Long-term outcome of 6-month maintenance chemotherapy for acute lymphoblastic leukemia in children.

In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1 (n=11) and ETV6-RUNX1 (n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1 and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.

Viscosity and drag force involved in organelle transport: investigation of the fluctuation dissipation theorem.

We observed the motion of an organelle transported by motor proteins in cells using fluorescence microscopy. Particularly, among organelles, the mitochondria in PC12 cells were studied. A mitochondrion was dragged at a constant speed for several seconds without pausing. We investigated the fluctuation dissipation theorem for this constant drag motion by comparing it with the motion of Brownian beads that were incorporated into the cells by an electroporation method. We estimated the viscosity value inside cells from the diffusion coefficients of the beads. Then the viscosity value obtained by using the beads was found to be slightly lower than that obtained from the diffusion coefficient for the organelle motion via the Einstein relation. This discrepancy indicates the violation of the Einstein relation for the organelle motion.

IL-8 in cerebrospinal fluid from children with acute encephalopathy is higher than in that from children with febrile seizure.

We identify possible differences in the cytokine/chemokine profiles in cerebrospinal fluid (CSF) from children with encephalopathy and febrile seizure. Interleukin (IL)-1beta, 2, 4, 5, 6, 7, 8, 10, 12, 13, 17, interferon-gamma, tumour necrosis factor-alpha, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1beta were measured simultaneously in CSF supernatants from children with encephalopathy (n = 8), febrile seizure (n = 16) and fever without neurological complications (n = 8). IL-8 in CSF from children with encephalopathy was significantly elevated compared to that in CSF from children with febrile seizure and fever without neurological complications. IL-8 in CSF was also higher than serum IL-8, suggesting that increased IL-8 was generated from glia cells or astrocytes, not by leakage from serum. Increased IL-8 in CSF in encephalopathy may protect against severe brain damage.

Comparison of the effects of polysulfone and polyester-polymer alloy dialyzers on glycemic control in diabetic patients undergoing hemodialysis.

BACKGROUND: Though different high-flux dialyzers are available, there are no comparative studies on their glycemic control effects on diabetic hemodialysis (HD) patients. In this crossover study, we compared the effects of polysulfone (PS) and polyester-polymer alloy (PEPA) dialyzers. METHODS: We recruited 47 diabetic HD patients. The conventional dialyzers were replaced with PS or PEPA dialyzers and the patients were treated for 16 weeks. Subsequently, after interchanging the PS and PEPA dialyzers, the treatment continued for another 16 weeks. For each dialyzer, we analyzed the glycemic control effect and measured their clearance and reduction rates of insulin. RESULTS: The PEPA dialyzer lowered the glycated albumin (GA) levels more significantly than the PS dialyzer. While the groups exhibited no differences in metabolic parameters, the clearance and reduction rates of insulin were more significant in the PS. A significant decrease was observed in the levels of GA, fasting plasma glucose, and glycated hemoglobin in patients with lower fasting C-peptide levels (< 6.0 ng/ml). CONCLUSION: Glycemic control in diabetic HD patients is affected by the type of dialyzer used. Our results indicate that the PEPA dialyzer is more potent in controlling glycemia than the PS dialyzer in diabetic HD patients.

The influence of hemodialysis membranes on the plasma insulin level of diabetic patients on maintenance hemodialysis.

AIM: The aim of the present study was to evaluate the alteration in plasma immunoreactive insulin (IRI) concentrations due to hemodialysis (HD) treatment by using three types of membranes in diabetic HD patients. METHOD: We recruited 20 outpatients on maintenance HD with diabetes for this crossover study. HD was performed using membranes made of cellulose triacetate (CTA), polyester-polymer alloy (PEPA), and polysulphone (PS). These membranes were used for 2 weeks (6 HD sessions) in each patient in a randomized order decided by drawing lots. Blood samples were obtained at the beginning and end of the HD session from the blood tubing at the arterial (A) site. At 60 min after the initiation of dialysis, blood samples were obtained from the blood tubing at both the A and venous (V) sites of the dialyzer. RESULTS: The plasma IRI levels decreased significantly at the sites an hour after initiating HD in all membranes. The clearance of IRI was significantly higher in the case of the PS membrane when compared with the CTA and PEPA membranes. CONCLUSIONS: It was concluded that plasma insulin is cleared by HD, and the rate differs for each membrane. Plasma insulin clearance with the PS membrane is higher than that with the PEPA and CTA membranes.

Combination therapy of pioglitazone with voglibose improves glycemic control safely and rapidly in Japanese type 2-diabetic patients on hemodialysis.

AIMS: Unfortunately, clinicians are diagnosing a growing number of patients on hemodialysis (HD) with insulin-resistant, Type 2 diabetes in Japan. While alpha-glucosidase inhibitors (alpha-GI) such as oral antidiabetic agents are indicated for Japanese diabetics on HD, pioglitazone and other PPARgamma agonists are now contraindicated. No prospective study has evaluated the use of thiazolidinediones in diabetics with end-stage renal disease (ESRD) in combination with alpha-GI. In this study we evaluated the efficacy and safety of pioglitazone in Japanese diabetics on HD. METHODS: An open-label randomized study was performed on 31 Type 2 diabetics on HD with unstable glycemic control receiving constant doses of voglibose. The patients were randomly assigned to two groups: a combination therapy group (pioglitazone group) administered pioglitazone (fixed dose 30 mg) plus voglibose, and a monotherapy group (control group) administered voglibose alone. The efficacy of the treatments was determined by monitoring glycemic control (plasma glucose and HbA1c) and insulin resistance. Insulin resistance was assessed using the homeostasis model assessment for insulin resistance (HOMA-R). Safety and tolerance were determined by monitoring clinical and laboratory parameters. RESULTS: The pioglitazone was effective in reducing plasma glucose and HbA1c from the baseline levels from Week 4 onward. It was also effective in reducing triglycerides. HOMA-R decreased significantly at 4 weeks in the pioglitazone group, and the decrease continued up to the last measurement at Week 12. Systolic and diastolic blood pressures at 4 weeks were statistically lower in the pioglitazone group than in the control group. No serious adverse effects such as hypoglycemia, liver impairment or rhabdomyolysis were observed in any of the patients. CONCLUSIONS: Pioglitazone was safe and effective as a treatment for diabetics on dialysis therapy. The 30 mg daily dose of pioglitazone was sufficient for Japanese HD patients, obese and nonobese alike. The combination therapy of pioglitazone with voglibose will add to the list of first-line drug treatments for glycemic control in uremic Type 2 diabetes.

[Problems in donor lung evaluation for transplantation with regard to airway infection].

The shortage of donor organs has been 1 of the major obstacles to solid organ transplantation. Typical lung donor criteria include clear lung field on chest radiograph, adequate oxygenation, acceptable lung compliance, and satisfactory bronchoscopic findings. To extend usage of available donors, liberalization of donor lung selection criteria has been facilitated, however, marginal donor lungs must be used with discretion, because donor lung injury, especially that related to infection, has a potential leading to early post-operative death of the recipient. From March 2000 to December 2006, we evaluated 15 braindead donors and at least 1 of the lungs from 9 donors was judged suitable for transplantation. One of 9 recipients developed severe pneumonia cased by carbapenems-resistant Pseudomonas aeruginosa possibly originating from the donor lungs, eventually leading to death. The chest radiograph and oxygenation of the donor had been satisfactory, however, a moderate amount of mucopurulent secretions was observed by bronchoscopic inspection and the donor had been given a cefozopran for 9 days before the procurement operation. Remaining 8 recipients were free from air-way infection in the early postoperative period. We discuss the status and problems of donor lung evaluation for transplantation with regard to donor lung infection.

Clinical study of influenza-associated rhabdomyolysis with acute renal failure.

AIMS: Influenza-associated rhabdomyolysis induces renal failure with a fatal outcome. The aim of this study is to evaluate the clinical features, diagnosis, and treatment efficacy of influenza-associated rhabdomyolysis patients with acute renal failure (ARF). MATERIALS AND METHODS: The subjects included 6 patients who had presented with rhabdomyolysis and ARF due to influenza infection on admission to our university hospital and its 2 affiliated hospitals between January 2002 and February 2004. We retrospectively examined the cases. RESULTS: All the patients (n = 6) were males, and none of them had received an influenza vaccine. The viruses were identified as influenza A (n = 5) and B (n = 1). Muscular weakness was observed in many cases (n = 5), whereas pain or tenderness was observed in only 1 case (n = 1). For anuric or oliguric patients (n = 4), blood purification therapy was performed, while for patients in whom the urine volume was normal (n = 2), conservative therapy was administered. CONCLUSION: Careful medical attention is necessary when patients have muscle pain and weakness. Early recognition of rhabdomyolysis allows prompt institution of an appropriate therapy that includes blood purification and may minimize the renal dysfunction associated with this disorder.

Electron microscopic studies on the occurrence of activated neutrophils in peripheral blood of children with acute leukemias.

Peripheral blood (PB) cells are examined to assess cellular maturity and the degree of bone marrow abnormality in children with acute leukemias. During the ultrastructural assessments of PB cells in these children, we noted a frequent occurrence of activated neutrophils. This phenomenon had not been reported previously. We here report for the first time the identification of activated neutrophils in PB of children with acute leukemias. To examine the impact of activated neutrophils, we compared two groups of children including 18 with acute lymphoblastic leukemia (ALL) and 7 with acute myelogenous leukemia (AML) by an ultrastructural leukocyte count method. Many cases (50%) showed more than 30% activated neutrophils per total neutrophil count in PB. Activated neutrophils were elongated or amoeboid-shaped cells ranging from 13-18 microns in greater diameter with a decreased number of granules in the cytoplasm. A significantly higher rate of activated neutrophils was observed in ALL as compared with AML (median: 42.97% vs. 10.64%). Non-leukemic hospitalized (n =3) and healthy (n = 3) control cases showed a median rate of 3.32% activated neutrophils in PB. These findings reveal that a significantly high rate of activated neutrophils occurs in PB of children with ALL which may be exploited in the diagnostic assessment of children with acute leukemias.

Pharmacokinetics of the antithyroid drug thiamazole in a chronic hemodialysis patient with hyperthyroidism.

There has been little information regarding the pharmacokinetics of antithyroid drugs in patients with endstage renal disease (ESRD). We report here the pharmacokinetics and dialyzability of the antithyroid drug thiamazole in a chronic hemodialysis patient with hyperthyroidism. The patient was a 46-year-old woman who complained of palpitations 3 years after starting chronic hemodialysis therapy, followed by several episodes of pulmonary edema. A diagnosis of hyperthyroidism due to Graves' disease was confirmed by a laboratory test for thyroid function and anti-thyroid-stimulating hormone (TSH) receptor antibodies. The plasma concentration of thiamazole was measured before and at 1, 3, 4, 5, 6, and 24 h after administration of the drug. The dialyzability of the drug was investigated during hemodialysis therapy. On the non-dialysis day, the serum half-life of thiamazole (6.4 h) was similar to that in healthy subjects (4-6 h). Further, thiamazole was removed via the dialyzer during dialysis therapy. The initial dose of thiamazole was set at 15 mg/day for the patient. Free thyroid hormone levels began to decrease 2 weeks after the initiation of thiamazole, followed by the normalization of the values after 1 month. The patient's symptoms also subsided. Several confirmations of the concentration of thiamazole in the plasma in the morning on the first dialysis day of the week did not disclose a trend of accumulation in the blood. Although this is a single case report, it is suggested that thiamazole can be used for patients with ESRD. Careful monitoring of thyroid function, however, is recommended, because the intrathyroid action of thiamazole in uremia is unknown.

Inhibition of neuronal nitric oxide synthase ameliorates renal hyperfiltration in streptozotocin-induced diabetic rat.

Systemic inhibition of nitric oxide synthase (NOS) in streptozotocin-induced (STZ-induced) diabetic rats results in decreases in glomerular filtration rate (GFR) and renal plasma flow (RPF) and an increase in renal vascular resistance (RVR). However, the exact isoform of NOS involved in diabetic renal hyperfiltration has not been determined. This study was conducted to clarify whether NO derived from neuronal NOS is involved in diabetic renal hyperfiltration when using a selective inhibitor of neuronal NOS, 7-nitro indazole (7-NI). Continuous infusion of NG-nitro-L -arginine methyl ester (L-NAME) at 5 microg/kg/min ameliorated renal hyperfiltration, decreased RPF, and increased RVR in diabetic rats without affecting the mean arterial pressure (MAP). 7-NI administered intraperitoneally in diabetic rats significantly reduced GFR without affecting MAP, but the renal hyperfiltration was still observed after the administration of 7-NI. The combined administration of L-NAME after 7-NI caused a further decrease in GFR in diabetic rats and ultimately resulted in normalization of GFR. 7-NI did not change any parameters of renal hemodynamics in control rats. Urinary excretion of nitrite/nitrate and cyclic guanosine monophosphate was significantly increased in diabetic rats over values found in control rats. Our results suggested that a local inhibition of NO in the kidney was involved in the amelioration of diabetic renal hyperfiltration and that NO derived from neuronal NOS is involved, at least in part, in renal hyperfiltration in STZ-induced diabetic rats.

The severity of hyperdynamic circulation may predict the effects of direct hemoperfusion with the adsorbent column using polymyxin B-immobilized fiber in patients with gram-negative septic shock.

It has been reported that direct hemoperfusion with the adsorbent column using polymyxin B-immobilized fiber (DHP with PMX-F column) ameliorates hyperdynamic circulation in septic shock and improves survival rate. However, the clinical characteristics of patients with an improvement of septic shock after DHP with PMX-F column have not been evaluated. To clarify this issue, the clinical profiles of 46 patients who were suggested to have gram-negative septic shock and treated using DHP with PMX-F column were analyzed retrospectively. Of 46 patients, 31 were diagnosed with gram-negative septic shock (G group). Mean arterial pressure (MAP) just before DHP with PMX-F column was not different between the G and the non-G group. As compared with the non-G group, the G group had a higher cardiac index (CI) and a lower systemic vascular resistance (SVR). Significant increases in MAP and SVR with a significant decrease in CI were observed after DHP with PMX-F column in the G group. In the non-G group, MAP was significantly increased after the DHP therapy, but systemic hemodynamics were unchanged. Patients in the G group who fulfilled the following criteria were considered as the effective group: MAP was elevated more than 10 mm Hg or 125% of the basal MAP and/or the dose of vasopressors was reduced after DHP with PMX-F column. Twenty-one patients (67.8%) were in the effective group. In comparison with the effective group, the noneffective group was characterized by a significant increase in CI before DHP with PMX-F column. All patients with a CI less than 6 L/min/m2 were in the effective group. These data suggest that DHP with PMX-F column was useful for patients with gram-negative septic shock who did not have severe hyperdynamic circulation.

[Diabetic nephropathy; clinical stage and prediction].

Diabetic nephropathy(DN) is the leading cause of end-stage renal disease in Japan. Clinical course of DN is divided into five stages. Stage 1 is a pre-nephropathy stage. Stage 2 is the period with microalbuminuria. Stage 3A is the stage with persistent macroproteinuria and well preserved renal function. Strict glycemic control and antihypertensive treatment with ACE inhibitors are capable of inducing remission in stage 2 of DN and probably in stage 3A. GFR less than 60 ml/min and urinary protein excretion more than 1 g/day are regarded as stage 3B. Serum creatinine concentration increases in stage 4. Antihypertensive therapy and low protein diet are major options of therapy both in stage 3B and 4. Stage 5 is the period with renal replacement therapy. Survival rate of patients on HD due to DN still remains unsatisfactory. Only 30-50% of type 2 diabetic patients develop DN, suggesting that there are several factors other than hyperglycemia which induce DN. Prediabetic hypertension and parenteral hypertension are regarded as predictors of DN. Smoking, male gender, and advanced age might be risk factors of DN. Recently it was demonstrated that insertion/deletion(I/D) polymorphism of angiotensin converting enzyme gene is associated with DN. In addition polymorphisms of several genes seem to be associated with DN. Development of DNA tips will make it possible to determine a number of gene polymorphisms. Accumulations of the information on gene polymorphisms from many patients with or without DN are expected to contribute detection of patients at high risk of developing DN.

Long-term oral intake of low-dose cadmium exacerbates age-related impairment of renal functional reserve in rats.

Our study was designed to clarify whether renal functional reserve (RFR) was impaired in rats chronically treated with oral low-dose cadmium (Cd). Rats (n = 15) were treated with 1 ppm of cadmium chloride added to drinking water. We measured RFR (representing the ability to increase glomerular filtration rate [GFR] and renal plasma flow [RPF] in response to infusion of glycine) at 2 and 10 months after initiation of exposure to Cd. Urinary excretion of Cd was significantly higher in 10-month Cd-treated rats than in age-matched control rats (provided with distilled water only). Weight gain was noted in Cd-treated rats, which was identical to that in age-matched control rats. Urinary volume and urinary excretions of sodium, protein, and glucose were similar in the two groups. There were no differences in the basal mean arterial pressure (MAP) and renal hemodynamics between 2-month Cd-treated and age-matched control rats. Infusion of glycine resulted in significant increases in GFR and RPF and a significant reduction in renal vascular resistance (RVR) in both 2-month Cd-treated and age-matched control rats (control, GFR: 133 +/- 10%, RPF: 148 +/- 8%; 2-month Cd-treated rats, GFR: 152 +/- 12% and RPF: 154 +/- 7%). The basal MAP and renal hemodynamics in 10-month Cd-treated rats were also identical to those in age-matched control rats. Infusion of glycine significantly increased GFR in 10-month control rats (132 +/- 15%), but not in 10-month Cd-treated rats (98 +/- 11%), but did not change MAP, RPF, and RVR in both groups. In addition to age-related pathological changes, mild renal interstitial edema and degenerative mitochondria with diminished matrix density and loss of the cristae in the proximal tubular cells were more frequent in 10-month Cd-treated rats. Our results suggest that long-term oral intake of low-dose Cd in rats exacerbate age-related impairment of renal functional reserve and degeneration of the proximal tubular epithelial cells.

Uncoupling between bone formation and resorption in ovariectomized rats with chronic cadmium exposure.

Osteoporosis, osteomalacia, and pathological fractures are characteristic features of Itai-Itai disease. The mechanisms of bone damage caused by cadmium (Cd) exposure have not been fully clarified. We investigated skeletal changes in ovariectomized rats with chronic Cd exposure, using bone histomorphometry and mechanical tests. Female Sprague-Dawley rats at the age of 8 weeks were ovariectomized. Eight weeks after ovariectomy, the rats were divided into two groups: Cd-OVX group (n = 15), ovariectomized rats given cadmium chloride (CdCl(2), 0.18 mg/rat) ip three times a week for 28 weeks; Cont-OVX group (n = 10), ovariectomized rats given distilled water alone for 28 weeks. Cd-OVX rats had a significant increase in serum concentration of intact osteocalcine and showed numerical but not significant increase in urinary excretion of deoxypyridinoline despite a significant decrease in glomerular filtration rate to 40% of the value in Cont-OVX rats. Bone mineral content (BMC) and density were significantly decreased in both the lumbar vertebral body and femur of Cd-OVX rats. Ultimate compressive load in the lumbar body and bending load in the midfemur were significantly lower in Cd-OVX rats than in Cont-OVX rats but the differences were not demonstrated when the values were corrected for BMC. Structural moduli in the lumbar vertebral body and the midfemur were not different between the two groups. Cd-OVX rats showed significant decreases in the trabecular bone volume and trabecular number with increased values in the indices of bone formation and resorption in the lumbar vertebral body cancellous bone in comparison with Cont-OVX rats. In the midfemur, Cd-OVX rats had significantly smaller cortical bone area than Cont-OVX rats but the moment of inertia was identical between the two groups. The indices of bone formation and resorption at endocortical surface of the midfemur were significantly increased in Cd-OVX rats over those in Cont-OVX rats, whereas the indices of bone formation at the periosteal surface were not different between the two groups. These data suggested that chronic Cd exposure exacerbated the uncoupling between bone formation and resorption in ovariectomized rats, which resulted in the osteopenia, structural changes of the bone, and decreased mechanical strength in ovariectomized rats with chronic Cd exposure.

A global platelet test of thrombosis and thrombolysis detects a prothrombotic state in some patients with non-insulin dependent diabetes and in some patients with stroke.

Platelet aggregation and spontaneous thrombolytic activity were assessed in patients with non-insulin dependent diabetes and stroke using a shear-induced and agonist-induced platelet aggregation test. The Thrombotic Status Analyser (TSA), induces platelet-rich thrombus formation solely by shear forces, while whole blood platelet aggregometry measures platelet reactivity to different agonists. These tests were employed in the present study because in earlier studies they both demonstrated that platelet aggregability in healthy volunteers was unchanged with age. On the other hand, it is known that thrombolytic activity decreases with age in males, but not in females. In diabetic patients shear-induced platelet aggregability varied according to the stage of nephropathy but platelet aggregation to collagen was suppressed at all stages. Platelet reaction to shear stress was enhanced in stroke patients with haemorrhagic episodes but not in patients with lacunar infarction. In contrast, platelet reactivity to collagen was suppressed and changes in ADP-induced platelet aggregability were inconsistent. Suppressed thrombolysis was observed only in diabetes with minor renal defect. Fibrinogen was increased in diabetes with stage III and IV nephropathy. Fibrinopeptide A (FPA) and D-dimer were increased in stroke. Thus, the observed increase in fibrinogen, FPA and D-dimer is inconsistent with changes in platelet aggregability. Our present findings suggest that a shear-induced platelet aggregation test is superior to other tests such as agonist-induced platelet aggregation and thrombotic markers such as fibrinogen, FPA and D-dimer in detecting a prothrombotic state. It is concluded that elderly males may have a prothrombotic state not because of platelet hyper-aggregability but because of suppressed thrombolytic activity. On the other hand, a prothrombotic state in patients with non-insulin dependent diabetes and after stroke may be due to changes in age-independent platelet aggregability.

Renal hemodynamics in Otsuka Long-Evans Tokushima fatty rat, a model rat of spontaneous non-insulin-dependent diabetes mellitus with obesity.

Renal hemodynamic features in obese non-insulin-dependent diabetic rats remain unknown. We investigated renal hemodynamic and morphologic changes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats at the age of 5 and 10 months compared with age-matched lean nondiabetic control rats (LETO). OLETF rats showed obesity compared with age-matched LETO rats. Hyperglycemia was mild in 5-month-old OLETF rats and moderate in 10-month-old OLETF rats. The absolute value for glomerular filtration rate (GFR) was significantly higher in OLETF rats than in age-matched LETO rats at the age of 5 and 10 months. Ten-month-old OLETF rats had significantly higher absolute values for renal plasma flow (RPF) than age-matched LETO rats but not 5-month-old OLETF rats. Stepwise multiple regression analysis revealed that body weight was a powerful determinant of GFR and RPF. When factored for body weight, no difference in GFR was demonstrated between 5-month-old OLETF and LETO rats, whereas 10-month-old OLETF rats still had significantly higher GFR and RPF than age-matched LETO rats. Renal hypertrophy was demonstrated in both 5- and 10-month-old OLETF rats even when factored for body weight. Glomerular volume was significantly increased in 10-month-old OLETF rats, but the ratio of glomerular volume to body weight was not different among the groups. Both absolute value for glomerular capillary length free from mesangial area and the value factored for glomerular area were significantly longer in OLETF rats than in age-matched LETO rats. Mesangial matrix expansion was remarkable in 10-month-old OLETF rats, and the glomerular sclerosis index was significantly higher in 10-month-old OLETF rats than in age-matched LETO rats. Stepwise multiple regression analysis revealed that body weight, hemoglobin A1c, and hypertriglyceridemia were powerful determinants for kidney weight and glomerular volume. These data suggest that renal hyperfiltration and hypertrophy observed in 10-month-old OLETF rats are related to diabetic metabolic disorders and that obesity-related conditions may be involved in the renal hemodynamic and morphologic features in OLETF rats.

Effect of acute thromboxane A2 inhibition on the renal hemodynamics in a spontaneously non-insulin-dependent diabetic rat, Otsuka Long-Evans Tokushima Fatty rat.

Thromboxane (TX) A2 plays important roles on renal injuries in streptozotocin (STZ)-induced diabetic rats, whereas its role on the renal injuries in non-insulin-dependent diabetic (NIDDM) rats remains unknown. We evaluated the effects of an intravenous infusion of TXA2 synthetase inhibitor (OKY-046, 6 mg/kg/h) on the clearances on inulin and para-aminohippurate (Cin, C(PAH)) in a spontaneously NIDDM rats, Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 8), and Long-Evans Tokushima Otsuka (LETO) rats (n = 7), served as control rats, at the age of 40-44 weeks. OLETF rats showed obesity, moderate hyperglycemia, and hyperinsulinemia. Urinary excretion of TXB2 was slightly higher and the ratio of TXB2 to 6-keto prostaglandin F1alpha (6-kPG) was significantly higher in OLETF rats (TXB2/6-kPG: 0.22 +/- 0.04 versus 0.12 +/- 0.02, P < 0.05). Both Cin and C(PAH) were significantly higher in OLETF rats than in LETO rats (Cin: 1.1 +/- 0.1 versus 0.7 +/- 0.1 mL/min/100 g BW, C(PAH): 3.1 +/- 0.2 versus 2.3 +/- 0.3 mL/min/100gBW, P < 0.01). OKY-046 did not restore Cin and C(PAH) in OLETF rats although it significantly decreased urinary excretion of TXB2, and thus ameliorated TXB2/6-kPG in OLETF rats. These data suggested that TXA2 was not involved in the renal hyperfiltration in OLETF rats at the age of 40-44 weeks, and that TXA2 might contribute to renal injuries in OLETF rats through mechanisms other than hemodynamic injury.

Renal hemodynamics in rats with cadmium-induced nephropathy.

Glomerular filtration rate (GFR) is known to decline in patients with cadmium (Cd)-induced nephropathy. However renal hemodynamics in Cd-induced nephropathy remain unknown. We investigated renal hemodynamics in experimental Cd-induced nephropathy. Male Sprague-Dawley rats were given 0.18 mg/rat of cadmium chloride i.p. three times a week for 3 and 16 months. Age-matched control rats were given physiological saline. Mean arterial pressures after 3 and 16 months were identical among the groups. In comparison with age-matched control rats, significant decreases in GFR associated with a significantly lower filtration fraction (FF) were demonstrated in both groups of Cd-treated rats, but the changes were more prominent in the 16-month Cd-treated rats. Renal plasma flow was significantly decreased in the 3-month Cd-treated rats whereas it was preserved in the 16-month Cd-treated rats because of anemia. Urinary sodium excretions in both groups of Cd-treated rats were significantly greater than those in the respective control rats. On light microscopic examination, only mild degeneration of tubular cells and interstitial edema in limited areas of the proximal tubules were observed in the 3-month Cd-treated rats. In the 16-month Cd-treated rats multifocal tubular atrophy and interstitial fibrosis in the outer cortex were noted. Electron microscopic examinations revealed conspicuous degenerative changes in the proximal tubular epithelial cells, diffuse thickening of glomerular basement membranes, and foot process fusions in 16-month Cd-treated rats. These data suggested that the decline in GFR in the Cd-treated rats resulted mainly from the decline in FF, which might be functional rather than structural in origin and might be associated with proximal tubular dysfunctions.