[Show abstract][Hide abstract] ABSTRACT: Paraneoplastic nephropathy is a rare complication of malignant disease. We present a case of cervical cancer with biopsy-proven membranous nephropathy and associated nephrotic syndrome. Irradiation to the specific neoplasm site and to the metastatic paraaortic lymph node tissues lead to regression of the nephrotic syndrome without causing severe adverse events. Radiation therapy can be the first choice in the treatment of paraneoplastic nephrotic syndrome if the primary neoplasm is unresectable. Invasiveness of intervention and patient prognosis should be carefully deliberated in the management of the two diseases.
Internal Medicine 01/2011; 50(1):47-51. DOI:10.2169/internalmedicine.50.4341 · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Organogenesis accompanies the establishment of the vascular system which begins with sprouting angiogenesis. Vascular endothelial growth factor (VEGF) provides the primary stimulation in the vascular sprouting process but the negative regulation of this process remains unclear. This study examined the role of the transforming growth factor-beta (TGF-beta) superfamily in vascular sprouting using a three-dimensional dorsal aorta culture system, in which the dissected tissue was embedded in type I collagen gel. The cultures were maintained under hypoxic conditions to enhance the expression of Flk-1, a receptor for VEGF, thereby ensuring the responsibility to VEGF. Under the culture conditions employed, the dorsal aorta formed many cord-like structures in response to VEGF. To examine the role of TGF-beta in vascular sprouting, each member of the TGF-beta superfamily was applied to this culture system. TGF-beta1, as well as TGF-beta2 and TGF-beta 3, inhibited capillary formation. Likewise, activin A, another member of TGF-beta superfamily, also abolished vascular sprouting, but bone morphogenetic protein 2 did not noticeably change the morphology. Both neutralizing anti-TGF-beta1 antibody and TGF-beta type I receptor (ALK5) inhibitor partially reversed the inhibitory effect of TGF-beta1. Furthermore, down-regulation of ALK5 with small interfering RNA rather than activin receptor-like kinase-1 (ALK1) reversed the effect of TGF-beta1. These data suggest that TGF-beta superfamily may act as an inhibitor of vascular sprouting mainly through ALK5 signaling pathway. We propose that VEGF may antagonize the TGF-beta autoregulatory action to initiate vascular sprouting.
The Tohoku Journal of Experimental Medicine 06/2009; 218(1):63-71. · 1.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endothelial nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) contribute to erythropoietin (EPO)-induced hypertension, a major adverse reaction associated with EPO therapy. To investigate the mechanism of EPO-induced hypertension, we examined circulating endothelial progenitor cells (EPCs) taken from 56 hemodialysis (HD) patients. Among these EPCs (which reflect the condition of the endothelium), we looked for EPO receptor (EPOR) mRNAs. A truncated form of EPOR acts as a dominant negative regulator of EPO signaling, leading to hypertension. We found that the ratio of truncated EPOR mRNA in EPCs has a correlation with EPO-induced increase in blood pressure (r = 0.36, P = 0.02). The ratio of truncated to total EPOR mRNA in EPCs had an inverse correlation with EPO-induced cGMP production in vitro (r = -0.31, P = 0.02). A similar correlation was observed in cultured human endothelial cells after transfection of the full-length or truncated forms of EPOR (r = -0.92, P < 0.001). It follows, therefore, that evaluation of EPOR isoform mRNA in EPCs can predict EPO-induced hypertension. The termination of the EPO signal by truncated EPORs may decrease NO/cGMP production after EPO exposure, thereby raising blood pressure.
[Show abstract][Hide abstract] ABSTRACT: Organogenesis accompanies the establishment of the vascular system which begins with sprouting angiogenesis. Vascular endothelial growth factor (VEGF) provides the primary stimulation in the vascular sprouting process but the negative regulation of this process remains unclear. This study examined the role of the transforming growth factor-β (TGF-β) superfamily in vascular sprouting using a three-dimensional dorsal aorta culture system, in which the dissected tissue was embedded in type I collagen gel. The cultures were maintained under hypoxic conditions to enhance the expression of Flk-1, a receptor for VEGF, thereby ensuring the responsibility to VEGF. Under the culture conditions employed, the dorsal aorta formed many cord-like structures in response to VEGF. To examine the role of TGF-β in vascular sprouting, each member of the TGF-β superfamily was applied to this culture system. TGF-β1, as well as TGF-β2 and TGF-β3, inhibited capillary formation. Likewise, activin A, another member of TGF-β superfamily, also abolished vascular sprouting, but bone morphogenetic protein 2 did not noticeably change the morphology. Both neutralizing anti-TGF-β1 antibody and TGF-β type I receptor (ALK5) inhibitor partially reversed the inhibitory effect of TGF-β1. Furthermore, down-regulation of ALK5 with small interfering RNA rather than activin receptor-like kinase-1 (ALK1) reversed the effect of TGF-β1. These data suggest that TGF-β superfamily may act as an inhibitor of vascular sprouting mainly through ALK5 signaling pathway. We propose that VEGF may antagonize the TGF-β autoregulatory action to initiate vascular sprouting.
The Tohoku Journal of Experimental Medicine 01/2009; 218(1):63-71. DOI:10.1620/tjem.218.63 · 1.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The dosing time-dependent difference of bone resorption by cyclosporin A was determined in normal rats. Rats were kept in rooms with a 12-h light/dark cycle. Cyclosporin A (3 mg/kg, once a day) or vehicle was given at either 2 h after light on (2 HALO) or 8 HALO, 14 HALO, 20 HALO for 24 weeks. Serum and 4-h urine samples were obtained before and at 12 and 24 weeks after the treatment. Body weight, creatinine clearance, serum parathyroid hormone, the trough level of cyclosporin A in whole blood and urinary excretion of Ca and P were not changed by the drug at every any dosing time. Serum Ca and P concentrations by the vehicle treatment differed with the dosing time. Furthermore, increases of these two parameters by the drug varied with dosing time; most prominently at the 2 HALO dosing, and were not seen at the 8 and 14 HALO dosings. Degree of bone resorption of the femur determined by dual-energy X-ray absorption, also varied with dosing time, most prominently at 2 HALO and less prominently at 14 HALO. Increase of urine deoxypyridinoline excretion, a marker of osteoclast activity, by the drug was highest at 2 HALO and lowest at 14 HALO, however parathyroid hormone and osteocalcin concentrations after cyclosporin A treatment did not vary with dosing time. Reduction of urinary nitric oxide (NO) was most prominent at 2 HALO and negligible at 14 HALO. We concluded that cyclosporin A-induced bone resorption and serum Ca and P increases were varied with dosing time. Sensitivity of osteoclasts by the drug was the major mechanisms of the phenomenon, while differences in pharmacokinetics, the parathyroid gland, osteoblasts and renal handling of Ca and P did not contribute to the phenomenon.
European Journal of Pharmacology 07/2007; 564(1-3):226-31. DOI:10.1016/j.ejphar.2007.02.007 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Homozygous Klotho mutant mice (KL(-/-) mice) exhibit multiple phenotypes resembling human ageing. Increases in the ratio of urinary calcium to urinary creatinine (uCa/uCr) and in serum Ca concentration and decreases in urinary Cr excretion and serum parathyroid hormone (PTH) concentration were reported; however, precise information about renal Ca handling was not reported in these animals.
We evaluated the PTH-induced increase in intracellular Ca(2+) concentration ([Ca(2+)]i) in cells of isolated perfused connecting tubules (CNTs) of KL(-/-) mice. We also determined fractional excretion of Ca from the urine and serum samples of the same animals (n = 7), and compared them with KL(+/+) mice and hemi-nephrectomized KL(-+/+) mice (n = 10 in each) as controls.
FECa was significantly higher in KL(-/-) mice than in controls (0.67 +/- 0.13 vs 0.20 +/- 0.04%). The PTH (10 nM)-induced increase in [Ca(2+)]i was diminished in KL(-/-) mice (58 +/- 5 vs 231 +/- 15 nM). Addition of 10 nM of 8-(4-chlorophenylthio)-cyclic adenosine 3',5'-monophosphate had a similar effect. The PTH-induced increase had completely disappeared by the removal of Ca from lumen and bath in both groups of animals. Removal of sodium (Na) from the solution increased [Ca(2+)]i to a similar extent in both groups. Conclusion. We conclude that renal Ca excretion estimated by determining FECa was defective in the KL(-/-) mice. Impairment of Ca absorption from the lumen by stimulation of PTH in CNTs is one of the mechanisms of this defect. Activity of the basolateral Na/Ca exchanger was preserved in this strain. Therefore, the pathway downstream after generation of second messengers following stimulation of PTH (such as the sorting of transporters of Ca absorption) might be impaired by disruption of the Klotho gene.
[Show abstract][Hide abstract] ABSTRACT: Vascular smooth muscle cell (VSMC) proliferation is a key event in the progression of arteriosclerosis. Clinical studies show that uremic toxins deteriorate the arteriosclerosis in renal failure patients. Indoxyl sulfate (IS) is a strong protein-bound uremic toxin, but the effect of IS on VSMC proliferation has not been studied. We examined the effect of IS on rat VSMC proliferation, assessed by a cell counting kit (4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] assay) and by [(3)H]thymidine incorporation in vitro. We further evaluated a contribution of mitogen-activated protein kinase (MAPK; p44/42 MAPK) to VSMC proliferation by IS. Immunohistochemical staining was performed for VSMCs using antirat organic anion transporter (OAT)3 antibody. The mRNA expressions of platelet-derived growth factor (PDGF)-A and -C chains, and PDGF-beta receptor were evaluated by real-time PCR. IS stimulated the proliferation of VSMCs in a concentration-dependent manner and activated p44/42 MAPK. Concentration of IS needed to stimulate the proliferation of rat VSMC was about 250 microM, which is compatible with that in the serum of end-stage renal failure patients. PD98059 (10 microM), a selective inhibitor of MAPK/extracellular signal-regulated kinase, inhibited the IS-induced (250 microM) VSMC proliferation and phosphorylation of MAPK. Probenecid (0.5 mM), an inhibitor and substrate of OAT, inhibited the IS-induced (250 microM) VSMC proliferation. Rat OAT3 was detected in VSMCs. The mRNA expressions of PDGF-C chain and PDGF-beta receptor were significantly increased by IS. We conclude that IS directly stimulates rat VSMC proliferation and activates MAPK in vitro. This might be one of the mechanisms underlying the progression of atherosclerotic lesions in end-stage renal disease patients.
Kidney International 06/2006; 69(10):1780-5. DOI:10.1038/sj.ki.5000340 · 8.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 72-year-old woman with renal insufficiency who was taking oral pilsicainide (150 mg/d) complained of feeling faint 3 days after she was prescribed oral cetirizine (20 mg/d). She was found to have a wide QRS wave with bradycardia. Her symptoms were relieved by termination of pilsicainide. The plasma concentrations of both drugs were significantly increased during the coadministration, and the cetirizine concentration decreased on cessation of pilsicainide despite the fact that treatment with cetirizine was continued, which suggested that the fainting was induced by the pharmacokinetic drug interaction. A pharmacokinetic study in 6 healthy male volunteers after a single dose of either cetirizine (20 mg) or pilsicainide (50 mg), or both, found that the renal clearance of each drug was significantly decreased by the coadministration of the drugs (from 475 +/- 101 mL/min to 279 +/- 117 mL/min for pilsicainide and from 189 +/- 37 mL/min to 118 +/- 28 mL/min for cetirizine; P = .008 and .009, respectively). In vitro studies using Xenopus oocytes with microinjected human organic cation transporter 2 and renal cells transfected with human multidrug resistance protein 1 revealed that the transport of the substrates of these transporters was inhibited by either cetirizine or pilsicainide. Thus elevated concentrations of these drugs as a result of a pharmacokinetic drug-drug interaction via either human multidrug resistance protein 1 or human organic cation transporter 2 (or both) in the renal tubular cells might have caused the arrhythmia in our patient. Although cetirizine has less potential for causing arrhythmias than other histamine 1 blockers, such an interaction should be considered, especially in patients with renal insufficiency who are receiving pilsicainide.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to compare the degree of taste disturbance by losartan, an angiotensin II receptor blocker, with that of perindopril, an angiotensin-converting enzyme inhibitor. Perindopril erbumine (2 mg), losartan potassium (25 mg), or vehicle was given to Japanese volunteers (n = 7) for 14 days in a randomized, placebo-controlled, 3-way crossover design with a 14-day washout period. Gustometry by filter-paper test and electrogustometry were performed before and at the end of each trial. Plasma renin activity (PRA) and serum and salivary zinc concentrations were measured. One subject dropped out because of a perindopril-induced dry cough, but no one claimed a taste disturbance. Detection thresholds of 4 basic tastes (sweet, salty, sour, and bitter) by the paper-disc test and electrogustometry were significantly worsened, and plasma renin activity was elevated by the drugs, whereas the deteriorating effects of 2 drugs did not significantly differ. These drugs did not affect zinc concentrations in plasma and saliva. It was concluded that losartan and perindopril similarly alter taste sensitivity during repeated dosing of the drugs.
The Journal of Clinical Pharmacology 12/2005; 45(11):1319-23. DOI:10.1177/0091270005280445 · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the degree of taste disturbance by candesartan and valsartan.
Candesartan cilexetil (4 mg day(-1)), valsartan (40 mg day(-1)), or vehicle was given to subjects (n = 8) for 13 days in a randomized, placebo-controlled, three-way crossover design with a 14-days washout period. Gustometry by filter-paper test and electrogustometry were performed before and at the end of each trial. Plasma renin activity and zinc concentrations in serum and saliva were measured.
Detection thresholds of four basic tastes (sweet, salty, sour and bitter) by paper-disc test and electrogustometry were significantly worsened and plasma renin activity was elevated after the test, while the effects of two drugs did not significantly differ. These drugs did not affect zinc concentrations.
Both candesartan and valsartan similarly alter taste sensitivity after the repeated dosing of the drug.
British Journal of Clinical Pharmacology 09/2005; 60(2):204-7. DOI:10.1111/j.1365-2125.2005.02394.x · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cyclosporine A (CsA) causes distal renal tubular acidosis (RTA) and osteoporosis. We have recently reported that the reduction of nitric oxide (NO) exacerbates this condition. Distal RTA may deplete bone mineral due to the chronic buffering of acid in the blood. The interaction of CsA and NO in causing metabolic acidosis and bone demineralization has not been studied previously. Nor has the salubrious effect of citrate therapy.
To examine the effect of systemic pH correction by citrate on renal electrolyte (Na, K, Cl, NH3, HCO3) excretion following acute water loading in CsA-treated and NO-reduced rats. We further evaluated femoral bone density and bone demineralization activity after the same treatments.
Rats received CsA, L-arginine (L-Arg), or nitro-L-arginine-methyl ester (L-NAME), or a combination of CsA+L-NAME plus or minus citrate. Urine and blood electrolytes were examined, as well as the urine excretion of deoxypyridinoline and the bone density of both femurs.
CsA and L-NAME reduced urine pH and the serum HCO3- concentration, and increased serum K+ and Cl- concentrations. The combination of CsA with L-NAME caused more severe deficits in the serum HCO3- concentration and elevations in serum K+ and Cl- concentrations than either drug alone. Both CsA and L-NAME reduced urinary nitrate excretion, which was reversed by co-administration of L-Arg. Co-administration of citrate or L-Arg improved the CsA- and L-NAME-induced acidosis and hyperkalemia. Bone resorption and density of the femurs were decreased by CsA and L-NAME and were additive for both drugs. Co-administration of citrate or L-Arg restored both bone resorption and density to normal levels.
CsA induces a hyperchloremic metabolic acidosis with hyperkalemia and a reduction in NO. The ensuing systemic acidosis causes bone resorption and demineralization. These effects were corrected by co-treatment with citrate. Citrate, at least in part, directly reduces the protonation of bone in animals treated with CsA and is recommended as a potential adjunct drug to prevent bone demineralization in patients chronically receiving CsA.
American Journal of Nephrology 05/2005; 25(3):233-9. DOI:10.1159/000085969 · 2.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study was undertaken to evaluate removal of 22-oxacalcitriol (OCT), an active and intravenously used vitamin D3 analogue with less calcaemic activity, by polysulphone haemodialyser in vivo and in vitro. We further compared the pharmacodynamic efficacy [suppression of intact parathyroid hormone (iPTH)] when given intravenously either during or at the end of the haemodialysis.
(i) Drug clearance by the polysulphone dialyser was measured during a single continuous infusion (5 microg) for 30 min into the arterial side of the dialyser in end-stage renal failure patients with secondary hyperparathyroidism (n = 7). (ii) The drug adsorption by the hollowfibre membrane during incubation for 30 min was measured in vitro. (iii) To evaluate efficacy, the drug was given (i.v. bolus) during or at the end of haemodialysis for 4 weeks in a cross-over fashion with a washout period of 8 weeks (n = 9). Serum Ca(2+), phosphate (P) and iPTH concentrations just before the initiation of the dialysis were monitored every week.
(i) OCT was significantly cleared by the polysulphone haemodialyser, but the clearance declined in a time-dependent manner to approach zero at 30 min. Arterial (at the place between the drug infusion site and the haemodialyser column) drug concentrations did not change during the infusion (mean = 2064 +/- 233 pg ml(-1)). Venous (just after the dialyser) drug concentrations at 10 min after the infusion were significantly lower than those of the arterial side (mean = 784 +/- 84 pg ml(-1)); however, they increased with time and reached those of the arterial side at 30 min. (ii) In vitro, OCT was adsorbed by the membrane. The amount of adsorption was concentration-dependent and was lower in the presence of human serum (55 +/- 4% without and 23 +/- 4% with serum at 600 pg ml(-1) of OCT). (iii) Although serum Ca(2+) and P increased and iPTH decreased by both treatment regimens (i.e. OCT administered either during or at the end of haemodialysis), these changes did not significantly differ. Mean differences (and 95% confidence interval) of Ca(2+), P, and iPTH at the end of the trial were 0.03 (-0.04, 0.09) mm, 0.41 (-0.43, 1.26) mg dl(-1) and 38 (-42, 88) pg ml(-1), respectively.
OCT is adsorbed by polysulphone dialyser in vitro and in vivo. However, the pharmacodynamic effectiveness was largely independent of the administration regimen of OCT given either during or at the end of haemodialysis.
British Journal of Clinical Pharmacology 12/2004; 58(5):488-95. DOI:10.1111/j.1365-2125.2004.02204.x · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple hepatic cysts are frequently observed in pa-tients with autosomal dominant polycystic kidney disease (ADPKD). However,
progressive hepatomegaly caused by multiple cysts is rare in such patients. We report a patient with ADPKD with multiple hepatic
cysts that caused severe abdominal symptoms. A woman with ADPKD, who was receiving hemodialysis, was admitted to our hospital
because of severe progressive hepatomegaly, associated with poor ingestion of food, abdominal distension, and supine dyspnea.
Before admission, aspiration and ethanol injections for hepatic cysts had been performed at other hospitals, but her symptoms
were not ameliorated. The results of liver function tests were all normal. Ultrasound scans and computed tomography (CT) scans
of the abdomen confirmed the presence of massive multiple hepatic cysts and small polycystic kidneys. Fenestration of the
hepatic cysts, resection of a lateral segment, and partial excision of segments 4, 5, and 8 of the liver were performed. Her
postoperative course was complicated with a biliary fistula, hepatic encephalopathy, and wound infection. Three months after
the operation, she was able to start on an oral diet. Eighteen months after the resection, she is free of abdominal distension.
The results suggest that, in patients receiving hepatic resection to prevent the symptoms of severe hepatomegaly with ADPKD,
care must be taken to avoid postoperative complications, particularly in hemodialysis patients.