[Physiopathology of lipoprotein glomerulopathy].
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Apolipoproteins E↗
Biomedical subjects
Takao Saito
Publications and source records attributed to Takao Saito.
Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases.
Lipoprotein glomerulopathy (LPG) is a unique entity of renal lipidosis characterized by peculiar histopathologic characteristics of lipoprotein thrombi and an abnormal plasma lipoprotein profile resembling type III hyperlipoproteinemia, with a marked increase in serum apolipoprotein E (apoE) concentrations. At present, 65 cases have been reported worldwide, although most patients are found in Japan and east Asian countries. Recently, we identified 4 types of novel apoE mutations associated with LPG. In particular, a mutation designated apoE Sendai, in which arginine 145 is substituted with proline, occurs in the majority of Japanese patients. The virus-mediated transduction of apoE Sendai resulting in the development of LPG in apoE-deficient mice confirms the etiologic role of apoE mutation in LPG. Conversely, experimental graft-versus-host disease induced in Fc receptor gamma-chain-deficient mice showed LPG-like lesions in glomeruli without apoE mutations. Considered together, we believe that intrinsic factors in the kidney also contribute to the induction of LPG. Today, apoE and related lipid abnormalities are reported to have an important role in the development of various renal diseases, eg, diabetic nephropathy and immunoglobulin A nephropathy. In this article, we review clinical and histopathologic features of LPG, describe the etiologic role of apoE variants and intrinsic renal factors, and discuss the impact of LPG on mechanisms of other renal diseases.
Adolescent↗
Pure red-cell aplasia caused by the antibody to recombinant erythropoietin, epoetin-beta, in a Japanese patient with chronic renal failure.
A 68-year-old male with chronic renal failure and anemia received recombinant human erythropoietin (rHuEPO), epoetin beta, for approximately 1 year. Although the agent was initially effective for improving anemia, anemia refractory to EPO administration appeared and then worsened later, and pure red-cell aplasia (PRCA) was diagnosed. Anti-EPO antibody was detected by radioimmunoprecipitation (RIP) assay in the patient's serum. The antibody inhibited the proliferation of EPO-dependent cell line in a dose-dependent manner neutralizing EPO activity. The antibody also reacted with the other epoetin alfa products. The antibody did not recognize the carbohydrate moieties or denatured epoetin beta. The result suggested that the antibody recognized the conformational epitope of epoetin beta peptide molecule. Withdrawal of EPO and administration of cyclosporine decreased the titers of antibody; however, erythroid progenitor has not yet regenerated although the requirement for red blood cell transfusion is decreasing.
Aged↗
A rare cause of posttransplantation nephrotic syndrome.
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Adult↗
Carnitine palmitoyltransferase II deficiency due to a novel gene variant in a patient with rhabdomyolysis and ARF.
Adult patients deficient in carnitine palmitoyltransferase II (CPT II) cannot generate sufficient amounts of energy, which results in rhabdomyolysis and acute renal failure (ARF). Its genetic basis has been recognized; but histopathologic changes, especially electron microscopic changes, have scarcely been described. The study subject is a patient with ARF caused by repetitive nontraumatic rhabdomyolysis. The acylcarnitine profile of serum and enzyme assay on skin fibroblasts confirmed the diagnosis of CPT II deficiency. Renal biopsy specimens were examined microscopically and immunohistochemically. The histological diagnosis was interstitial nephritis with acute tubular necrosis caused by rhabdomyolysis. Myoglobin in tubules was detected by means of immunohistochemistry and electron microscopy. The genetic structure of CPT II was analyzed in the patient and his family. Eight pairs of polymerase chain reaction (PCR) primers were designed to cover the coding region. Each PCR-amplified gene product was subjected to DNA sequencing, which unveiled heterozygosity at the CPT II locus consisting of a deletion of cytosine and thymine at codon 408, resulting in a stop signal at 420, as well as a mutation of arginine to cysteine at codon 631. The frame shift at 408 has never been described before. DNA sequencing of the family showed the deletion mutation from the mother and the point mutation from the father. We describe renopathological findings in a patient with CPT II deficiency associated with rhabdomyolysis, which suggested the pathological role of myoglobin casts in the development of tubular necrosis. Genetic analysis of the patient identified a novel variant of the CPT II gene.
Adult↗
Reaction properties of catalytic antibodies encapsulated in organo substituted SiO2 sol-gel materials.
Catalytic antibodies (38C2 and 84G3) were encapsulated in hybrid organic-inorganic sol-gel powder prepared from tetraethoxysilane (TEOS) and organoalkoxysilanes, then used to catalyze enantioselective aldol reactions. Sol-gel immobilization enhanced antibody stability with respect to the effect of temperature and organic solvent concentration.
Antibodies, Catalytic↗
Phorbol myristate acetate induces neutrophil death through activation of p38 mitogen-activated protein kinase that requires endogenous reactive oxygen species other than HOCl.
Stimulation of normal mouse neutrophils with phorbol 12-myristate 13-acetate resulted in an acceleration of chromatin condensation and phosphatidylserine externalization that was not associated with caspase-3 activation. Caspase-independent death was completely inhibited by GF109203X and SB202190, specific inhibitors for protein kinase C and p38 mitogen-activated protein kinase respectively. Activation of p38 mitogen-activated protein kinase was completely suppressed by GF109203X, indicating that this enzyme is regulated by protein kinase C. On the other hand, cell death was abolished in NADPH oxidase-deficient neutrophils lacking superoxide production. Of note, p38 mitogen-activated protein kinase was activated by phorbol 12-myristate 13-acetate in normal and myeloperoxidase-deficient neutrophils lacking production of HOCl, whereas no activation was observed in NADPH oxidase-deficient neutrophils. These results strongly suggest that activation of p38 mitogen-activated protein kinase is regulated by endogenously generated superoxide or its metabolites other than HOCl, a critical regulator of inducer-stimulated death of neutrophils.
Animals↗
Clinical efficacy of apple polyphenol for treating cedar pollinosis.
A double-blind comparative study was conducted on cedar pollinosis patients in order to evaluate the treatment efficacy of apple polyphenol (Ap). Ap was administered (500 mg) once daily for 12 weeks, starting about 2 weeks prior to cedar pollen dispersion. Pollinosis symptoms during the study were evaluated according to the classification in the guidelines for allergic rhinitis diagnosis and treatment. The results show that the sneezing score was significantly lower for the Ap group than with the placebo group during the early period of pollen dispersion and during the main dispersion period. In addition, no adverse reactions were induced by Ap during the study. These results suggest that Ap may alleviate the symptoms of cedar pollinosis.
Anti-Allergic Agents↗
[Advance in the treatment of progressive renal dysfunction. 2. Nephrotic syndrome].
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Humans↗
A randomized open-label comparative study of conventional therapy versus mizoribine onlay therapy in patients with steroid-resistant nephrotic syndrome (postmarketing survey).
BACKGROUND: A previous double-blind 24-week clinical trial of mizoribine (MZ) vs placebo in steroid-resistant primary nephrotic syndrome (SRPNS) showed that MZ was more effective than placebo in reducing the rate of deterioration of renal function. The present study was conducted to evaluate the efficacy and safety of MZ in patients with SRPNS after 2 years' treatment. METHODS: A multicenter randomized open-label controlled trial in patients with SRPNS was conducted as a 2-year prospective postmarketing study. RESULTS: There was a significant imbalance in the baseline serum albumin level (s-Alb) between the conventional therapy (CT) and MZ onlay therapy groups. Early dropouts were more frequent in the subset of patients in the CT group having a baseline s-Alb < or =3 g/dl. Therefore, the primary analysis (urinary protein level (UP)-improving effect) was performed using a mixed-effects model, with stratification according to the baseline s-Alb value. The analysis revealed that, in the subset of 34 patients with membranous nephropathy (MN) within the stratum of patients with baseline s-Alb < or =3 g/dl (n = 52), the rate of change (slope of change in the UP level/month), in terms of the log (UP+0.2), was -0.0577 in those allocated to the MZ group and -0.0227 in those allocated to the CT group (P = 0.058). In the stratum of patients with a baseline s-Alb >3 g/dl (n = 97), there were no significant differences in the UP between the two treatment groups. Hence, MZ onlay therapy was not considered to be efficacious in this group of patients. No serious adverse reactions to the drug were observed. CONCLUSIONS: The present study yielded significant results, in that it suggested the possibility that long-term MZ therapy may afford further reduction of the UP, in addition to that obtained following CT, in particular, in MN patients in a severe nephrotic state.
Adult↗
Altered expression of NDST-1 messenger RNA in puromycin aminonucleoside nephrosis.
Sulfated portions of glycosaminoglycan (GAG) side chains in heparan sulfate proteoglycan (HSPG) are thought to play an important role in charge-dependent selectivity of glomerular filtration against plasma proteins. Heparan sulfate N-acetylglucosamine N-deacetylase/adenosine 3'-phosphate 5'-phosphosulfate: unsubstituted glucosamine N-sulfotransferase (NDST) is the key enzyme regulating sulfation of GAG chains. In this study we investigated transcriptional expression of NDST-1, 1 of 4 isozymes of NDST, in glomeruli of rats with puromycin aminonucleoside (PAN) nephrosis. Nephrosis was induced in rats with a single intraperitoneal injection of 150 mg/kg PAN. On days 10 and 35, expression of NDST-1 messenger RNA (mRNA) in glomeruli was analyzed with the use of Northern-blot analysis. Immunohistochemical studies were also performed with the use of monoclonal antibodies that react specifically with the N-sulfated portion of the GAG chain of HSPG and agrin, a major core protein of HSPG in glomerular basement membrane (GBM). In addition, we studied the expression of NDST-1 mRNA in cultured glomerular epithelial cells (GECs) and glomerular mesangial cells in the presence of PAN. On day 10, when significant proteinuria developed, the ratios of glomerular expression of NDST-1 mRNA against glyceraldehyde-phosphate dehydrogenase mRNA in PAN-treated rats were decreased to 48% +/- 6% of those in controls (P<.05). Immunohistochemical studies revealed that staining for N-sulfated GAG chains of HSPG on GBM was markedly reduced on day 10 in PAN-treated rats but that staining for agrin was unchanged. In contrast, on day 35, when PAN-treated rats recovered from proteinuria, we noted no differences in glomerular expression of NDST-1 mRNA and staining intensity for N-sulfated GAG chains on GBM between PAN-treated rats and controls. Incubation of GECs for 24 hours in the presence of 50 ng/mL PAN resulted in the reduction of the expression of NDST-1 mRNA (67% +/- 12% of those in controls, P<.05). In summary, we found alteration of the expression of NDST-1 mRNA, accompanying a loss of N-sulfated GAG chains of HSPG on GBM without changes in the core protein agrin, in the course of PAN nephrosis. These data suggest an important role for this enzyme in heparan sulfate assembly in GBM and GEC and in the pathogenesis of proteinuria in PAN nephrosis.
Amidohydrolases↗
Detoxification of bisphenol A and nonylphenol by purified extracellular laccase from a fungus isolated from soil.
Purified laccase from a fungus (family Chaetomiaceae) was used for the enzymatic oxidation of bisphenol A and nonylphenol, endocrine-disrupting chemicals. It rapidly oxidized both chemicals in the absence of mediators and within 24 h their estrogenic activities were completely removed.
Journal Article↗
Relationship of predialytic intact parathyroid hormone on secondary hyperparathyroidism in chronic maintenance haemodialysis patients.
METHODS AND RESULTS: In order to clarify the predialytic factors influencing the onset of secondary hyperparathyroidism (SHPT) in patients on chronic maintenance haemodialysis, the time-course changes of serum levels of intact-PTH (i-PTH) during haemodialysis for 5 years were investigated. The subjects were 69 non-diabetic patients who had a serum aluminium level of less than 1.85 nmol/L at the end of observation. Patients were divided into two groups based on i-PTH levels obtained at the start of dialysis; the high group (H group) consisted of patients whose i-PTH levels were more than 22.00 pmol/L, the low group (L group) had levels less than 22.00 pmol/L. In the H group, i-PTH was 41.46 +/- 2.87 pmol/L at the start of dialysis (vs L group, P < 0.0001) and 15.82 +/- 2.85 pmol/L after haemodialysis initiation. In the L group, i-PTH levels did not significantly change and was 11.69 +/- 2.50 pmol/L 12 months after the start of dialysis (at the 12th month). However, at the 60th month, the i-PTH level was 33.24 +/- 5.30 pmol/L in the H group, and 9.85 +/- 2.13 pmol/L in the L group (P < 0.005). CONCLUSION: It is suggested that control of i-PTH levels in the predialytic period may be important to suppress SHPT throughout haemodialysis.
Adult↗
Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan.
BACKGROUND: Idiopathic membranous nephropathy (IMN) is a representative form of refractory nephrotic syndrome in Japan. Although IMN is thought to run a more benign course in Japanese than in the Caucasian population, risk factors and appropriate treatment are controversial issues. METHODS: The research group supported by a grant for "Progressive Renal Disease" from the Ministry of Health, Labor and Welfare, Japan, carried out a national survey of patients with IMN and nephrotic syndrome. Of 1066 nephrotic patients with histopathologically proven IMN registered from 1975 to 1993 in 85 institutions, 949 patients were studied. RESULTS: The overall renal survival rates were 95.8%, 90.3%, 81.1%, and 60.5% at 5, 10, 15, and 20 years after diagnosis, respectively. When clinical and histopathologic features at onset of nephrotic syndrome were evaluated by multivariate analysis, male gender, old age (> or =60 years), high serum creatinine concentration (> or =1.5 mg/dL), and the development of tubulointerstitial lesions (> or =20% of the biopsy sample area) were significant predictors of progression to end-stage renal disease (ESRD). The renal survival rate in patients on steroid therapy was significantly higher than in patients on supportive therapy alone. Patients achieving a remission showed a significant reduction of risk for progression. CONCLUSION: IMN is a disease with a comparatively good prognosis in Japan even when it is associated with nephrotic syndrome. Steroid therapy, which has not been recommended for IMN in most review articles, seems to be useful at least for Japanese patients. In particular, a remission from heavy proteinuria likely results in a favorable outcome.
Adult↗
Renoprotective effect of angiotensin-converting enzyme inhibitor combined with alpha1-adrenergic antagonist in spontaneously hypertensive rats with renal ablation.
To assess the renal benefits of combined angiotensin-converting enzyme inhibition and alpha(1)-adrenergic antagonism, we studied the antihypertensive and renoprotective effects of temocapril (TMP) alone and in combination with doxazosin (DOX) in spontaneously hypertensive rats (SHR)/Izumo rats with renal ablation. Five-Sixths-nephrectomized rats were assigned to receive TMP (10 mg/kg/day) (TMP group), TMP plus DOX (2 mg/kg/day) (TMP+DOX group), or vehicle (control group) orally for 12 weeks. Both systolic blood pressure (SBP) and urinary excretion of albumin (UalbV) in the control group progressively increased during the experimental period and were significantly higher than in sham-operated rats. Treatment with either TMP or TMP plus DOX had similar antihypertensive effects in this rat model. Twelve weeks after initiation of treatment, the SBP values in the control, TMP, and TMP+DOX groups were 265+/-8, 157+/-4, and 163+/-3 mmHg, respectively, in comparison with 233+/-4 mmHg in sham-operated rats (p<0.0001 control vs. sham, p<0.001 TMP vs. control, p<0.001 TMP+DOX vs. control). UalbV, serum creatinine (Scr), blood urea nitrogen (BUN), and heart weight/body weight (HW/BW) ratio were significantly lower in the TMP and TMP+DOX groups than in the control group (UalbV: p<0.05; Scr: p<0.01; [BUN, HW/BW ratio]: p<0.0001; and [UalbV, Scr, BUN, HW/BW ratio]: p<0.0001 vs. control, respectively). The index of glomerular sclerosis (IGS) and relative interstitial volume (RIV) were significantly lower in the TMP+DOX group than in the control group (IGS: p<0.05; RIV: p<0.01). Especially, UalbV, IGS, and RIV were significantly better in the TMP+DOX group than in the TMP group ([IGS, RIV]: p<0.05; UalbV: p<0.01). These results suggest that simultaneous administration of TMP and DOX provides greater renoprotective effects than administration of TMP alone.
Adrenergic alpha-1 Receptor Antagonists↗
[Refractory nephrotic syndrome].
In Japan, refractory nephrotic syndrome is defined as a pathological condition resistant to the treatment using corticosteroids and other immunosuppressive for 6 months or more. The Research Group on Progressive Renal Disease sponsored by the Ministry of Health Labor and Welfare of Japan reported that 10 to 12% of the cases with idiopathic nephrotic syndrome were classified into this type and that the most common cause in adults is idiopathic membranous nephropathy (40%) and the second is focal segmental glomerulosclerosis (20%). In these conditions, less than 10% progressed to end stage renal disease (ESRD) when urine protein decreased under 1 g/day by the treatment. Persistent proteinuria is not only a marker of irreversible glomerular lesions but also a risk factor for tubulointerstitial lesions, which plays a significant role in progression into ESRD.
Angiotensin-Converting Enzyme Inhibitors↗
[Guidelines for handling and assessment of renal biopsy specimens: Brief report from the committee for standardization of renal pathology diagnosis, JSN].
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Biopsy↗