Minimal change nephrotic syndrome and prohibitin-2 gene polymorphism.

BACKGROUND: Patients with minimal change nephrotic syndrome (MCNS) often also have allergic diseases. Abnormalities of Th2-derived cytokines and T-cell functions contribute to development of these diseases. On the other hand, imbalances between reactive oxygen species (ROS) and antioxidants have been implicated in MCNS and progression of atopic dermatitis. ROS, produced mainly within mitochondria, subject cells to oxidative stress, while prohibitin 2 protects mitochondria by increasing tolerance to ROS. Additionally, podocin, a member of the slit diaphragm protein complex, contains PHB-like domain that serves as a signaling platform regulating podocyte function through associated transmembrane proteins. PATIENTS AND METHOD: Then, we performed exome sequencing analysis in five patients with frequently relapsing their MCNS associated with allergic disease and serum IgE concentrations of 2000 IU/L or higher. RESULTS: We detected a heterozygous prohibitin 2 polymorphism, c.873-3_873-2 delCA (rs111523336), in 1 patient. This mutation in exon 9 caused frameshifts in regions connected to splicing sites, where they could disrupt transcription of prohibitin 2. Frequency of this polymorphism in exon 9 is 7.3% among Japanese. Increase in peripheral blood ROS even MCNS remission state suggests the heterozygous prohibitin 2 variant may contribute to give more susceptibility towards the recurrence of MCNS as well as atopic skin disease. This increase may have progression of atopic dermatitis, which sometimes heralded. CONCLUSION: The prohibitin-2 polymorphism may reduce ROS tolerance in glomerular epithelium and led to high local exposure to ROS, increasing permeability of the glomerular basement membrane to result in proteinuria. Imbalance between ROS and antioxidants together with failure of signal transduction in the glomerular slit membrane caused by prohibitin 2 abnormality could have contributed to nephrotic syndrome in our patients. Prohibitin 2 analysis is needed in additional MCNS patients with concomitant allergic disease.

Mild forms of toxic shock syndrome toxin-1-mediated exanthematous disease related to Staphylococcus aureus infection.

The present report describes three patients with toxic shock syndrome toxin (TSST)-1-associated exanthematous disease. In all patients, fever and systemic erythema without hemodynamic disturbance occurred following cellulitis of the lower limbs. At the site of infection, TSST-1 producing Methicillin-susceptible Staphylococcus aureus was detected. They defervesced and erythema resolved in response to administration of an antimicrobial drug, thereby avoiding severe illness. These patients did not meet the criteria for a clinical diagnosis of toxic shock syndrome. Measurement of T-cell receptor Vß2-positive T cells in the peripheral blood early after onset of symptoms was useful for diagnosis.

Non-invasive renal artery embolization for renal dysplasia accompanied by hypertension.

Renovascular hypertension caused by renal dysplasia often is resistant to drug therapy. For a 14-year-old girl with such refractory hypertension, a non-invasive right renal ablation by embolization with anhydrous ethanol using a shepherd 's-crook' balloon catheter, was done. Blood pressure then rapidly normalized. Apart from mild fever after the procedure, no adverse effects occurred. In patients with mild renal artery stenosis and hypertension resistant to anti-hypertensive drug therapy, renal artery embolization may be a useful option.

Guillain-Barré syndrome and Crohn disease: a case report.

Development of both Crohn disease and Guillain-Barré syndrome likely involves autoimmunity associated with excessive inflammatory cytokines. We treated a girl who developed Guillain-Barré syndrome during the course of Crohn disease. Although high-dose γ-globulin therapy administered initially for Guillain-Barré syndrome was ineffective, plasmapheresis ameliorated her acute neuropathic symptoms. Crohn disease was managed with Salazopyrin administration and enteral feeding. Chronic inflammation of the intestinal mucosa caused by Crohn disease can allow presentation of microbial intestinal antigens normally hidden from the immune system. Such presentation could incite an extraintestinal immune response on the basis of molecular mimicry, leading to activation of systemic autoimmunity against the nervous system. Accordingly, concurrence of Guillain-Barré syndrome and Crohn disease in our patient appeared to result from shared autoimmune mechanisms and systemic and local increases in cytokine concentrations. The patient also developed erythema nodosum and gall stones, relatively common complications of Crohn disease. However, Guillain-Barré syndrome is rare.

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

BACKGROUND: In 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. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: Locally excessive venous pressure may cause reversible adrenal dysfunction with transitory Addisonian symptoms. Children with cryptogenic malaise or severe orthostasis should be evaluated for LRVES.

GSTT1 gene abnormality in minimal change nephrotic syndrome with elevated serum immunoglobulin E.

INTRODUCTION: Imbalance between T-helper 1 (Th1) and 2 (Th2) lymphocytes and effects of reactive oxygen species (ROS) upon glomerular capillary walls have been implicated in minimal change nephrotic syndrome (MCNS). METHODS: By polymerase chain reaction and comparative genomic hybridization, we evaluated mutations of the GSTT1 gene (GSTT1), a member of the glutathione S-transferase (GST) supergene family associated with both protection of cells from ROS and control of allergic reactions and serum immunoglobulin (Ig) E. RESULTS: Among 15 children with MCNS, IgE elevation (over 2,000 IU/l) and GSTT1 deletion was found in 2 who showed severe allergic symptoms. Serum ROS concentrations in these 2 patients were significantly higher than in healthy controls or other MCNS patients. In addition, a Th2 shift caused by increased serum interleukin (IL)- 4 was observed. CONCLUSION: These results suggest presence of a GSTT1 abnormality in some children with MCNS having marked serum IgE elevations and various allergic complications. Defective ROS degradation and Th1/Th2 imbalance caused by GSTT1 abnormality could initiate proteinuria leading to MCNS.

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 3years, we observed MDR-1 expression over 3years. Maximal and minimal MDR-1 expression were 90,000 and 7800 copies/µg RNA, respectively. In a 4-year-old boy who initially developed SRNS at 3years, we determined MDR-1 expression over 2years. Maximal and minimal MDR-1 expression were 42,000 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.

Pathogenesis of focal segmental glomerular sclerosis in a girl with the partial deletion of chromosome 6p.

Focal segmental glomerular sclerosis (FSGS) is a leading cause of the nephrotic syndrome and characterized by the sclerosing lesions that affect one or more segments of some glomeruli. We encountered a female patient with a partial deletion of chromosome 6p, who presented proteinuria at age 3 years. Detailed chromosomal analysis disclosed an interstitial deletion of 6p: del(6)(p22.1p22.3). No abnormality such as hydronephrosis or renal agenesis was disclosed by imaging, but FSGS was present in a renal biopsy specimen. The patient is currently 11 years old and shows mental retardation with mild deterioration in the renal function. To address the defective genes in the present patient, we carried out comparative genomic hybridization (CGH), showing that E2F3 on chromosome 6p is absent in this patient. E2F3, a member of the E2F family transcription factors, inhibits expression of vascular endothelial growth factor (VEGF) and induces apoptosis during vascular development. The deletion of E2F3 was also detected by employing a PCR method, suggesting that glomerular architecture had been compromised in this patient. Serum VEGF concentrations were elevated to 177 ± 21.4 pg/mL (upper limit of 33.3 pg/mL), when she was 6 years old, associated with the enhanced expression of VEGF in glomeruli. These findings suggest that the dysregulation of VEGF synthesis caused by the deletion of E2F3 may be associated with development of FSGS. In conclusion, among patients with idiopathic FSGS, an abnormality of E2F3 may exist on chromosome 6p. Therefore, one might consider chromosomal analyses in children with FSGS who have mental retardation.

Renal tubular dysgenesis and tubulointerstitial nephritis antigen in juvenile nephronophthisis.

AIM: The relationship between abnormalities of tubular architecture and tubulointerstitial nephritis antigen (TIN-ag) in juvenile nephronophthisis (J-NPH) was evaluated. METHODS: Sixteen J-NPH patients were examined. Nephrocystin-1, TIN-ag, type IV collagen, Fas antigen and the C5b-9 complement complex were stained by immunohistochemical methods. RESULTS: Renal tubules of patients with J-NPH showed morphological abnormalities of tubular basement membranes (TBM) and frequent apoptosis of tubular epithelial cells. Additionally, the C5b-9 complement complex was deposited within the TBM in the absence of immunoglobulin deposition, suggesting complement-dependent TBM injury. Localization of TIN-ag in the TBM of J-NPH patients disclosed a partial defect or discontinuity in 14 of the 16 patients, while type IV collagen immunoreactivity was relatively preserved. These findings suggest that tubulogenesis is disturbed during nephronogenesis in J-NPH patients because of a defect in nephrocystin, an NPHP gene product. TBM defects induce further morphological abnormalities such as cystic dilation of tubules; as tubular function impairment advances, the incomplete tubules may be injured by C5b-9 complement complexes, followed by apoptotic cell death. CONCLUSION: TIN-ag, which is important in early nephrogenesis, lacks normal activity, and vulnerable and incomplete tubules with deficient TIN-ag expression are formed. Removal of these defective tubules by apoptosis combined with the C5b-9 complement complex could be the primary reason for progression to end-stage renal disease in J-NPH patients.

Cyclosporine A causes maturation failure in embryonic-type glomeruli persisting after birth.

INTRODUCTION: We analyzed renal histologic and immunohistologic findings in children with nephrotic syndrome (NS) who did (n=5) or did not (n=17) develop cyclosporine A (CyA) nephropathy despite appropriately low serum CyA concentrations being maintained over 2 years. METHODS: To discriminate embryonic-type from mature glomeruli, we performed staining for type IV collagen a1, laminin ß1 and laminin ß2. Staining patterns were used to semiquantitatively assess glomerular immaturity (glomerular immaturity index, or GII). RESULTS: In follow-up biopsy specimens, residual embryonic-type, collapsed embryonic-type and sclerotic glomeruli that had failed to differentiate were observed. Patients with early-onset CyA nephropathy had a high GII. In patients with a high GII, arteriopathy developed early in CyA treatment. Arteriopathy was observed mostly near embryonic-type glomeruli. Taken together, these glomeruli (surviving embryonic-type, collapsing embryonic-type, and sclerotic glomeruli) essentially equaled the total number of embryonic-type glomeruli in specimens obtained before CyA treatment. CONCLUSION: Our findings indicate a need for caution in CyA therapy for patients with NS, even for a relatively short course of administration, because some patients may have embryonic-type glomeruli or immature arterioles that predispose them to CyA nephropathy.

A patient with Henoch-Schönlein purpura manifesting unusual symptoms and clinical course.

We evaluated and treated a girl with Henoch-Schönlein purpura (HSP), who initially developed redness, swelling, and pain in all 4 limbs accompanied by Raynaud syndrome and then had convulsions and disturbance of consciousness. HSP was diagnosed based on later findings of purpura in both legs and a decrease in factor XIII activity not accompanied by thrombocytopenia. She was normotensive. A skin biopsy specimen showed small-vessel vasculitis accompanied by immunoglobulin A deposition. The cause of erythema and limb pain, convulsions, and disturbed consciousness presumably was vasculitis. The possibility of HSP should be considered in patients with limb pain despite initial absence of purpura and in patients with central nervous system symptoms such as convulsions.

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.

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 family 1, a boy showed serious cardiovascular complications associated with heart failure, and his mother also had clinically active SLE, including nephritis. A boy in family 2 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 family 1 and his mother and the boy in family 2 possess a GG genotype in CTLA-4 exon 1 at +49 together with a 106-bp fragment length of the 3' untranslated region (UTR) in exon 4. No association with disease activity was found for polymorphism of the promoter region in exon 1 at -318 in either family. Disorders of the CTLA-4 gene, especially a GG genotype in exon 1 at +49 and/or 106-bp fragment length of the 3'UTR in exon 4, may be involved in early development of SLE in Japanese children, such as the boys described here.

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. METHODS: MMF therapy was given to 11 patients with FRNS who had relapse despite CyA therapy, and one patient with SRNS who had been receiving combined therapy using steroid and CyA until immediately before the start of MMF. MMF was administered at a daily dose of 750-1000 mg/m(2) in two divided doses. RESULTS: Ten of the 11 patients with FRNS were able to maintain remission. Among them, seven patients remained relapse free for 1 year, and two patients had a decrease in the frequency of relapse after initiation of MMF therapy. One patient, however, had repeated cycles of remission and relapse, and was considered resistant to MMF therapy. The total prednisolone dose during the period from month 6 to month 12 after the start of MMF therapy was significantly lower than that during the 6 month period before the start of MMF therapy. The patient with SRNS, who had not achieved remission despite CyA administration, had complete remission on MMF. No serious adverse effects were seen in any of the present patients. CONCLUSION: MMF could be useful in CyA-treatment-refractory FRNS and CyA-resistant SRNS.

A boy undergoing maintenance hemodialysis who developed mediastinal lymph node tuberculosis.

The incidence of tuberculosis (TBC) in patients undergoing maintenance hemodialysis is reported to be higher than that in the general population. We report an 8-year-old boy receiving such treatment for chronic renal failure who developed mediastinal lymph node TBC. He showed only intermittent fever, recurring every 2 weeks, with no other symptoms suggesting TBC. Although staining and culture of pharyngeal swab and gastric juice specimens failed to provide evidence of TBC, a lymph node biopsy specimen disclosed typical pathologic findings of tuberculoma, including caseating granulomas. Antituberculous therapy with isoniazid (INH), rifampicin, pyrazinamide, and ethambutol was given for 12 months, resulting in complete resolution of the TBC, with no subsequent recurrence. To our knowledge, mediastinal lymph node localization of TBC is relatively rare, in a patient on maintenance hemodialysis, especially in a child.

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 1.0 g/24 h. 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.

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 6 years, including large amounts of low-molecular-weight proteins such as beta(2)- and alpha1-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 tRNA(Leu(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.

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.

Comparison of antiproteinuric effects of two different combination therapies in children with IgA nephropathy.

BACKGROUND: Because moderate or severe proteinuria is a representative factor indicative of longterm poor prognosis in IgA nephrology, an anti-proteinuric treatment which can be administered longterm with few side effects is necessary. We report here a comparison of antiproteinuric effects in two patient groups treated with different combination therapies. METHODS: Group A comprised 12 patients with IgA nephropathy, who had 24-h proteinuria of 0.5 gm(2) or more, moderately severe renal histology, and normal renal function, and were treated with a combination of drugs, i.e., prednisolone, an immunosuppressant (mizoribine), an anti-platelet drug (dipyridamole), and an angiotensin-converting enzyme inhibitor. Group B consisted of 18 patients who had baseline characteristics similar to those of the patients in group A and were treated with our previous protocol (a combination of prednisolone, cyclophosphamide, and dipyridamole). Twenty-four-hour proteinuria and creatinine clearance were measured every 6 months. The primary endpoint was reduction of 24-h proteinuria by less than 25% compared with the baseline value. RESULTS: The proportion of patients that exhibited the primary endpoint, as assessed by the Kaplan-Meier method, was found to be significantly higher in group A than in group B (logrank test; P = 0.024). None of the patients in the two groups experienced serious adverse effects. CONCLUSIONS: The results suggested that the use of drugs in combination with cyclophosphamide was beneficial for patients with moderately severe IgA nephropathy. Because moderate or severe proteinuria is a representative factor indicative of longterm poor prognosis in IgA nephropathy, an anti-proteinuric treatment which can be administered longterm with few side effects is necessary. We report here a comparison of antiproteinuric effects in two patient groups treated with different combination therapies.

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

We describe a patient with IgA nephropathy associated with Crohn disease. IgA nephropathy first appeared at the age of 10 years. 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 13 years, 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.