[Show abstract][Hide abstract] ABSTRACT: Background:
Combination drugs containing an angiotensin receptor blocker and a calcium channel blocker have been widely commercialized in recent years, and their advantages, such as improvements in adherence, and reductions in medication costs, have been greatly emphasized. However, the actual situations and the impact of switching to combination drugs in clinical practice of nephrology are not fully understood.
This study was conducted in outpatients of nephrology who received antihypertensive medicines, and who switched to combination drugs. Changes in the potency of the antihypertensive drugs, and blood pressure were examined retrospectively before and after changing treatments. In addition, the study also involved patients' questionnaire, which examined changes in blood pressure at home, the presence or absence of missed doses, the impact on medication-related expenses, and the level of patients' satisfaction with regard to combination drugs.
Survey results from 90 participants revealed that changing to combination drugs resulted in a reduction of missed doses, a decrease in blood pressure measured in an outpatient setting, and a reduction in medication-related expenses in total patients, non-chronic kidney disease (CKD) patients, and CKD patients.
Our study shows that switching to combination antihypertensive drugs resulted in an improvement in adherence and a reduction in medication-related expenses, and revealed that patient satisfaction was high. Combination drugs for hypertensive patients may be beneficial in both medical and economical viewpoints.
[Show abstract][Hide abstract] ABSTRACT: In addition to skeletal muscle and the nervous system, α-dystroglycan is found in the podocyte basal membrane, stabilizing these cells on the glomerular basement membrane. Fukutin, named after the gene responsible for Fukuyama-type congenital muscular dystrophy, is a putative glycosyltransferase required for the post-translational modification of α-dystroglycan. Chimeric mice targeted for both alleles of fukutin develop severe muscular dystrophy; however, these mice do not have proteinuria. Despite the lack of a functional renal defect, we evaluated glomerular structure and found minor abnormalities in the chimeric mice by light microscopy. Electron microscopy revealed flattening of podocyte foot processes, the number of which was significantly lower in the chimeric compared to wild-type mice. A monoclonal antibody against the laminin-binding carbohydrate residues of α-dystroglycan did not detect α-dystroglycan glycosylation in the glomeruli by immunoblotting or immunohistochemistry. In contrast, expression of the core α-dystroglycan protein was preserved. There was no statistical difference in dystroglycan mRNA expression or in the amount of nephrin and α3-integrin protein in the chimeric compared to the wild-type mice as judged by immunohistochemistry and real-time RT-PCR. Thus, our results indicate that appropriate glycosylation of α-dystroglycan has an important role in the maintenance of podocyte architecture.
Kidney International 10/2010; 79(3):311-6. DOI:10.1038/ki.2010.403 · 8.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 56-year-old female developed rapidly progressive glomerulonephritis in the course of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated pachymeningitis that had been found four years previously. On admission, her serum creatinine increased from 0.8 mg dL to 1.84 mg dL and to 3.66 mg dL every 3 to 4 weeks. Urinalysis revealed that urinary protein excretion was 1.25 g day and 3+ hematuria. MPO-ANCA titer was found to be 50 EU and anti-glomerular basement membrane (GBM) antibody was also elevated to as high as 174 EU. Renal pathology revealed cellular to fibrocellular crescents in 21 out of 23 glomeruli with interstitial inflammation and fibrosis. Immunohistochemistry with anti IgG antibody showed linear staining along the glomerular capillary walls. Following plasma exchange and methylprednisolone pulse therapy, oral prednisolone at a dose of 50 mg day was instituted, but without significant effect. Subsequent cyclophosphamide pulse therapy was effective, resulting in the stabilization of serum creatinine at 2 mg dL and disappearance of urine abnormalities. In addition, the MPO-ANCA titer and anti-GBM antibody titer of the patient decreased to within the normal range in one month and three months, respectively. Pulmonary lesions were not found throughout the course. Recently the emergence of anti-GBM antibody-associated crescentic glomemrulonephritis in the course of MPO-ANCA-associated vasculitis has increasingly been reported. Accumulation of such cases may unravel the pathogenesis of these diseases. one month and three months, respectively. Pulmonary lesions were not found throughout the course. Recently the emergence of anti-GBM antibody-associated crescentic glomemrulonephritis in the course of MPO-ANCA-associated vasculitis has increasingly been reported. Accumulation of such cases may unravel the pathogenesis of these diseases.
[Show abstract][Hide abstract] ABSTRACT: A 25-year-old female at 10 weeks of her first pregnancy abruptly developed severe hypertension as high as 230/160 mmHg and thus was referred to our hospital. Her past history was unremarkable and no medication or supplement was prescribed. The laboratory findings revealed that plasma renin activity was 59.0 ng mL hr and plasma aldosterone concentration was 1700 pg mL together with serum creatinine of 0.42 mg dL and serum potassium of 2.8 mEq L. Urinalysis revealed insignificant findings. Her hypertension was extremely resistant to antihypertensive agents, including hydralazine, alpha-methyldopa, and alpha beta blocker, leading to suspicion of secondary hypertension as a cause. Adrenal tumor was not detected but Doppler ultrasonography suggested the constriction of the right renal artery consistent with renovascular hypertension. Considering the following imaging test and medications, the patient and her family decided to abort the pregnancy. 3D-CT and MR angiography showed stenosis of the right renal artery, therefore, percutaneous transcatheter renal angioplasty was performed, resulting in normalization of the blood pressure without antihypertensives. Two years later she successfully gave birth uneventfully. Her hypertension was presumably irrelevant to preeclampsia because it occurred at 10 weeks of pregnancy and proteinuria was not associated. The stenosis of the right renal artery was probably due to fibromuscular dysplasia, which is one of the major causes of renal artery stenosis in young women. This patient was such a case and presented a difficult decision on how to treat and whether or not to abort. We will discuss the mechanism of hypertension in pregnancy and the advantages and disadvantages of available treatments for such cases.
[Show abstract][Hide abstract] ABSTRACT: Although foot process effacement is a characteristic alteration of podocytes in the proteinuric state, whether this is the cause or the result of proteinuria is not understood. We studied the morphology and molecular background of foot process effacement in relation to proteinuria, using the passive Heymann nephritis (PHN) model.
Foot process effacement was evaluated by electron microscopy. C3 deposition and the expression of alpha 3-integrin, a major adhesion molecule of podocytes, and actin cytoskeleton were examined by immunofluorescent staining. alpha 3-Integrin was also evaluated by immunoelectron microscopy. Western blotting was performed to examine whether anti-Fx1A recognizes alpha 3 beta 1-integrin.
Foot process effacement accompanied by decreased expression of alpha 3-integrin was already observed from day 1 after the injection of anti-Fx1A, but albuminuria was not observed until day 5. Complement activation, a key pathogenesis in PHN, was estimated to occur from day 2 after the appearance of foot process effacement. The degree of foot process effacement had not changed before the onset of albuminuria, while after the onset of albuminuria it significantly deteriorated with increased expression of actin. By immunoelectron microscopy, alpha 3-integrin decreased exclusively at the site of deposits. Western blotting showed anti-Fx1A recognizing beta1-integrin.
These findings indicate that complement-independent foot process effacement related to decreased expression of alpha 3 beta 1-integrin in a very early phase of PHN is not a prerequisite for proteinuria, and the deterioration of foot process effacement related to actin reorganization after the onset of albuminuria might be a secondary response to proteinuria.
Journal of nephrology 01/2009; 22(4):484-90. · 1.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the renoprotective effects and safety of angiotensin II receptor blocker (ARB) for patients with stage 4-5 chronic kidney disease.
An ARB, candesartan cilexetil, was administered to 13 patients (ARB group, n = 7; control group, n = 6) with a serum creatinine level of 2.52-5.95 mg/dl whose blood pressure had been maintained below 140/90 mmHg by the use of drugs other than ARBs. Routine measurements were conducted for 48 weeks, and renal survival analysis was observed for up to 3 years with the endpoints being doubling of the serum creatinine level, entry to hemodialysis, or death. The results were compared with those of the control group that was not treated with ARB.
No significant changes were observed in the blood pressure in either group. Proteinuria significantly decreased from 0.95 +/- 0.51 to 0.39 +/- 0.12 g/day (paired t test, P = 0.033) in the ARB group, but did not change in the control group. Creatinine clearance in the control group decreased significantly from 16.2 +/- 5.7 to 10.4 +/- 4.8 ml/min per 1.73 m2 (paired t test, P = 0.011), but did not change in the other group. Thus, the slopes of the reciprocal serum creatinine values became less steep in the ARB group as compared with the control (-0.002 +/- 0.015 vs. -0.025 +/- 0.015 dl/mg per month; unpaired t test, P = 0.019). Kaplan-Meier analysis revealed that ARB exhibited more favorable renal outcome at 3 years (log-rank, P = 0.025). No serious adverse events were noted in the study.
These results show that ARB reduces proteinuria and protects renal function even in the advanced renal failure.
[Show abstract][Hide abstract] ABSTRACT: A urinary test for detecting the anti-H. pylori antibody using immunochromatography (RAPIRAN) is considered suitable for the screening purpose. However, this may yield spurious results in the presence of proteinuria. The present study was conducted to evaluate the diagnostic performance of RAPIRAN in patients with proteinuria. Urine and serum samples of adult inpatients with proteinuria were used for analyses. The diagnosis of H. pylori infection was made based on the seropositivity of anti-H. pylori antibody using 2 different serum tests. Fifty-one subjects were eligible for analyses. The serum tests showed negative and positive in 25 and 26 patients, respectively. Two of 25 seropositive patients had a negative result in RAPIRAN, and 1 provided invalid data. All of seronegative patients showed negative in RAPIRAN. The overall accuracy was 95.0%. The present study showed that RAPIRAN has diagnostic quality enough to use clinically also in patients with proteinuria.
[Show abstract][Hide abstract] ABSTRACT: Eosinophilia in haemodialysis patients probably results from allergy to haemodialysis-related materials, including dialyzer membranes. We examined the effects of vitamin E-bonded dialyzers on eosinophil counts in haemodialysis patients.
We enrolled seven patients who were on regular haemodialysis and had sustained eosinophilia. White blood cell, eosinophil, CD4- and CD8-positive lymphocyte counts, and serum interleukin-5 (IL-5) and IgE levels were determined before, 2 and 4 weeks after switching to vitamin E-bonded dialyzers.
Eosinophil and CD4-positive lymphocyte counts and serum IL-5 were significantly (P = 0.003, 0.003 and 0.031, respectively) decreased after switching to vitamin E-bonded dialyzers. CD8-positive lymphocyte counts and serum IgE levels were unaltered. Crossover tests in two cases reproduced the higher eosinophilia within 4 weeks after returning to the original non-vitamin E-bonded dialyzer. Conclusion: Vitamin E-bonded dialyzers may ameliorate eosinophilia through a mechanism mediated by a decrease in IL-5 secretion by CD4-positive lymphocytes.
[Show abstract][Hide abstract] ABSTRACT: The transmembrane component of the dystroglycan complex, a heterodimer of alpha- and beta-dystroglycan, was recently localized at the basal cell membrane domain of podocytes, and it was speculated that it serves as a device of the podocyte for maintaining the complex podocyte foot process architecture, and for regulating the exact position of its ligands, the matrix proteins laminin and agrin, in the glomerular basement membrane (GBM). The redistribution of dystroglycan in two experimental rat models of foot process flattening and proteinuria-i.e., podocyte damage induced by polycationic protamine sulfate perfusion, and reactive oxygen species (ROS)-associated puromycin aminonucleoside nephrosis-was examined. In both experimental diseases, aggregation and reduced density of alpha-dystroglycan by endocytosis by podocytes was observed. In in vitro solid-phase binding assays, protamine and ROS competed with the binding of alpha-dystroglycan with purified laminin and a recombinant C-terminal fragment of agrin that contains the dystroglycan-binding domain. These changes were associated with disorder of the fibrillar components of the lamina rara externa of the GBM, as confirmed quantitatively by fractal analysis. These results indicate that both polycation and ROS induce similar changes in the distribution of podocyte alpha-dystroglycan that involve competitive disruption of alpha-dystroglycan/matrix protein complexes, endocytosis of the liberated receptor by podocytes, and disorganization of the matrix protein arrangement in the lamina rara externa. This links functional damage of the dystroglycan complex with structural changes in the GBM.
Journal of the American Society of Nephrology 09/2004; 15(8):2079-89. DOI:10.1097/01.ASN.0000133531.43177.21 · 9.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alpha- and beta-dystroglycan were detected at the base of foot processes of human glomeruli by immunoelectron microscopy. Perfusion of isolated rat kidneys with the polycationic compound protamine sulfate was found to induce rapid (i.e. within 15 min) flattening of foot processes in an energy- and actin-dependent fashion. Here we provide evidence that (i) glomeruli possess large amounts of a specifically composed complex; (ii) this complex may undergo changes in human glomerular disease; and (iii) flattening of foot processes is directly associated with dissociation of laminin-dystroglycan complexes.
[Show abstract][Hide abstract] ABSTRACT: Because reactive oxygen species (ROS) are involved in the development of puromycin aminonucleoside nephrosis (PAN), we examined whether superoxide dismutase (SOD) could ameliorate this condition. Phosphatidyl choline-bound SOD (PC-SOD) has higher affinity for the cell membrane than recombinant human SOD (rhSOD). In this study, PC-SOD had a longer half-life in the circulation and also higher affinity to renal fractions (glomerulus, brush border, and tubulus) than rhSOD. PAN was induced in rats with single injections of puromycin aminonucleoside. Rats were divided into four groups: group P, PAN rats without treatment; group PC-T and group rh-T, PAN rats treated with 30,000 U/kg PC-SOD and rhSOD, respectively; and group C, normal controls. The effect of PC-SOD versus rhSOD on PAN was evaluated by morphological podocyte changes (podocyte density along the GBM) and alpha(3) integrin expression at days 4 and 10. Proteinuria was measured over time until day 14. Distribution and quantitation of alpha(3) integrin were studied by confocal laser scan microscopy. On day 4, glomerular ROS was measured by chemiluminescence without stimulation. PC-SOD decreased proteinuria to the control level, but rhSOD only decreased proteinuria by 31%. PC-SOD significantly improved podocyte density (P < 0.05 versus group P). Total alpha(3) integrin expression decreased in the P and rh-T groups at day 4 and then had recovered by day 10, but the polarity of the site of expression did not recover. PC-T preserved both the amount and polarity of integrin expression on days 4 and 10. PC-SOD significantly suppressed ROS generation in PAN (P < 0.05). These findings suggest that alpha(3) integrin regulates glomerular permeability by maintaining podocyte shape and adhesion, which is disrupted by ROS overproduction.
American Journal of Kidney Diseases 07/2000; 35(6):1175-85. DOI:10.1016/S0272-6386(00)70056-4 · 5.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transforming growth factor (TGF)-beta is a regulator of extracellular matrix accumulation. Both TGF-beta receptors, type I (TbetaRI) and type II (TbetaRII), may be required for signal transduction in the TGF-beta pathway. The aim of this study was to investigate the relationship between the TGF-beta pathways and glomerular basement membrane (GBM) accumulation in vivo.
We examined TbetaRI, II, and III protein expression on visceral glomerular epithelial cells (GEP) in relation to GBM alterations in passive Heymann nephritis (PHN), anti-GBM nephritis and anti-thymocyte serum (ATS) nephritis. Renal tissues were examined by pre-embedding immunoelectron microscopy 3, 7 and 14 days after induction of nephritis in rats.
In normal control rats TbetaRI was not detected on GEP, TbetaRII expression was very occasionally found on GEP and TbetaRIII was seen in the cytoplasm of the GEP. TbetaRI, TbetaRII, and TbetaRIII were constitutively expressed on glomerular endothelial cells. By day 3 of anti-GBM nephritis and PHN, expression of TbetaRI, TbetaRII, and TbetaRIII was still similar to that of normal control rats, and GBM alterations in both models were not prominent except for deposit formation in PHN. From day 7 onwards, in both models, expression of TbetaRI and TbetaRII on GEP increased in association with GBM thickening. Expression of TbetaRIII in the cytoplasm of the GEP was increased, with occasional positive staining being seen on the urinary surface of the GEP from day 7 onwards. On the other hand, at day 3 of ATS nephritis, increased expression of TbetaRI and TbetaRII on GEP was noted, but from day 7 onwards, expression of TbetaR II on GEP dramatically decreased. Expression of TbetaRIII in the cytoplasm of the GEP also transiently increased at day 3. GBM thickening was not noted in ATS nephritis.
The results suggest that persistent upregulation of expression of TbetaRI, TbetaRII and possibly TbetaRIII on GEP may contribute to GBM matrix accumulation in vivo.
[Show abstract][Hide abstract] ABSTRACT: We evaluated the role of obesity in proteinuria by treadmill exercising of simple obese subjects and non-obese subjects with non-insulin dependent diabetes mellitus in whom the albumin excretion rate at rest was within normal range. Non-obese healthy volunteers were studied as the controls. The fractional renal clearances of four endogenous proteins, albumin, IgG, IgG4, and β2-microglobulin were measured before, during, and after treadmill exercise in 17 simple obese and 15 non-obese diabetic subjects, and in 21 normal subjects. Exercise increased the fractional albumin clearance in all groups. In diabetic subjects, the fractional IgG4 clearance also increased: fractional β2-microglobulin clearance increased in normal controls and in diabetics. In obese subjects, the fractional clearances of albumin, IgG, and IgG4 were similar to those in normal controls, but fractional β2-microglobulin clearance was significantly lower. These results suggest that enhanced microalbuminuria in obese subjects is probably of glomerular origin. In normal subjects and diabetics, exercise-induced microproteinuria is probably of both glomerular and tubular origin. Defect in the charge-selective barrier of the glomerular capillary wall has been implicated in diabetics. Thus some additional factors relevant to obesity must be taken into account in the consideration of the mechanism of microalbuminuria in diabetics with obesity.
[Show abstract][Hide abstract] ABSTRACT: In proliferative glomerulonephritis, both macrophages and mesangial cells generate reactive oxygen species (ROS), contributing to the development of glomerular injury. We have attempted to determine which cell produces ROS during anti-Thy1 nephritis (ATN) in rats. The generation of ROS was studied using luminol amplified chemiluminescence (GCL) on isolated glomeruli. Immunohistochemical studies used avidin-biotin complex (ABC) to label macrophages and mesangial cells. Immediately after ATN induction, mesangiolysis and infiltration with ED-1 positive cells (referred to as macrophage) was noted with a peak at day 1. After day 4, mesangial proliferation appeared with a decrease of the ED-1 positive cells and a prominent increase of PCNA positive cells (regarded as mesangial cells). In the early phase of ATN, GCL, reflecting ROS generation, increased along with the appearance of ED-1 positive cells. GCL subsequently decreased as mesangial cells increased. This suggested that macrophage were the principal participants in ROS generation in the early phase of ATN although mesangial cells cannot be completely disregarded in the generation of ROS and development of glomerular injury.
[Show abstract][Hide abstract] ABSTRACT: The ultrastructural localization of immune complex (IC) and inflammatory mediator systems in the glomerulus was investigated
in active in situ IC glomerulonephritis employing cationized ferritin in rats. Glomerulonephritis was induced by unilateral
renal perfusion of cationized ferritin as antigen (Ag) in preimmunized rats, and anti-ferritin antibody (Ab), C3 and the rat
C5b–9 complex were localized by means of immunogold electron microscopy. Ag–Ab complexes were initially formed subendothelially,
associated with C3, and attracted platelets, polymorphonuclear leucocytes (PMN) and monocytes. Then Ag–Ab complexes, without
C3, passed across the glomerular basement membrane to re-aggregate subepithelially accompanied by C3 deposition after 1 day.
Ag–Ab complexes without C3 accumulated in the inter-podocyte space within 1 day and were seen in the epithelial cells at 6
h. C5b–9 complexes were found in subepithelial immune deposits and in membrane vesicles of the epithelial cells, but only
in very small amounts in subendothelial immune deposits. Accumulated platelets, PMN, and monocyte were in direct contact with
endothelial cells or subendothelial IC. PMN and monocytes contained Ag, Ab and C3 in intracytoplasmic vacuoles. Ag–Ab complexes
were also found in the mesangial matrix adjacent to the subendothelial region after 2 h and increased slightly in number,
with expansion of the mesangial area thereafter. Most ICs formed in the subendothelial space rapidly formed lattices of a
size that activated C3 and were then translocated to the subepithelial space. The potential ability of C3 to solubilize ICs
in the subendothelial region may be important in this process. Endocytosis of subendothelial ICs by PMN and/or monocytes and
the movement of ICs to the mesangial matrix may also contribute to the removal of IC from the subendothelial space.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/1997; 431(1):53-61. DOI:10.1007/s004280050069 · 2.65 Impact Factor