Hidehiko Yanagida

Heparin-binding EGF-like growth factor is expressed by mesangial cells and is involved in mesangial proliferation in glomerulonephritis

Heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), a new member of the EGF family, is mitogenic for several types of cells, through binding to cell surface heparan sulphate proteoglycans. This study has attempted to delineate HB‐EGF expression by mesangial cells and to identify its role in experimental and human glomerulonephritis. Rat mesangial cells, cultured in the presence of phorbol acetate, hydrogen peroxide, interleukin‐1β, and tumour necrosis factor‐α, expressed HB‐EGF mRNA. Recombinant HB‐EGF stimulated rat mesangial cells to proliferate and to express types I and III collagen. In the rat anti‐Thy‐1.1 nephritis, glomerular HB‐EGF mRNA was up‐regulated and peaked at days 5–7; its expression at the protein level in the glomerulus was prominent at days 5–10. By immunofluorescence, HB‐EGF was positive predominantly in the mesangial area of renal tissues from 23 of 45 patients with various types of human glomerulonephritis, showing a significant correlation with the grade of mesangial proliferation; there was no staining in tissues from patients with minimal change nephrotic syndrome and normal kidney tissues. These data provide the evidence that HB‐EGF is synthesized and expressed by mesangial cells and stimulates mesangial cell proliferation and collagen synthesis in vitro. HB‐EGF is a potential mediator in mesangial cell proliferation and matrix expansion in experimental and human glomerulonephritis. Copyright

An adolescent with IgA nephropathy and Crohn disease: pathogenetic implications.

Abstract. We describe a patient with IgA nephropathy associated with Crohn disease. IgA nephropathy first appeared at the age of 10xa0years. Combined therapy with prednisolone, cyclophosphamide, warfarin, and angiotensin-converting enzyme inhibitor resulted in clinical improvement over the following year, and remission was maintained. At the age of 13xa0years, the patient developed Crohn disease and IgA nephropathy recurred. Significant increases in serum IgA were associated with progression of Crohn disease. An elemental diet combined with oral prednisolone resulted in clinical improvement of Crohn disease and in remission of nephropathy and normalization of serum IgA concentration. The clinical course of the two diseases was linked, suggesting a common pathogenetic mechanism involving an IgA immune response to mucosal challenge in the intestine.

Mycophenolate mofetil therapy for children with intractable nephrotic syndrome.

Background: Cyclosporin A (CyA) can suppress relapses and reduce proteinuria in frequent‐relapse nephrotic syndrome (FRNS) and steroid‐resistant nephrotic syndrome (SRNS). However, some patients remain resistant to CyA therapy. The purpose of the present paper was to evaluate mycophenolate mofetil (MMF) treatment in pediatric patients with CyA‐resistant intractable nephrotic syndrome.

A boy with mitochondrial disease: asymptomatic proteinuria without neuromyopathy

Mitochondrial disorder is a relatively rare disease during childhood. Previous studies concluded that renal complications in this disease most often occur in patients with mitochondrial encephalomyopathies. We describe a boy with mitochondrial disease who presented with proteinuria while lacking neuromyopathy. Proteinuria was detected at the age of 6xa0years, including large amounts of low-molecular-weight proteins such as β2- and α1-microglobulin. Renal functions were normal. Proximal tubular dysfunction and other renal manifestations were absent. Episodic neurologic problems such as migraine and nervous system diseases including epilepsy, depression, schizophrenia and amytrophic lateral sclerosis (ALS) were found in the boy’s family members. Renal tubular basement membrane atrophy and interstitial fibrosis with mononuclear cell infiltration were observed. Ultrastructural examination showed mitochondria, mainly in the proximal tubules, which varied in size and had disoriented cristae. Mutation analysis using mitochondrial DNA (mtDNA) extracted from renal tissues demonstrated a A→G point mutation at nucleotide position 3243 in the tRNALeu(UUR) gene, while there was no mutation found in mtDNA extracted from peripheral leukocytes. Awareness among pediatricians of mitochondrial disorders, detection of low-molecular-weight proteinuria, renal ultrastructural examination and mutation analysis of mtDNA obtained from renal tissues could be important for early diagnosis of this disease.

A tubulointerstitial nephritis antigen gene defect causes childhood-onset chronic renal failure.

Tubulointerstitial nephritis antigen (TIN-ag), which has been localized to the renal tubular basement membrane, is a target antigen in some forms of TIN. Physiologically, TIN-ag is thought to be important in maintaining the structure of renal tubular basement membrane. Here we describe a child with chronic renal failure showing a human TIN-ag gene (hTIN-ag) deletion. Immunohistochemical examination using an antihuman TIN-ag monoclonal antibody showed attenuation or lack of TIN-ag staining along the renal tubular basement membrane, whereas nephrocystin staining was normal in renal tubules. Polymerase chain reaction detected no amplification band corresponding to hTIN-ag in this patient. Testing for a deletion in this gene showed nearly complete deletion. By using array-comparative genomic hybridization method, large deletion of a gene mapped on chromosome 6p11-6p12 was demonstrated, corresponding to the locus where hTIN-ag is located. Therefore, an hTIN-ag defect may be a potent cause of end-stage renal failure in childhood.

Clinicopathologic features, outcome, and therapeutic interventions in four children with isolated C3 mesangial proliferative glomerulonephritis

Since isolated C3 mesangial proliferative glomerulonephritis in the absence of systemic disease (i-C3-GN) is an uncommon chronic glomerular disease, long-term prognosis and optimal therapeutic intervention for it are not yet fully defined, especially in children. We report clinical features, outcome, and interventions in 4 patients, ranging from 6 to 18 years old, with i-C3-GN. Microscopic or macroscopic hematuria with or without proteinuria was first noted between 3 and 8 years. When present, proteinuria ranged from 0.2 to 1.0xa0g/24xa0h. Persistent hypocomplementemia and circulating immune complexes were found in 1 patient. None of the patients had nephrotic syndrome or hypertension. Percutaneous renal biopsy specimens showed varying degrees of mesangial proliferative glomerulonephritis; 2 patients showed mild mesangial proliferation, while others exhibited moderate histologic severity. In 1 patient with a mild mesangial increase, tubulointerstitial changes were associated. Both patients exhibiting mild mesangial changes followed a benign clinical course with normal renal function over 10 years of follow-up. Patients with moderately severe mesangial alteration manifested slight renal function loss and moderate proteinuria at the time of biopsy, but these largely resolved after a six-month course of prednisolone combined with cyclophosphamide, warfarin, and an angiotensin-converting enzyme inhibitor. Thus, clinical manifestations and the need for aggressive treatment appear to vary among pediatric patients with i-C3-GN. Therapy combining prednisolone with immunosuppression seemed to reduce proteinuria and improve glomerular function in patients with moderately severe mesangial proliferation.

Clinical manifestations and analyses of the cytotoxic T-lymphocyte associated-4 gene in two Japanese families with systemic lupus erythematosus

Although still incompletely understood, the etiology of systemic lupus erythematosus (SLE) is considered to involve both genetic and environmental factors. We encountered two boys with severe SLE from unrelated families and analyzed the gene that encodes cytotoxic T-lymphocyte-associated (CTLA)-4, a protein important in T-cell activation and immune tolerance. Abnormal function of the gene may participate in causation of autoimmune disease, including SLE. In familyxa01, a boy showed serious cardiovascular complications associated with heart failure, and his mother also had clinically active SLE, including nephritis. A boy in familyxa02 developed severe renal complications and peripheral vasculitis accompanied by disseminated petechiae in the lower extremities. His paternal grandfather had died from fibrinous pneumonia caused by SLE. They showed high SLE Disease Activity Index (SLEDAI) score. Analysis of the CTLA-4 gene indicated that the boy in familyxa01 and his mother and the boy in familyxa02 possess a GG genotype in CTLA-4 exonxa01 at +49 together with a 106-bp fragment length of the 3′ untranslated region (UTR) in exonxa04. No association with disease activity was found for polymorphism of the promoter region in exonxa01 at −318 in either family. Disorders of the CTLA-4 gene, especially a GG genotype in exonxa01 at +49 and/or 106-bp fragment length of the 3′UTR in exonxa04, may be involved in early development of SLE in Japanese children, such as the boys described here.

Antiproliferative effect of fluvastatin and thiazolidinedione in mesangial cells of diabetic rats

Treatment with hydroxymethylglutaryl coenzyme A reductase inhibitors and thiazolidinedione derivatives may prevent the development of diabetic nephropathy. The precise mechanisms of the beneficial effects of these agents in mesangial cells are uncertain. We cultured mesangial cells from Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for human type 2 diabetes mellitus. The effects of fluvastatin and/or troglitazone on DNA synthesis were determined. Fluvastatin in combination with troglitazone markedly inhibited DNA synthesis and induced apoptosis in mesangial cells from OLETF rats. Combined therapy with fluvastatin and thiazolidinedione derivatives may be effective for suppression of mesangial cell proliferation in the early phase of diabetes, thereby possibly slowing the evolution of diabetic glomerulopathy.

Newly-identified symptoms of left renal vein entrapment syndrome mimicking orthostatic disturbance

BackgroundIn addition to the urinary abnormalities, symptoms of left renal vein entrapment between the aorta and superior mesenteric artery (left renal vein entrapment syndrome, LRVES) may include abdominal and flank pain as well as chronic fatigue. We investigated various LRVES symptoms in this study.MethodsIn 53 pediatric LRVES patients treated at our department, 22 had a score of 5 points or higher on orthostasis. Initial evaluation of LRVES by abdominal ultrasonography showed a stenotic-to-prestenotic vein diameter ratio of 0.2 or less. Definitive diagnosis was made by computed tomography and magnetic resonance angiography. Cortisol, catecholamine (CA), and brain natriuretic peptide (BNP) were also measured.ResultsThe frequency of LRVES was 2.5 times higher in girls than in boys. Low or very low body mass indexes were seen in both sexes. The most common initial finding was urine abnormalities, followed by dizziness and malaise. In 6 patients, orthostasis precluded school attendance. Ten patients had orthostasis scores above 12. Patients unable to attend school had either low levels of plasma or urinary cortisol. Midodrine significantly decreased orthostasis scores. Some patients required treatment with fludrocortisone. Plasma CA, renin, and BNP levels were all normal.ConclusionsLocally excessive venous pressure may cause reversible adrenal dysfunction with transitory Addisonian symptoms. Children with cryptogenic malaise or severe orthostasis should be evaluated for LRVES.

Low-density lipoprotein adsorption therapy can restore drug sensitivity for immunosuppressants via inhibitory effects upon MDR-1 gene expression.

In two patients with steroid‐resistant nephrotic syndrome (SRNS), we investigated the relationship between clinical findings during immunosuppressive therapy and multiple drug resistant gene‐1 (MDR‐1) expression. MDR‐1 was detected by real‐time polymerase chain reaction (PCR). In a boy who initially developed SRNS at 3u2003years, we observed MDR‐1 expression over 3u2003years. Maximal and minimal MDR‐1 expression were 90u2003000 and 7800 copies/µg RNA, respectively. In a 4‐year‐old boy who initially developed SRNS at 3u2003years, we determined MDR‐1 expression over 2u2003years. Maximal and minimal MDR‐1 expression were 42u2003000 and 6900, respectively. MDR‐1 evaluation requires determination of MDR‐1 expression at several time points in a clinical course. Establishment of a normal expression may be needed for each individual patient. Increasing MDR‐1 during remission was followed soon by recurrences, an observation that may be a guide for therapeutic choice. LDL influences a humoral factor involved in MDR‐1 expression. Both patients responded to LDL adsorption therapy because of elevated LDL levels. While cyclosporine A therapy gradually decreased MDR‐1 expression, LDL adsorption therapy decreased expression sharply. Based on the results of the present study, LDL adsorption therapy could contribute to the amelioration of drug sensitivity for immunosuppressants including corticosteroids via inhibitory effects on MDR‐1 expression.