 for C, P < 0.001). The serum leptin/body fat mass ratio was significantly correlated with the weight change of the patients during a follow-up evaluation period of 17 months (r = -0.37, P < 0.05 for men, n=27 and r = -0.53, P < 0.005 for women, n=28), indicating the possibility that a relatively high level of serum leptin had induced weight loss in the hemodialysis patients. The serum leptin/body fat mass ratio also showed a significant inverse correlation with the duration of hemodialysis (r = -0.31, P < 0.05 for men and r = -0.49, P < 0.05 for women). A multiple regression analysis indicated that the body fat mass was significantly correlated with serum leptin concentration, whereas the fat distribution did not have any relationship with leptin. These data indicate that a high level of serum leptin relative to the body fat mass might be associated with weight loss in long-term hemodialysis patients. The serum leptin level relative to the body fat mass also seems to have been affected by the duration of hemodialysis.

Stimulation of the locus coeruleus suppresses trigeminal sensorimotor function in the rat.

The nucleus locus coeruleus (LC) has been implicated in the modulation of the spinal sensorimotor function. The aim of the present study was to examine the effect of electrical stimulation of the LC on sensorimotor function in the trigeminal system. The following two cases of sensorimotor behaviors mediated by the trigeminal brainstem sensory nuclear complex were examined: (1) the activity of the masseter muscle evoked by pressure on the region of the temporomandibular joint (TMJ); and (2) the activity of the digastric muscle evoked by electrical stimulation of the tooth pulp, resulting in the jaw-opening reflex. In the first case, LC stimulation at 10, 30 and 50 microA resulted in a 70%, 68% and 55% reduction in the magnitude of electromyogram (EMG) activity of the masseter muscle compared with the control (without LC stimulation), respectively. The threshold intensity for the onset of masseter EMG activity increaced to 106%, 111% and 121% of the control with 10, 30 and 50 microA LC stimulation, respectively. In the second case, EMG magnitude in response to the digastric muscle decreased to 42% of the control when 30 microA of LC stimulation was delivered. These results suggest that descending influences from the LC can act in suppression of the trigeminal sensorimotor function.

Thalamic- and cerebellar-projecting interpolaris neuron responses to afferent inputs.

Thalamic- and cerebellar-projecting interpolaris neuron responses to afferent inputs from the temporomandibular joint (TMJ) and/or the masseter muscle (Mm) were examined in rats. Of 230 neurons tested, 24 could be antidromically stimulated from the contralateral ventral posteromedial thalamic nucleus (VPM), and 27 of 91 neurons tested were stimulated from the ipsilateral posteromedial part of crus II of the cerebellar cortex. None had dual projections. The thalamic-projecting neurons were recorded in the dorsomedial region of the interpolaris; most cerebellar-projecting neurons were at the medial border of the interpolaris. Ten of 24 thalamic- and 17 of 27 cerebellar-projecting neurons received nociceptive information. Afferent inputs from the TMJ and the Mm converged on 6 of 24 thalamic-projecting neurons and on 16 of 27 cerebellar-projecting neurons. In both the thalamic- and cerebellar-projecting neurons, there was no difference between the non-nociceptive and nociceptive neurons in mean antidromic latency. The results suggest that the interpolaris integrates and relays afferent inputs from deep oral structures.

Pseudohyperkalemia occurring in a patient with chronic renal failure and polycythemia vera without severe leukocytosis or thrombocytosis.

Pseudohyperkalemia is defined as a serum potassium concentration 0.4 mEq/l greater than the plasma concentration. The basis of this phenomenon is the release of intracellular potassium from platelets, leukocytes, or erythrocytes, commonly in the setting of extreme leukocytosis (> 10 x 10(4)/microl) or thrombocytosis (> 60 x 10(4)/microl). We report a case of pseudohyperkalemia in a patient with chronic renal failure and polycythemia vera without the finding of severe leukocytosis or thrombocytosis (white blood cell count 1.88 x 10(4)/microl and platelet count 37.9 x 10(4)/microl, respectively). The serum potassium concentration was 8.2 mEq/l, while the plasma potassium level was 6.4 mEq/l in a sample obtained simultaneously. The concentrations of platelet factor IV and beta-thromboglobulin, known to be markers of platelet activation, were greater than 100 ng/ml and 200 ng/ml, respectively, indicating that platelet activation may have been related to the development of pseudohyperkalemia in this patient. These findings suggest that pseudohyperkalemia should be considered when hyperkalemia is seen in a patient with chronic renal failure and myeloproliferative disorders.

Hypercalcemia in a patient with B-cell acute lymphoblastic leukemia: a role of proinflammatory cytokine.

The complication of hypercalcemia is reported to occur only in 2.5-4.8% of patients with acute lymphoblastic leukemia (ALL). We herein report a 53-year-old female patient with early B-cell ALL, complicated with extreme hypercalcemia (15.2 mg/dL). Bone X-ray revealed osteolytic changes in many locations. Serum 1,25(OH)2vitaminD3 and parathyroid hormone (PTH) levels were suppressed below normal ranges on admission. The circulating parathyroid hormone-related protein (PTHrP) value was within a normal range (< 1.1 pmol/L). Serum concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and soluble IL-2 receptor were increased to 72 pg/ml, 25.3 pg/ml, and 1469 U/ml, respectively. Following the induction chemotherapy, the serum calcium level was promptly normalized accompanied with decreases in serum TNF-alpha, IL-6 and soluble IL-2 receptor values to 34 pg/ml, 6.35 pg/ml, and 737 U/ml, respectively. Serum PTHrP values remained within detectable levels. To our knowledge, this is the first case of B-cell ALL in a patient who developed hypercalcemia with elevated concentrations of TNF-alpha, IL-6, and soluble IL-2 receptor, but not related to PTHrP. High circulating proinflammatory cytokines may have contributed to development of ALL-induced osteolysis and hypercalcemia in the present case.

Reversible acute renal failure in idiopathic nephrotic syndrome.

Acute renal insufficiency developed in four idiopathic nephrotic patients with minimal change or mild proliferative glomerulonephritis. The reduction in glomerular filtration rate (CInulin) was not in proportion to the renal plasma flow (CPAH) as evidenced by a low filtration fraction. Diuretic therapy failed to reverse renal insufficiency, and renal biopsy showed no evidence of interstitial nephritis, acute tubular necrosis or interstitial edema. Corticosteroid therapy induced a recovery of renal function with a decrease in proteinuria. These observations suggest that acute renal insufficiency in the idiopathic nephrotic syndrome might be caused by impaired glomerular permeability.

Nephrogenic diabetes insipidus associated with bilateral ureteral obstruction.

Nephrogenic diabetes insipidus associated with ureteral obstruction is rare. We report a case of nephrogenic diabetes insipidus associated with ureteral obstruction caused by ileal leiomyosarcoma in a 32-year-old man. The treatment with trichlorothiazide and diclofenac sodium reduced urine output from 8 L/day to 4 L/day. Six months after nephrostomy, urine output decreased to 2.5 L/day without any drug administration. This case suggests that ureteral obstruction may cause an increase in urine output to 8 L/day and that surgical treatment for ureteral obstruction is effective in reducing urine output in nephrogenic diabetes insipidus patients with ureteral obstruction.

Spontaneous bacterial peritonitis in an adult patient with nephrotic syndrome.

Most cases of spontaneous bacterial peritonitis (SBP) in association with nephrotic syndrome are children. The complication of SBP in adults with nephrotic syndrome is extremely rare. Herein, we report a 25-year-old man with nephrotic syndrome and chronic renal failure who suffered from SBP. Citrobacter freundii was isolated from ascites. Irreversible deterioration of renal function followed the development of SBP, though the peritonitis was cured with antibiotic treatment. This case suggests that SBP is a rare, but serious complication of adult nephrotic syndrome with ascites.

The proliferation and differentiation of neonatal epidermal melanocytes in F1 hairless mice of HR-1 x HR/De in serum-free culture.

To investigate the characteristics of the proliferation and differentiation of epidermal melanocytes in F1 hairless mice of HR-1 x HR/De parents in vitro, cell suspensions of the neonatal epidermis were cultured in a serum-free medium supplemented with dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) and/or basic fibroblast growth factor (bFGF). The differentiation of melanocytes was induced by treatment with DBcAMP. In contrast, the sustained proliferation of melanoblasts was induced by combined treatment with DBcAMP and bFGF. The melanoblasts could be subcultured in serum-free medium supplemented with the two factors in the presence of keratinocytes, but not in their absence. This is the first report of successful culture of melanoblasts and melanocytes from hairless mice; it is expected to be useful in understanding the mechanism of the development of pigmented spots in the epidermis of (HR-1 x HR/De)F1 mice, which are reported to be induced by repeated exposure to ultraviolet light B.

[The ventilatory response to CO2 during end-expiratory negative extra-thoracic pressure and PEEP].

The effects of end-expiratory negative extra-thoracic pressure (EENETP) and PEEP on the ventilatory response to CO2 were studied in seven healthy volunteers. The changes in functional residual capacity during EENETP -20 cmH2O and PEEP 5 cmH2O were 13.9 and 12.9 ml.kg-1, respectively. The slopes of CO2 response (minute ventilation/end-tidal CO2) during ZEEP, EENETP and PEEP were 0.913, 0.622, 0.693 l.min-1.mmHg-1, respectively. The slopes during EENETP and PEEP were significantly decreased. These results indicate that EENETP and PEEP could worsen the CO2 response in patients with respiratory failure, especially, with chronic obstructive pulmonary disease in which functional residual capacity is increased.

[A case of schwannoma of intrathoracic right phrenic nerve].

A 22-year old man was admitted because of an abnormal shadow on his chest X-ray film. Radiographic findings revealed that the tumor was located in the right middle mediastinum. At operation a smooth round tumor was found arising from the right phrenic nerve. The tumor was removed with phrenic nerve. Pathohistological examination revealed this tumor was benign schwannoma. Intrathoracic schwannoma usually arise from intercostal and sympathetic nerve and that arising from phrenic nerve is very rare. We removed the tumor by means of cutting his right phrenic nerve because of complete resection. Postoperatively he did well without any respiratory distress. And his respiratory function studies recovered normal 9 months after the operation. We think that schwannoma arising from phrenic nerve should be removed completely and in such a case cutting of the one side phrenic nerve is at ease if the patient have normal respiratory function.