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Koichi Nakanishi

Publications and source records attributed to Koichi Nakanishi.

14 recordsLinked to original sources
PubMed2006

The effect of aldosterone blockade in patients with Alport syndrome.

Recent studies indicate that adding the mineralocorticoid receptor antagonist spironolactone (SP) to angiotensin converting enzyme inhibitors (ACEI) or ACEI and angiotensin receptor blocker (ARB), which is known as a triple blockade, enhances the more beneficial effects on urinary protein excretion of patients with chronic kidney diseases. In this study, we explored the effects of SP on urinary protein excretion in patients with Alport syndrome featuring persistent proteinuria in spite of the long-term use of ACEI (lisinopril) or both ACEI and ARB (candesartan). Five patients with Alport syndrome were enrolled and SP treatment (25 mg/day) was started. At the start of SP administration, all patients showed good renal function and none of them suffered from hypertension. We decided to assess the effect of SP by determining the morning urinary protein/creatinine ratio (U-P/C) and estimated glomerular filtration rate (EGFR). After SP treatment was started, U-P/C was significantly reduced at 3, 6, 12 and 18 months, while EGFR did not change. The drop in systolic and diastolic blood pressure was statistically significant and serum potassium level was slightly elevated. None of the patients showed signs of severe hyperkalemia (>5.0 mEq/l). These results suggest that aldosterone receptor blockade combined with ACEI and ARB therapy offers a valuable adjuvant treatment for the reduction of proteinuria in patients with Alport syndrome as in those with other chronic kidney diseases. SP can thus be expected to constitute a good renoprotective agent for Alport syndrome. These preliminary data indicate that large-scale trials of this therapy should be done.

Adolescent↗
PubMed2006

High-dose mizoribine treatment for adolescents with systemic lupus erythematosus.

BACKGROUND: In treating pediatric patients with systemic lupus erythematosus (SLE), it is necessary to quickly attain remission to avoid sequelae in various organs and to maintain it over a long period. However, to maintain remission, the prolonged use of immunosuppressants which have various adverse effects, is often necessary in addition to steroids, and complications due to such immunosuppressants pose very important problems. A regimen of mizoribin (MZR) at 150 mg/day divided into two or three doses has been recommended, but while this regimen has been safe, its efficacy has not been satisfactory. However, MZR produces effects dose-dependently, and the dose recommended to date may have been insufficient for the treatment of children with SLE. METHODS: The authors administered oral MZR at 300 mg/day in two divided doses, which is twice the conventional dose for adults, to five adolescents with SLE. Three of these five were markedly steroid-dependent patients and two had previously been treated with steroids only. Thereafter, the authors evaluated the safety and efficacy of the regimen by following the patients for at least 7 months after the beginning of treatment. RESULTS: Patients 1 and 2 had been treated with prednisolone (PSL) and cyclosporine (CyA), but as the duration of CyA administration became long, it was replaced with 300 mg MZR. This transition could be accomplished smoothly. Patient 3 showed repeated recurrence during the treatment with PSL and CyA or CPM, but the symptoms could be controlled by the addition of 300 mg MZR. In patients 4 and 5, the control of symptoms with PSL alone was judged to be difficult, and concomitant administration of MZR at 300 mg was started. This resulted in a decrease in the dose of PSL. The Cmax (C2) of MZR was 1.33 microg/mL or higher in all five patients, and the efficacy of the treatment was satisfactory. Concerning side-effects, hyperuricemia was noted in two patients, but it was resolved in one of them by reducing the dose of MZR and in the other spontaneously while the treatment was continued. Temporary exacerbation of hair loss was observed in two patients, but it disappeared in both of them after a few months. CONCLUSION: MZR could be administered at a high dose effectively and safely. However, monitoring of the serum uric acid level was necessary. High-dose MZR therapy showed an efficacy and safety that would warrant its application to steroid-dependent pediatric patients with SLE.

Adolescent↗
PubMed2005

Long-term follow-up of atypical membranoproliferative glomerulonephritis: are steroids indicated?

Atypical membranoproliferative glomerulonephritis (MPGN) has been reported to have a good prognosis when treated with corticosteroids. However, this recommendation is based on uncontrolled trials and is associated with many complications. The purpose of our study is to determine whether steroid therapy is indicated for atypical MPGN. The cases of seven patients with atypical MPGN are reported in this study. Urinary abnormalities of five of them were detected by urine screening at school, of two because of macrohematuria. Hypocomplementemia was noted in six patients. All but one patient were treated without corticosteroids, and five with angiotensin-converting enzyme inhibitors (ACEI) and/or the Chinese herbal medicine Sairei-to (TJ-114). One patient recovered spontaneously from proteinuria and was therefore not treated, and one who developed severe proteinuria during observation was treated with corticosteroids. After an average follow-up period of 10.0 years, five patients showed normal urinary findings, one had hematuria and one proteinuria. At the most recent follow-up, the renal function of all patients remained within the normal range, and serum C3 had returned to normal levels in five out of six. These findings suggest that the indication of steroid therapy for atypical MPGN should be re-examined, since most of the patients with atypical MPGN seem to have an excellent prognosis without treatment with corticosteroids.

Adolescent↗
PubMed2005

Cyclosporin A absorption profiles in children with nephrotic syndrome.

A single blood concentration measurement of Neoral 2 h after administration (C2) is a new concept in therapeutic drug monitoring (TDM). In most adult patients, the concentration of cyclosporin A (CyA) peaks within 2 h after Neoral administration. Therefore, monitoring the area under the concentration-time curve over the first 4 h post-dose (AUC0-4) is considered to be the most reliable strategy for Neoral TDM. In addition, C2 is considered to be the most accurate predictor of AUC0-4, with which C2 correlates best. Thus, in adult patients, C2 monitoring is recommended as the best single-point TDM method for Neoral. However, in paediatric patients, the effectiveness of C2 monitoring is still unclear. We examined the trough concentration (C0), C1, C2, C3, and C4 of CyA in 60 patients (1 to 20 years old, mean age 7.42+/-0.67 years) who had nephrotic syndrome treated with Neoral. The peak concentration of C0-C4 was C1 or C2 in 38 patients (early peak group) and C3 or C4 in 22 patients (late peak group). C2 in the late peak group was significantly lower than that in the early peak group (422+/-50.1 vs. 665 +/-53.8 ng/ml, P =0.0008), although the administered doses of Neoral and C0 were similar between these groups. Therefore, TDM by C2 using the same standard as in the early peak group might result in an overdose of CyA in the late peak group. As the concentration peaked at 3 h or more after Neoral administration in the late peak group, AUC0-4 does not necessarily reflect the Neoral absorption profile. As more than 33% of the paediatric patients were in the late peak group, TDM by AUC0-4 or C2 should be used carefully in paediatric patients treated with Neoral.

Absorption↗
PubMed2005

Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome.

BACKGROUND: Congenital nephrotic syndrome (CNS) causes significant renal failure, and is classified into two types: (1) Finnish type; and (2) other, including diffuse mesangial sclerosis. Mutations of NPHS1 and NPHS2, which encode the slit diaphragm components nephrin and podocin, cause CNS and autosomal-recessive familial steroid-resistant nephrotic syndrome, respectively. Most patients with Finnish-type CNS in Europe and the United States have NPHS1 mutations. However, NPHS2 mutations have been detected in some cases. Mutations in ACTN4, encoding alpha-actinin-4, cause an autosomal-dominant focal segmental glomerulosclerosis. alpha-actinin-4 stabilizes the podocyte cytoskeleton structure, connecting with actin filaments. WT1 mutations, causing Wilm's tumor, have been demonstrated in some CNS patients with diffuse mesangial sclerosis. Systematic investigation of genes for CNS in Japan has never been performed. METHODS: To clarify the role of mutations in these four genes, we used polymerase chain reaction (PCR) and direct sequencing to investigate all exons and exon-intron boundaries for these genes in 13 unrelated CNS patients from regional pediatric kidney disease centers in Japan. RESULTS: A novel homozygous nonsense mutation of NPHS1, E246X in exon 7, and a novel homozygous deletion mutation of NPHS1, 2156_2163del in exon 16 were detected in one patient each. A novel homozygous nonsense mutation of NPHS2, R196X in exon 5, was found in one patient, and the same heterozygous nonsense mutation was detected in another. No ACTN4 or WT1 mutations were detected. CONCLUSION: These studies demonstrate that mutation of NPHS1 is not a major cause of CNS in Japanese patients, and that mutation of NPHS2 can be responsible for CNS in this population.

Actinin↗
PubMed2004

Evaluation of the inferior vena cava in potential pediatric renal transplant recipients.

Vascular anomalies due to occlusion or thrombosis of the inferior vena cava (IVC) may be hazardous to renal transplantation, and preoperative vascular evaluation is important for safe and successful surgery. The purpose of this study was to assess the utility and accuracy of two-dimensional time-of-flight (2D-TOF) magnetic resonance venography (MRV) as an alternative to conventional angiography for evaluating the IVC and iliac vein in potential pediatric renal transplant recipients. Four children with chronic renal failure were evaluated with 2D-TOF MRV by superior presaturation pulse and target maximum intensity projection. The whole MRV examination and filming required less than 30 min. All four patients had a normal IVC and iliac vein. Two of the patients underwent renal transplantation, and the MRV findings were in total agreement with the final anatomy revealed intraoperatively. MRV is accurate for evaluating the condition of the IVC and iliac vein. It is a reliable, noninvasive and rapid technique that can be considered as an alternative to invasive angiography for evaluation of children scheduled for transplantation. We recommend the use of this noninvasive procedure to ascertain the patency of the IVC in all infants and children with a history of indwelling catheters in the IVC or those with a propensity to thrombosis, i.e., all recipients with nephrotic syndrome. The insertion of catheters in the femoral vein in children who may become candidates for renal transplantation should be discouraged.

Adolescent↗
PubMed2003

A-20C angiotensinogen gene polymorphism and proteinuria in childhood IgA nephropathy.

We have previously reported that the TT genotype of the angiotensinogen gene and the ID/DD genotype of the angiotensin-converting enzyme gene are associated with increased severity of proteinuria in IgA nephropathy in Japanese children. Recently it was reported that polymorphism at -20 from adenine to cytosine in the angiotensinogen gene, increasing the level of this transcript, was associated with the progression of renal dysfunction in adult IgA nephropathy. We therefore investigated whether this polymorphism is involved in IgA nephropathy in Japanese children. We identified this polymorphism in 105 children with IgA nephropathy and 119 healthy adults using polymerase chain reaction/restriction fragment length polymorphism analysis. At the time of biopsy, all patients had normal blood pressure and renal function. There were no differences in the genotypes and allele frequencies of this polymorphism between patients with IgA nephropathy and controls. The number of patients with the AC/CC genotype showing heavy proteinuria (>or=1.0 g/day per m(2) body surface area) at biopsy was significantly higher than that with the AA genotype ( P=0.039, chi-squared test). The AC/CC genotype of this polymorphism may be associated with an increased severity of proteinuria, suggesting that this polymorphism may play a significant role in the progression of IgA nephropathy in Japanese children.

Adenine↗
PubMed2003

Genetic disorders of human congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital abnormalities of the kidney and urinary tract, CAKUT are common in humans, occurring at a frequency of approximately 1 in 500 fetal ultrasound examinations. CAKUT are major causes of chronic renal failure in infants and young children, but little is known about the molecular pathogenesis of these disorders. To date, several gene mutations have been identified as a cause of human CAKUT: these include PAX2, KAL, EYA1, AGTR2 and HNF-1beta. At present, there is only limited information regarding how mutations alter gene expression during development to cause some CAKUT. The most convincing information comes from the multiorgan malformation syndromes with specific gene mutations. However, these syndromes are relatively rare, and most CAKUT appear to occur in isolation. The goal of this review is to provide an overview of these genetic disorders for CAKUT. An understanding of the genetic aspects of human CAKUT will help to unravel the pathogenesis of these disorders and may facilitate the design of genetic screening tests for early diagnosis and appropriate genetic counseling. Moreover, a deeper insight into the relationship between abnormal genes and the pathogenesis of abnormalities of CAKUT will provide an etiological classification of CAKUT. In addition, the importance of developing a registry of patients with various forms of CAKUT is discussed. This information will allow us to combine molecular biology and classical epidemiologic methods, and to continue expanding our knowledge regarding CAKUT.

DNA-Binding Proteins↗
PubMed2003

Group A streptococcal antigen in the glomeruli of children with Henoch-Schönlein nephritis.

BACKGROUND: Although the pathogenesis of Henoch-Schönlein nephritis (HSN) remains unclear, there is substantial evidence that it is an immune complex-mediated disease. HSN is preceded by upper-respiratory tract infection in 30% to 50% of patients, but there is no evidence that group A streptococcal (GAS) infection has a pathogenetic role in this disease. Recently, nephritis-associated plasmin receptor (NAPlr), a GAS antigen, was found primarily in the glomerular mesangium of patients with early-stage acute poststreptococcal glomerulonephritis. METHODS: To determine the possible role of NAPlr in HSN, expression of the receptor was determined in glomeruli using fluorescein isothiocyanate-labeled rabbit polyclonal anti-NAPIr antibody, and serum antistreptolysin O (ASO) titers were measured in children with HSN. RESULTS: Ten of 33 patients (30%) with HSN showed segmental or global mesangial staining with NAPlr antibody, whereas only 4 of 120 patients (3%) with other renal diseases were positive (P < 0.001, Fisher's exact test). Patients with HSN also showed significantly greater ASO titers than patients with other renal diseases (P = 0.03, Mann-Whitney U test). Serum ASO titers were significantly greater in patients with HSN with than without glomerular NAPlr antigen (P = 0.03, Mann-Whitney U test). CONCLUSION: These findings suggest that the deposition of NAPlr in the mesangium, induced by GAS infection, may have a role in the pathogenesis of HSN in some patients. Am J Kidney Dis 41:366-370.

Adolescent↗
PubMed2001

Segment-specific c-ErbB2 expression in human autosomal recessive polycystic kidney disease.

c-ErbB2 (also referred to as Neu or HER2), a transmembrane glycoprotein with intrinsic tyrosine kinase activity, is structurally related to epidermal growth factor receptor (EGFR) and forms active heterodimers with EGFR as well as other members of the EGFR family. c-ErbB2 is reported to mediate differentiation and proliferation in epithelial cells and is expressed in a tissue-specific and developmental stage-specific manner. Given the role of EGFR in cystic renal epithelial hyperplasia and the immature phenotype of cystic renal epithelial cells, the segment-specific expression pattern of c-ErbB2 in human autosomal recessive polycystic kidney disease (ARPKD) was examined in nine ARPKD kidney specimens ranging from gestational age 17 wk through postnatal age 4 wk. c-ErbB2 staining of human ARPKD samples showed increased expression with increasing gestational age compared with normal human fetal and postnatal kidneys. This increased c-ErbB2 expression was primarily localized to the apical surfaces of cystic collecting tubule cells, similar to the pattern of EGFR expression, and paralleled collecting tubular cyst formation and growth.

ErbB Receptors↗
PubMed2001

Role of CFTR in autosomal recessive polycystic kidney disease.

An extensive body of in vitro data implicates epithelial chloride secretion, mediated through cystic fibrosis transmembrane conductance regulator (CFTR) protein, in generating or maintaining fluid filled cysts in MDCK cells and in human autosomal dominant polycystic kidney disease (ADPKD). In contrast, few studies have addressed the pathophysiology of fluid secretion in cyst formation and enlargement in autosomal recessive polycystic kidney disease (ARPKD). Murine models of targeted disruptions or deletions of specific genes have created opportunities to examine the role of individual gene products in normal development and/or disease pathophysiology. The creation of a murine model of CF, which lacks functional CFTR protein, provides the opportunity to determine whether CFTR activity is required for renal cyst formation in vivo. Therefore, this study sought to determine whether renal cyst formation could be prevented by genetic complementation of the BPK murine model of ARPKD with the CFTR knockout mouse. The results of this study reveal that in animals that are homozygous for the cystic gene (bpk), the lack of functional CFTR protein on the apical surface of cystic epithelium does not provide protection against cyst growth and subsequent decline in renal function. Double mutant mice (bpk -/-; cftr -/-) developed massively enlarged kidneys and died, on average, 7 d earlier than cystic, non-CF mice (bpk -/-; cftr +/+/-). This suggests fundamental differences in the mechanisms of transtubular fluid secretion in animal models of ARPKD compared with ADPKD.

Animals↗
PubMed2000

Proximal tubular cysts in fetal human autosomal recessive polycystic kidney disease.

Standard texts describe human autosomal recessive polycystic kidney disease (ARPKD) as a cystic kidney disease in which lesions are localized to collecting tubules. Murine models of ARPKD consistently demonstrate an early phase of proximal tubular (PT) cystic involvement, which disappears shortly after birth. This is followed by a phase of collecting tubular (CT) cyst formation and progressive enlargement leading to compromise of renal function and death. Because the description of cystic lesions in human ARPKD has been largely based on postnatal specimens, PT cyst formation was hypothesized to be a characteristic feature of fetal human, as well as murine, ARPKD. This study examines nephron segment-specific cyst localization histochemically by lectin binding in 11 human ARPKD specimens obtained at different fetal and postnatal ages. PT cysts were found in human fetal specimens from gestational age 14 wk to 26 wk. The percentage of cysts involving PT segments ranged from 2 to 41%. The cystic index of PT cysts ranged from 2 to 5. In all specimens in which PT cysts were found, both the percentage of CT cysts and their cystic index were equal to or greater than the percentage of PT cysts and the associated PT cystic index. PT cysts were absent in all kidney specimens older than 34 wk gestational age. It is concluded that human ARPKD, like murine ARPKD, has a transient phase of PT cyst formation during early fetal development.

Embryo, Mammalian↗