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.

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.

Environmental stress modifies glycemic control and diabetes onset in type 2 diabetes prone Otsuka Long Evans Tokushima Fatty (OLETF) rats.

This study was designed to investigate the effects of environmental stress on metabolic derangements and the expression of diabetes phenotype in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of human type 2 diabetes (NIDDM). Acute environmental stress, i.e., exposure to water with immobilization for 1 h, caused a transient increase in blood glucose with decreased insulin secretion, and the stress-induced hyperglycemia augmented with age. The increased glycemia was associated with increased plasma levels of catecholamines and corticosterone. Short-term stress, the same stress of 1 h/day for 10 days, caused a significant decrease of food intake, which led to weight reduction in OLETF rats, aged 50 weeks. Blood glucose and insulin responses in OGTT showed no change before or after the short-term stress, despite the weight reduction. In chronic stress experiments, i.e., exposure to the same kind of stress for 6 days/week from 8 to 75 weeks of age, stressed rats did not gain weight, compared to control rats. Blood HbA1c levels and the index of insulin resistance after a 4-h unfed period were significantly lower in stressed rats than in controls from 35 and 45 weeks of age on, respectively. The occurrence of diabetes, diagnosed by OGTT, was also significantly lower in the rats subjected to chronic stress than in controls. These results suggest that chronic stress from 8 weeks of age inhibited weight gain, probably due to changes in eating behavior, preventing the deterioration of insulin resistance in OLETF rats. Plasma leptin levels were not modulated by stress, and correlated with body weight in the rats under chronic stress and in controls. These results suggest that in type 2 diabetes, blood glucose derangement due to stress is presumably associated not only with changes in counterregulatory hormones involved in glucose metabolism, but also with stress-induced changes in eating behavior.

Skeletal changes in rats bearing mammosomatotrophic pituitary tumors: a model of acromegaly with gonadal dysfunction.

Growth hormone (GH) exerts potent effects on bone metabolism, resulting in an increased bone formation in animals and humans. Acromegaly has been associated with increased bone turnover, whereas the net effect of the increased bone metabolism has been obscured because patients with acromegaly are often associated with hypogonadism. We investigated changes in cortical and cancellous bone in adult rats implanted mammosomatotrophic pituitary tumor cells (GH3) as a model of acromegaly with gonadal dysfunction. Acromegaly model rats were prepared by implanting GH3 cells into female Wistar-Furth rats at 17 weeks of age. At 28 weeks of age, GH3-bearing rats (GH rats) showed very high serum GH levels and a moderate increase in serum prolactin levels, resulting in low circulating estradiol levels. The GH rats showed significant increases in body weight and in length and volume of both the femur and vertebral body. Bone mineral content values of either the midfemur or the whole lumbar body were significantly greater in the GH rats compared with littermate controls, while the areal bone mineral density values of the respective bones were not different between the two groups. The parameters of mechanical strength of the femur were significantly larger in the GH rats than in controls, whereas those of the lumbar vertebral body cylinder specimen were not different between the two groups. Respective normalized mechanical parameters of the femur and the vertebral body were the same in the GH rats as in controls. In the midfemur, the GH rats showed a significant increase in the total cross-sectional area without influencing the bone marrow area, resulting in an increase in the cortical bone area and the moment of inertia compared with controls. The indices of periosteal bone formation in the midfemur were greater in the GH rats compared with controls, but the endocortical bone formation and resorption were not different between the two groups. In the vertebral body cancellous bone, the GH rats had an increase in bone turnover rate, whereas the structural parameters were not different between the two groups. These results from GH3-bearing rats demonstrate that an excess of GH increases cortical bone mass in rats accompanied with estrogen deficiency, while no large effect on vertebral body cancellous bone mass is seen.

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.

Dedifferentiated liposarcoma with an inflammatory malignant fibrous histiocytoma-like component presenting a leukemoid reaction.

A rare case of dedifferentiated liposarcoma (well-differentiated liposarcoma with an inflammatory malignant fibrous histiocytoma (MFH)-like anaplastic component) occurring in a 69-year-old male is presented. The patient had noticed a dull pain in his left loin and thigh for about 1 month. Computed tomography examination revealed a low-density mass lesion, measuring about 6 cm in diameter, in the left iliopsoas muscle, and it was surgically removed. Grossly, the lesion was composed of an encapsulated, soft, whitish mass and an adjacent, well-demarcated, yellowish hard nodule, measuring about 2.5 cm in diameter. Microscopically, both lesions showed features of an inflammatory variant of MFH and a sclerosing type of well-differentiated liposarcoma, respectively. To our knowledge, only two cases of dedifferentiated liposarcoma combined with inflammatory MFH as a dedifferentiated component have been recorded in the literature. The salient feature of the present case is a systemic inflammatory reaction, as shown by prominent leukocytosis (up to 73,900/mm3) and the elevated serum value of C reactive protein (up to 26.0 mg/dL), which were transiently reduced after surgery. The inflammatory reaction was suggested to be induced by cytokines, such as granulocyte colony-stimulating factor and interleukin-6, which were probably produced by the tumor cells in the present case, because the elevated serum values of those cytokines were decreased after surgery.

The characteristics of renal hemodynamics in diabetic spontaneously hypertensive rats in comparison with diabetic Wistar-Kyoto rats.

Diabetic Sprague-Dawley (SD) rats are known to exhibit renal hyperfiltration and hyperperfusion accompanied by renal hypertrophy. We examined whether such characteristics of renal hemodynamics in diabetic SD rats are also observed in diabetic spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. SHR and WKY rats were divided into four groups: D-S, diabetic SHR; N-S, nondiabetic SHR; D-W, diabetic WKY rats; and N-W, nondiabetic WKY rats. Streptozotocin (STZ), 90 mg, was intraperitoneally injected to induce diabetes. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by a clearance method with paraaminohypurate and insulin, respectively, 7-12 days after diabetes induction. In D-S and D-W, there was no increase in the kidney weight and RBF, in spite of significant increases in GFR and fasting blood sugar levels. These results indicate that, in both WKY and SHR, diabetes does not always produce renal hypertrophy and does not result in an increase in RBF.

Acute effect of calcium blocker on renal hemodynamics in diabetic spontaneously hypertensive rat.

This study was done to examine the acute effect of a calcium channel blocker on renal hemodynamics in the diabetic spontaneously hypertensive rat (SHR). Streptozotocin was used to induce diabetes, and barnidipine (B) was used as a calcium blocker. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by a clearance method with paraaminohypurate (PAH) and inulin, respectively. Rats were divided into two groups: nondiabetic SHR, N-SHR; diabetic SHR, DM-SHR. B increased RBF in N-SHR (7.44 +/- 1.99 versus 8.50 +/- 1.97 mL/min/g.kw) while there was no change in DM-SHR. B reduced renovascular resistance (RVR) in DM-SHR and N-SHR. B increased GFR in N-SHR (1.15 +/- 0.24 versus 1.34 +/- 0.25 mL/min/g.kw), in spite of no changes in DM-SHR. B did not modify filtration fraction (FF) in both groups. These results indicate (1) in SHR, B exerts beneficial effects on hypertensive renal damage by reducing mean arterial pressure (MAP), RVR, RBF, and GFR; (2) in diabetic SHR, B is less effective in restoring renal hyperfiltration in spite of reducing RVR.

[Tubulointerstitial injuries in heavy metal intoxications].

The kidney is one of the organs susceptible to heavy metal intoxication. The total body burden and "saturation" level in renal tissue are important limiting factors to the onset of renal injuries. Acute or chronic exposure to many of heavy metals can induce renal tubulointerstitial injuries, including acute tubular necrosis, chronic tubulointerstitial nephritis, Fanconi syndrome, renal tubular acidosis, and renal tubular dysfunction without morphological changes. Chronic cadmium intoxication can cause irreversible Fanconi syndrome with chronic tubulointerstitial nephritis. Both urinary low-molecular weight protein excretion and urinary cadmium excretion (greater than 200-400 ppm) are the most reliable earlier markers of tubulointerstitial injury in chronic cadmium intoxication. The role of metallothionein is central to an understanding of cadmium-induced nephropathy. Acute lead intoxication in children can cause reversible Fanconi syndrome. Hypertension, hyperuricemia, and elevated serum creatinine, without Fanconi syndrome, are clinical manifestations of chronic lead exposure in adults. Nuclear inclusion body in proximal tubular cell is characteristic. Chronic exposure to inorganic germanium can cause chronic renal failure without urinary abnormalities, due to tubular degeneration and interstitial fibrosis, mainly in the thick ascending limb of Henle and distal tubulus.

Acute and chronic effects of thromboxane A2 inhibition on the renal hemodynamics in streptozotocin-induced diabetic rats.

We examined acute and chronic effects of thromboxane (TX) A2 inhibition on the renal hemodynamics at early and late stage of untreated streptozotocin (STZ)-induced diabetic rats. Two weeks and 28 weeks after the induction of diabetes, renal blood flow (RBF) under anesthesia was measured with an electromagnetic flowmeter before and after TXA2 inhibition. In two-week-old diabetic rats, a specific TXA2 synthetase inhibitor, OKY-046, or a specific TXA2 receptor antagonist, Sulotroban, increased renal vascular resistance (RVR) and ameliorated the hyperperfusion. The renal vasoconstrictive effect of OKY-046 was blunted by an angiotensin converting enzyme (ACE) inhibitor, MK422, or an angiotensin II receptor antagonist, Saralasin. On the contrary, OKY-046 ameliorated the renal hypoperfusion by decreasing RVR in 28-week-old diabetic rats. Chronic oral administration of OKY-046 ameliorated not only the renal hyperperfusion but increased urinary albumin excretion (UAE) at two weeks, but also the renal hypoperfusion, filtration fraction and UAE at 24 weeks. It is suggested that TXA2 might, at least in part, play important roles in the hyperperfusion by modulating activity of the renin-angiotensin system at an early stage of untreated diabetic rats and in the hypoperfusion at the late stage of untreated diabetic rats, and that TXA2 is also involved in the increase of UAE. These results support roles for TXA2 in the progression of renal injury in STZ-induced diabetic rats.

Effects of recombinant human erythropoietin (EPOCH) on the coagulation and fibrinolytic systems and platelet function in pre-dialysis patients with chronic renal failure.

The purpose of this study was to investigate whether or not the systems of coagulation and fibrinolysis are activated after human recombinant erythropoietin therapy in patients with end-stage renal failure and renal anemia. Six thousand IU of human recombinant erythropoietin (EPOCH) were administered intravenously to 11 patients once a week for 8 weeks. Coagulation, fibrinolysis and platelet as well as renal functions were investigated before and after the EPOCH therapy. Platelet count did not increase in spite of improvement in anemia. No changes in prothrombin time, activated partial thromboplastin time, concentrations of fibrinogen, fibrinopeptide A, thrombin antithrombin III complex, fibrin/fibrinogen degradation products (FDP), FDP-E, FDP-D dimer, plasmin alpha 2-plasmin inhibitor complex were observed. Platelet factor 4 and beta-thromboglobulin also were unchanged. Reciprocal changes in serum creatinine concentrations over the duration of therapy were compared before and after therapy. There was no significant difference between the reciprocal changes in serum creatinine concentrations before and after therapy. The increases in hemoglobin did not correlate with the changes in coagulation, fibrinolysis and the other parameters, except for the change in prothrombin time. These results indicate that coagulation, fibrinolysis and platelet systems in end-stage renal failure patients were not affected by EPOCH administration, in spite of increase in hemoglobin.

[The effects of acute administration of cadmium chloride on renal hemodynamics in rats].

The decreases of glomerular filtration rate (GFR) and renal blood flow (RBF) after acute administration of cadmium have been reported. The recent studies about renal failure induced by heavy metals revealed that the decrease of glomerular ultrafiltration coefficient is an important contributing factor in the onset of acute renal failure and that the changes of renal hemodynamics are less prominent factors. To clarify whether the changes of renal hemodynamics contribute to the decrease of GFR caused by cadmium, we evaluated the changes of renal hemodynamics and inulin clearance after acute intravenous infusion of cadmium chloride in rats. Cadmium chloride was continuously infused at the rate of 3.0 mumol/kg/min into SD rats. Mean arterial pressure was significantly increased immediately after the infusion of cadmium and unchanged during the experiment. 20 minutes after the infusion of cadmium, inulin clearance was decreased by 70% of the control value but RBF and renal vascular resistance (RVR) were unchanged. Filtration fraction was significantly decreased. 30 minutes after the infusion of cadmium, inulin clearance was further decreased by 51% of the control value. At the period, significant decrease of RBF (72% of control value) and increase of RVR (156% of control value) were observed. Urinary excretion of sodium and the ratio of urinary sodium to urinary inulin excretion were unchanged until 20 minute and were significantly decreased 30 minutes after the infusion of cadmium. Urinary volume was not changed throughout the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of urinary fibrin/fibrinogen degradation products by latex photometric immunoassay.

Intraglomerular coagulation and fibrinolysis could be involved in the exacerbation of renal diseases, and urinary fibrin/fibrinogen degradation products (FDP) may be applicable as an index. Although the urinary FDP can be estimated by the latex agglutination method, this technique has disadvantages such as a poor sensitivity and is of the semiassay type. Recently, a new method of measurement which improves on these disadvantages, termed the latex photometric immunoassay (LPIA) method, has been developed. However, since FDP measurement by LPIA was designed for the purpose of serum FDP estimation, a measurement technique for urinary FDP has not yet been established. The purpose of the present study was to devise a measurement procedure for urinary FDP employing the LPIA method, and to obtain data on the normal levels of urinary FDP in healthy subjects. The results obtained may be summarized as follows. (1) The urinary pH and coexistent substances such as bovine serum albumin, glucose, urea, bilirubin, ascorbic acid, and hemoglobin, did not influence the urinary FDP measurement. (2) No changes in urinary FDP were observed after 28-day storage at -20 degrees C or -80 degrees C in the presence or absence of tranexamic acid. (3) The coefficient of variation was 5.3%. (4) The normal level of FDP excretion was 3.33 +/- 7.95 micrograms/day. The present data demonstrated that the LPIA method enables the urinary FDP to be measured quantitatively with a good sensitivity.

Clinical significance of urinary fibrin/fibrinogen degradation products (FDP) as measured by latex photometric immunoassay in renal diseases.

It is possible that abnormalities of intraglomerular coagulation and fibrinolysis are involved in the exacerbation of kidney diseases. Urinary fibrin/fibrinogen degradation products (FDP) are regarded as an index of the intraglomerular coagulation and fibrinolysis. Although the conventional latex agglutination method for detecting urinary FDP has disadvantages such as a poor sensitivity and is of the semiassay type, latex photometric immunoassay (LPIA), a recently developed technique, is an assay with a high sensitivity. The present study was undertaken in an attempt to clarify the significance of urinary FDP as measured by latex photometric immunoassay in renal diseases. The subjects comprised were 60 patients with 15 kinds of renal diseases. Occasional urine samples and blood samples withdrawn at the time of urinary collection were examined. The FDP and FDP-E fractions (FDP-E) were measured by LPIA, and the FDP-D fraction (FDP-D) and fibrinopeptide A (FPA) were measured by enzyme immunoassay. The highest level of urinary FDP was seen in cases with diabetic nephropathy, followed by renal amyloidosis and chronic glomerulonephritis. While no correlation was noted between the urinary FDP levels and blood FDP levels, positive correlations were observed among the urinary protein, urinary FDP-E, FDP-D and FPA. The urinary FDP also revealed an inverse correlation with the l/serum creatinine. All cases with high levels of urinary FDP displayed renal dysfunction. These findings suggest that quantitative assay of the urinary FDP using LPIA is important for determining the degree of abnormality of intraglomerular coagulation and fibrinolysis in renal diseases.

Role of intrarenal coagulation and anticoagulant therapy in the progression of diabetic nephropathy.

The aim of the present study was to clarify the role of intrarenal coagulation in the progression of renal dysfunction and to assess the efficacy of anticoagulant therapy in diabetic nephropathy patients. Forty-one diabetic patients were divided into 2 groups: group 1 (G-1), 20 patients with nephropathy; and group 2 (G-2), 21 patients without nephropathy. The levels of fibrinopeptide A (FPA) and fibrinopeptide B beta 15-42 (FPB beta 15-42), fibrin/fibrinogen degradation products-D dimer (FDP-D dimer), and FDP-E products (FDP-E) and FDP, which are sensitive parameters of coagulation and fibrinolysis, were measured by radioimmunoassay, enzyme immunoassay (EIA), and latex photometric immunoassay, respectively, in both the blood and urine. The levels of urinary FPA, FDP-D, FDP-E, and FDP were found to be much higher in G-1 than in G-2. Significant relations were observed among the urinary levels of these four parameters. The renal function in all cases with higher levels of urinary parameters was severely deteriorated. Following heparin administration to these patients, marked reductions of the urinary FPA, FDP-D, and FDP-E and improvement of nephrotic syndrome were observed. The present data suggest that in diabetic nephropathy: (1) intrarenal coagulation is likely to occur and to induce progression of renal dysfunction; and (2) heparin therapy could be effective in diabetic nephropathy when the patients are selected according to the above parameters of coagulation and fibrinolysis.