Once-Daily Low-Dose Cyclosporine A Treatment with Angiotensin Blockade for Long-Term Remission of Nephropathy in Frasier Syndrome.

Cyclosporine A is known to be effective in some genetic podocyte injury. However, the efficacy of cyclosporine A depends on the degree of histopathological findings, and the relationship between long-term use and renal prognosis remains unknown. Frasier syndrome is a rare genetic disorder caused by intronic mutations in WT1, and is characterized by progressive glomerulopathy, a 46,XY disorder of sex development, and an increased risk of gonadoblastoma. We report here a 16-year-old phenotypically female patient with Frasier syndrome. A renal biopsy at the age of seven years showed segmentally effaced podocyte foot processes with no evidence of glomerulosclerosis. Steroid-resistant proteinuria progressed to the nephrotic range at the age of 10 years, which responded to once-daily administration of cyclosporine A with low two-hour post-dose cyclosporine A (C2) levels; she then achieved stable partial remission in combination with renin-angiotensin system (RAS) blockade. At the age of 12 years, examinations for delayed puberty confirmed the diagnosis of Frasier syndrome. The second renal biopsy showed widespread foot process effacement and a minor lesion of segmental glomerulosclerosis without findings suggestive of cyclosporine A nephropathy. She maintained partial remission and normal renal function with the continuation of once-daily low-dose cyclosporine A. The C2 levels required for the remission were between 212 and 520 ng/ml. Cyclosporine A dosages sufficient for maintaining the C2 levels were 1.1-1.2 mg/kg per day. In conclusion, the long-lasting treatment of once-daily low-dose cyclosporine A with RAS inhibition was effective for induction and maintenance of partial remission in Frasier syndrome.

Acne conglobata in a long-term survivor with trisomy 13, accompanied by selective IgM deficiency.

Trisomy 13 (T13) is a congenital chromosomal disorder that is usually fatal within 2 years of birth, and only a few patients have been reported to reach adolescence. Here, we report a male long-term survivor of T13, currently 15 years of age, with a several-year history of extensive acne conglobata (AC) with abscesses on the face and neck. Methicillin-resistant Staphylococcus aureus was consistently isolated from the pustular lesions. Serum IgM levels were extremely low at 10 mg/dl. There were no abnormalities in neutrophil and total B cell number, or in serum IgA and IgG levels. Increased CD8+ T cell counts and inversion of the CD4/CD8 ratio were observed repeatedly. The patient's clinical features and laboratory data support a diagnosis of selective IgM deficiency (SIgMD) with concurrent AC. Immunoglobulin replacement therapy elevated serum IgM levels to the normal range and reduced the severity of AC. We suggest that T13 may represent a syndromic disorder associated with multiple organ malformation and a risk of developing immunodeficiency involving SIgMD. Because pediatric SIgMD is rare and an immunological abnormality in T13 patients has not previously been reported, we describe the patient's clinical course.

Impact of periodontal treatment in combination with tonsillectomy plus methylprednisolone pulse therapy and angiotensin blockade for pediatric IgA nephropathy.

BACKGROUND: We previously reported the efficacy of extensive eradication of infectious foci in oral and ENT lesions, combined with tonsillectomy plus methylprednisolone (MP) pulse therapy, for curing pediatric Henoch-Schönlein purpura (HSP) and HSP nephritis. In the present study, we used this therapy in patients with pediatric IgA nephropathy (IgAN) to assess whether similar results could be obtained. PATIENTS AND METHODS: In 11 pediatric patients newly diagnosed with IgAN, exploration for infectious foci showed severe oral infection, including dental caries and apical periodontitis, in many. The overall decayed, missing and filled teeth score was elevated to 5.91. Two patients had rhinosinusitis. After extensive treatment of infectious foci, patients underwent tonsillectomy plus MP pulse therapy with angiotensin II receptor blockade. RESULTS: Clinical remission was achieved in all patients with pediatric IgAN (various histologic grades). Remission was achieved by 7.2 ± 5.7 months after initiation of steroid therapy, and disappearance of proteinuria by 3.3 ± 3.0 months. The mean duration of oral steroid administration was 9.5 ± 3.6 months. No relapse has occurred during follow-up of 4.3 ± 2.4 y. CONCLUSIONS: Careful examination and thorough elimination of infectious foci in oral and ENT lesions can optimize the effect of tonsillectomy plus MP pulse therapy, promoting recovery from IgAN.

Periodontal and ENT therapy in the treatment of pediatric Henoch-Schönlein purpura and IgA nephropathy.

Henoch-Schönlein purpura (HSP) and IgA nephropathy (IgAN) are both IgA1-related vasculitis caused by vascular deposition of IgA1-containing immune complexes. A pathological role of the tonsils in the development of HSP and IgAN has been suggested. Tonsils are a mucosaassociated lymphoid organ. Since oral and sinonasal cavities are anatomically directly connected to the tonsils, delivering exogenous antigens into the tonsils to induce local and systemic antibody responses, we examined the infectious status of these cavities when we treated HSP and IgAN. In 40 HSP children (6.7±2.5 years), apical periodontitis, rhinosinusitis, and otitis media were identified in 21 (53%, 4.9±2.8 affected teeth), 19 (48%), and 4 (10%) of them, whereas in 11 IgAN children (10.4±2.5 years), these diseases were observed in 6 (55%, 5.8±4.6 affected teeth), 2 (18%), and 0 (0%) of them, respectively. We first treated the patients with extensive eradiation of infectious foci, including antimicrobial treatment and root canal therapy. In 31 HSP patients, such dental and/or ENT therapy resulted in a complete cure without development of nephritis or recurrent attacks. For the remaining 9 HSP and 11 IgAN patients, we further performed tonsillectomy plus methylprednisolone (MP) pulse therapy to control their intractable symptoms, including aggravated purpura, recurrent HSP attacks or nephritis. Using this therapeutic strategy, all of the HSP patients attained clinical remission. All of the IgAN patients with various histological grades also achieved normalization of urinalysis by 7.2±5.7 months after the start of steroid therapy. No relapses were observed in both diseases during followup for 2-10 years. In pediatric HSP and IgAN, apical periodontitis and rhinosinusitis may be involved in abnormal immune responses in both the tonsils and whole body. We conclude that extensive elimination of these infectious foci is beneficial to optimize the effect of tonsillectomy plus MP pulse therapy.

Efficacy of early dental and ENT therapy in preventing nephropathy in pediatric Henoch-Schönlein purpura.

In a previous study, we demonstrated the benefit of tonsillectomy for early recovery from Henoch-Schönlein purpura (HSP) nephritis (HSPN), suggesting the pathological role of tonsils in HSP (Inoue et al., Clin Nephrol 67:298-305, 2007). In this study, we evaluated the efficacy of extensive eradication of infectious foci directly connected to the tonsils, including those involved in oral as well as ear, nose, and throat (ENT) diseases, in reducing the nephropathy in HSP. For this purpose, we examined the focal points of infection in 40 newly diagnosed HSP patients. After these focal points of infection had been identified, they were extensively eradicated; when the clinical course was intractable, we also considered tonsillectomy. After administering such therapy to HSP patients, we prospectively followed them up for 0.6 to 8 years. The identified focal infections included dental caries in 28 (70%), apical periodontitis in 21 (53%), rhinosinusitis in 19 (48%), tonsillitis in five (13%), and otitis media in four (10%) of the 40 patients. Seventeen patients (43%) had more than two simultaneous infectious foci, whereas, in five (13%), no infectious focus was found. In 32 patients, antimicrobial treatment with concurrent dental and/or ENT therapy resulted in a complete cure without development of HSPN or recurrent attacks. In eight patients, we performed tonsillectomy-adenotonsillectomy to treat their clinical symptoms, including aggravated purpura and recurrent attacks of HSP or HSPN. All patients were completely cured. The overall incidence of HSPN was only three out of the 40 patients (8%). Oral and ENT diseases were found with high percentages in HSP patients. Early and extensive treatment for these lesions and tonsillectomy-adenotonsillectomy for intractable cases may prevent the complication of HSPN, contributing to the early curing of HSP.

Reconstruction of tubular structures in three-dimensional collagen gel culture using proximal tubular epithelial cells voided in human urine.

Human proximal tubular (PT) epithelial cells were isolated from urine and monoclonally cultured as monolayers for 1 wk, after which they were subcultured between two layers of collagen gel, designated a "collagen gel sandwich." Under these culture conditions, PT cells formed three-dimensional tubular structures exhibiting distinct polarized cell morphology. Scanning and transmission electron microscopic studies showed that they bore numerous microvilli at the apical surface and that they closely contacted the collagen gel at the basal surface. These studies indicate that PT cells exfoliated in urine still exhibit the potential to proliferate and form organized structures mimicking in vivo tubules. Because of the current lack of useful culture systems for human tubular epithelial cells originating from kidney tissue, we suggest that this unique culture system using voided PT cells in urine could open up new avenues to study not only the mechanisms of morphogenesis but also the physiology of human PT cells.

LPA as a determinant of mesangial growth and apoptosis.

Mesangial cell proliferation is a prominent feature of progression in many forms of renal diseases, including immunoglobulin A nephropathy, lupus nephritis, hemolytic uremic syndrome, and diabetic nephropathy. Platelet-derived growth factor (PDGF) has received much attention as the major mediator of mesangial cell proliferation by autocrine/paracrine mechanisms involving up-regulation of mesangial PDGF and its receptor on mesangial cells. In this review, we wish to spotlight lysophosphatidic acid (LPA), which in combination with PDGF, undoubtedly plays a key role as an autocrine and paracrine mediator in regulating mesangial cell growth. We not only showed that PDGF acts as a bimodal molecule for mesangial cells, inducing mesangial cell proliferation and death simultaneously, but also showed that LPA is a survival factor suppressing PDGF-induced mesangial cell death, thereby remarkably enhancing mesangial mitogenic response by PDGF. We believe that a better understanding of the mechanisms of mesangial cell proliferation by the combined action of PDGF and LPA could lead to novel diagnostic as well as therapeutic strategies, and thus help to better control proliferative glomerulonephritis.