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Background: There are few published reports on kidney transplantation (KT) in physically handicapped patients with mental retardation. The aim of this study is to clearly identify the outcome of KT in these patients and clarify whether handicapped patients can be candidates for KT. Methods: Our study identified 25 multiply handicapped transplant recipients from 8 institutions. Causes of mental retardation were chromosomal abnormality in 5 patients, genetic syndrome in 10 patients, developmental brain anomaly in 2 patients, and other or unknown causes in 8 patients. Primary diseases leading to end-stage renal disease were congenital urinary tract anomaly in 12 patients, focal segmental glomerulosclerosis in 3 patients, cystic kidney disease in 3 patients, and other in 7 patients. Results: Twenty-three patients received living-related transplants from a parent and 2 patients received cadaver transplants. Twenty-two patients were on peritoneal dialysis therapy, 2 patients were on hemodialysis therapy at the time of KT, and 1 patient underwent preemptive KT. Eleven acute rejection episodes occurred in 8 patients. All episodes were completely reversed with treatments that included mainly methylprednisolone pulse therapy. Posttransplantation lymphoproliferative disorder occurred in 2 patients. Follow-up data showed that all grafts were functioning during a mean observation period of 41.1 months (range, 4 to 187 months). All persons providing primary support for patients were satisfied with the KT and believed that quality of life was improved in both transplant recipients and themselves. Conclusion: Results indicate that KT is not contraindicated in handicapped patients, but cannot determine which patients are unsuitable to undergo KT.

A prospective trial of adrenocorticostertoid (steroid) withdrawal after pediatric renal transplantation was begun in 1990. Ninety-four pediatric renal transplant recipients were enrolled in our multicenter study. Immunosuppressive therapy with cyclosporine (CyA), methylprednisolone (MPL), and mizoribine (MZ) was started after transplantation. MPL was reduced to administration on alternate days in 69 patients (73.4%) and was withdrawn in 27 patients (28.7%). Rejection episodes occurred in nine patients (33.3%) after withdrawal of MPL. It occurred within 3 months after withdrawal of MPL in two patients and more than 6 months in the others. Among them, two patients lost the grafts. Thirteen-year patient survival rate and graft survival rate were 94.6 and 83.1%, respectively. Forty-four of the 94 patients reached their final height. Mean final height was 155.0 cm in males and 146.3 cm in females and their height standard deviation score was -2.6 s.d., the same as that at the time of transplantation. Management of growth retardation before transplantation and further reduction in the steroid dose after transplantation will increase the final height of children with chronic renal failure.

We report the case of a 4.5-year-old girl with microscopic polyangiitis (MPA) manifesting antineutrophil cytoplasmic autoantibody (ANCA)-positive necrotizing crescentic glomerulonephritis and pulmonary hemorrhage. She was initially on induction therapy with corticosteroids and azathioprine. Plasma exchange (PE) combined with immunosuppressants was used to treat an episode of recurrent pulmonary hemorrhage, and achieved remission. At 9.8 years of age her kidney disease relapsed, associated with renal dysfunction and increased proteinuria. To minimize the toxic effects of immunossuppressants, she was treated with PE again, and her renal dysfunction resolved. Plasma exchange was effective in reducing the risk of death and preserving long-term renal function without the severe adverse effects of immunosuppressants. Our preliminary results indicate that PE is likely to be a treatment option for children in acute phase of ANCA-associated MPA, who should be protected from the toxic effects of immunosuppressants.

A retrospective investigation was conducted by members of the Japanese Society for Pediatric Nephrology from 1990 to 1997 to define the clinical features and outcomes in children with antineutrophil cytoplasmic autoantibody (ANCA)-positive glomerulonephritis associated with propylthiouracil treatment. Seven Japanese pediatric patients who had myeloperoxidase-specific ANCA-positive biopsy-proven pauci-immune necrotizing crescentic glomerulonephritis associated with propylthiouracil administration were entered in the study. Three patients had nephritis alone, and four had nephritis and extrarenal organ system vasculitis. Females predominated, and the mean age at onset was 14 yr. Propylthiouracil was reduced or discontinued in all patients and was switched to methimazole in three patients. For the treatment of nephritis, five patients received corticosteroids; three had pulse methylprednisolone, one had plasma exchange, and one had plasma exchange and pulse methylprednisolone before initiating oral prednisolone. The remaining two patients received cyclophosphamide and corticosteroids, one of whom had pulse methylprednisolone before initiating oral prednisolone and cyclophosphamide. All patients achieved remission. In general, ANCA titers correlated with the response to treatment and disease activity, with some exceptions. No patient progressed to end-stage renal disease, renal dysfunction, or death during the follow-up period (58 +/- 25 mo; range, 32 to 108 mo). All but one patient remained euthyroid. In conclusion, this experience suggests that the clinical disease spectrum of ANCA-positive disease associated with propylthiouracil treatment is similar in pediatric and adult patients and that the overall prognosis may be better than that in the non-drug-induced ANCA-positive disease.

小児慢性腎不全患者における維持血液透析 (HD) ではブラッドアクセスが大きな問題である. 今回, 小児維持HD患者における長期留置用ダブルルーメンカテーテルの有用性を明らかにする目的で, Hickman Catheter® (Bard社) 使用群とPerm Cath® (Quinton社) またはHEMO-CATH® (Medcomp社) カテーテル使用群間で合併症の種類やその頻度について比較検討したので報告する. 16例の小児慢性腎不全患者 (平均年齢6.2歳, 平均体重14.1kg) で使用された合計19本のカテーテル (Hickman Catheter® 12本, Perm Cath® 2本, そしてHEMO-CATH® 5本) を対象とした. Hickman Catheter®では他の2種に比べて脱血不良や返血圧上昇が, 一方, Perm Cath®やHEMO-CATH®ではカテーテル内血栓, 出口部感染, そしてカテーテルの押出しが合併症として問題であった. 平均留置期間は5.2か月 (0.8-19か月) で, 4本は菌血症や脱血不良にて抜去されたが, 13本のカテーテルは腎移植や腹膜透析への移行のために選択的に抜去され, 残り2本は現在も使用中である. 以上の結果より, 小児のブラッドアクセスとして長期留置用ダブルルーメンカテーテルは有用であるが, その使用に際しては, カテーテルの特性を十分に考慮することが重要と思われた.

Growth impairment is a major complication of chronic kidney disease (CKD) in children. However, no cohort studies have examined the growth of Asian children with pre-dialysis CKD. We sent cross-sectional surveys to 113 Japanese medical institutions that were treating 447 children with CKD stages 3–5 in 2010 and 2011. Of 447 children included in our survey conducted in 2010, height and CKD stage were evaluable for 297 children in 2011, and height standard deviation score (height SDS) was calculated in these children. Height SDS decreased with increasing CKD stage (P

We report a case of atypical hemolytic uremic syndrome (aHUS) in a 4-year-old boy. Although the patient had the typical triad of aHUS (microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury), urgent dialysis was not indicated because he had neither oliguria nor severe electrolyte abnormality. He was given eculizumab as first-line therapy, which led to significant clinical improvement, thus avoiding any risk of complications associated with plasma exchange and central venous catheterization. Retrograde functional analysis of the patient's plasma using sheep erythrocytes indicated an increase in hemolysis, suggesting impairment of host cell protection by complement factor H. The use of eculizumab as first-line therapy in place of plasma exchange might be reasonable for pediatric patients with aHUS.

The risk of progressing to end-stage kidney disease (ESKD) and factors associated with progression in children with chronic kidney disease (CKD) are unclear, especially in Asian children.We started a nationwide, prospective cohort study of 447 Japanese children with pre-dialysis CKD in 2010, with follow-up in 2011. Progression to ESKD was analyzed by Kaplan-Meier analysis according to CKD stage. Cox regression analysis was used to identify risk factors for progression.Data were analyzed for 429/447 children. Five patients died, of which four died before progression to ESKD. Fifty-two patients progressed to ESKD (median follow-up 1.49 years), including 9/315 patients with stage 3 CKD, 29/107 with Stage 4 CKD and 14/25 with Stage 5 CKD. One-year renal survival rates were 98.3, 80.0 and 40.9%, for Stages 3, 4 and 5 CKD, respectively. Risk factors for progression to ESKD included CKD stage [versus Stage 3; Stage 4: hazard ratio (HR) 11.12, 95% confidence interval (CI) 4.22-29.28, P0.001; Stage 5: HR 26.95, 95% CI 7.71-94.17, P0.001], heavy proteinuria (2.0 g/g urine creatinine; HR 7.56, 95% CI 3.22-17.77, P0.001) and age (2 years: HR 9.06; 95% CI 2.29-35.84, P = 0.002; after starting puberty: HR 4.88; 95% CI 1.85-12.85, P = 0.001).In this cohort, 12.5% of children with pre-dialysis CKD progressed to ESKD with a median-follow-up of 1.49 years. Children with advanced (Stage 4/5) CKD were particularly likely to progress. To our knowledge, this is the first, nationwide, prospective cohort study of children with pre-dialysis CKD in Asia.

A 38-yr-old man with factor H dysfunction and unknown glomerular disease received first and second renal transplantations (Tx) from living-related donors. His examination showed a low percentage activity of factor H (31%). Factor H dysfunction has been known to be associated with type II or III membranoproliferative glomerulonephritis (MPGN), haemolytic uraemic syndrome and IgA GN. The first graft from his mother showed diffuse mesangial deposit of IgA. His son has had IgA GN and his data also revealed a low percentage activity of factor H (33%) He and his son both showed a low activity of C3. Moreover, his father, who was the donor of the second Tx, had a low percentage activity of factor H (25%), and presented with mild glomerular deposit of C3 at operation, while he has been healthy through his entire 67 yr of life. Each of them had a low percentage activity of factor H. These findings through three generations suggested the inheritance of factor H dysfunction. The patient presented with proteinuria 3 months after the first Tx. At the first biopsy 30 months after the first Tx, light microscopy revealed minor glomerular abnormalities with electron dense deposits in subepithelial, intramembranous and mesangial regions, while immunofluorescence showed massive glomerular deposits of C3. In the second biopsy 51 months after the first Tx, the glomerulonephritis developed mesangial proliferation and crescent formation, accompanied by more massive C3 deposit and intramembranous, mesangial and subepithelial dense deposits. He then required redialysis. At the second and third biopsies within 2 months after the second Tx, the renal graft showed similar findings to the first biopsy after the first Tx. He perhaps presented with a recurrence of complement-associated GN, showing an atypical form of MPGN after Tx. These findings suggest that factor H dysfunction may play an important role of a certain pathogenesis of GN.

Background Posttransplant recurrence is frequent in patients who received renal transplantation for focal segmental glomerulosclerosis (FSGS). The recurrence has been ascribed to a circulating permeability factor or factors. We have used plasmapheresis (PP) to treat recurrent FSGS and also studied whether preoperative PP is effective in preventing recurrence of FSGS. Methods We retrospectively analyzed 21 allografts of 20 patients with nephrotic syndrome and biopsyproven FSGS. They were divided into two groups depending on whether they had prophylactic PP; a prophylactic (n=15) and a nonprophylactic group (n=6). PP was performed two to three times prophylactically and therapeutically until proteinuria was markedly reduced. In each session, 50-75 ml/kg of the patient's plasma was exchanged with 5-8% albumin. Results FSGS recurred in 9 of 21 allografts, 4 of 6 in the nonprophylactic group, and 5 of 15 in the prophylactic group. Therapeutic PP was performed in seven of nine recurrent patients without definite adverse effect, with satisfactory results except in one patient. Children lost proteinuria after 6 to > 100 sessions of PP and the number correlated with the pretreatment level of proteinuria. The mean follow-up periods were 62.7 and 41.6 months for the prophylactic and nonprophylactic groups, respectively. At the last follow-up, 66.7% of relapsing and 81.8% of nonrelapsing patients had a functioning graft. Conclusion PP appears to be effective for the prevention and treatment of posttransplant recurrence of FSGS, although further consideration of cost/benefit and risks is required before a conclusive judgement can be made.

原発性巣状糸球体硬化症 (FSGS) の組織学的バリアントのひとつであるcellular lesionを, 病初期高度に認めた男児例に対して, LDL吸着療法を行い完全寛解が得られたので報告する. 症例は全身性の浮腫で発症し, ネフローゼ症候群を呈した11歳男児で, 腎生検にて原発性FSGS cellular variantと診断した. 経過中ステロイド抵抗性を示したため, LDL吸着療法を開始したところ完全寛解が得られた.FSGS cellular variantは典型的FSGSと比較して, 腎機能予後は明らかに不良とされている. しかし一方では, 寛解が得られた場合, その予後は良好であったと報告されている. そのためFSGS cellular variantに対する治療上, 寛解を目指して適切な治療を行うことが重要であるが, 本症例の経験より, LDL吸着療法を早期から積極的に実施する意義は大きいと考えられた.

Atypical hemolytic uremic syndrome (aHUS) is rare and comprises the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recently, abnormalities in the mechanisms underlying complement regulation have been focused upon as causes of aHUS. The prognosis for patients who present with aHUS is very poor, with the first aHUS attack being associated with a mortality rate of approximately 25%, and with approximately 50% of cases resulting in end-stage renal disease requiring dialysis. If treatment is delayed, there is a high risk of this syndrome progressing to renal failure. Therefore, we have developed diagnostic criteria for aHUS to enable its early diagnosis and to facilitate the timely initiation of appropriate treatment. We hope these diagnostic criteria will be disseminated to as many clinicians as possible and that they will be used widely.

Dietary advice by dietitians based on various factors of nutrient intake and dietary habit is important for preventing postoperative complications in adult kidney transplant recipients, but little is known about whether such advice is also important for pediatric, adolescent, and young adult kidney transplant recipients. The purpose of this study was to examine the nutrient intake profiles and dietary habits of these recipients and to ascertain the need for dietary advice by dietitians.This study involved 22 kidney transplant recipients with an estimated glomerular filtration rateor =60 mL/min/1.73 m2 with no dietary restrictions. Nutrient intake was measured using a food frequency questionnaire based on food groups and evaluated using the reference values given in the Dietary Reference Intakes for Japanese (DRIs-J)for 2010 and the daily average intake of the National Health and Nutrition Survey Japan, 2010.The mean age of the patients at the time of enrollment was 17.6+/-4.4 years(8.7 28.5 years). Energy and carbohydrate intakes were below the DRIs-J reference value in 18 patients(81.8 %), and the ratio of total fat to total energy was above the DRIs-J reference value in 20 patients(90.9 %). Vitamin B, vitamin B6, magnesium, and zinc intakes were below the DRIs-J reference value in all patients (100 %). Food group intakes that were less than 75 % of the values reported in the National Health and Nutrition Survey Japan were pulses and algae in 18 patients(81.8 %), green and yellow vegetables in 14 patients(63.6 %), other vegetables in 19 patients(86.4 %), and nuts and seeds in 16 patients(72.7 %).This study suggests that dietary advice by dietitians is necessary for pediatric, adolescent, and young adult kidney transplant recipients to improve their nutrient intake and dietary habits.

Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-related vasculitis and nephritis were recently reported in about 30 patients with hyperthyroidism. The objective of this study was to clarify the prevalence of ANCA and the relationship between ANCA and thyroid antibodies in children with Graves’ disease. Titers of myeloperoxidase (MPO)-ANCA in sera of 51 patients with childhood onset Graves’ disease (16 before treatment, 25 and 10 treated with PTU and methimazole, respectively) were measured by enzyme-linked immunosolvent assay. Antithyroglobulin antibodies (TGAbs) and antithyroperoxidase antibodies (TPOAbs) were also measured by RIA in 25 PTU-treated patients. No patients had clinical manifestations of vasculitis and nephritis. MPO-ANCA was positive in 6.7% of patients before treatment and in 64.0% of those treated with PTU and in none of those treated with methimazole. MPO-ANCA had a significantly positive correlation with TGAbs (P < 0.05) and no significant correlation with TPOAbs. These findings show the high prevalence of the MPO-ANCA positivity in PTU-treated childhood onset Graves’ disease, suggesting that PTU may not be preferred as the first line for the treatment of children with Graves’ disease. The significant correlation between MPO-ANCA and TGAbs indicates that the severity of Graves’ disease may be a factor responsible for the MPO-ANCA positivity. The cross-reactivity between MPO-ANCA and TPOAbs may not play a role in the high prevalence of MPO-ANCA in the patients exposed to PTU.

症例は8歳女児で, 原発性巣状糸球体硬化症を原疾患として95年7月に腹膜透析導入となった. 98年11月にアスペルギルス腹膜炎 (起炎菌は真菌のrRNA解析よりAspergillus (Neosartorya) fennelliaeと同定) を発症し, 途中空腸壁の穿孔を合併した. 直ちに, CAPDカテーテルを抜去するとともに, 従来のnon-lipid Amphotericin B (AMPH-B) よりも副作用が少なく投与量の増量が可能であるliposomal AMPH-Bや, 胃酸の作用を必要とせず腸瘻からの投与が可能なItraconazole (ITCZ) oral solutionを導入, さらに適切な栄養管理 (経静脈栄養に空腸人工肛門肛門側からの経腸栄養を併用) など集学的治療にて救命し得た.アスペルギルス腹膜炎は稀な疾患であるが致死的であり, 早期診断と適切な治療が必要であるため, 今回使用したIiposomal AMPH-Bが本邦でも臨床使用できることが望まれる.

Mechanisms of glomerular macrophage infiltration in lipid-induced renal injury. Background A number of studies have demonstrated an important role for macrophages (Mφ) in lipid-induced glomerular injury; however, little is known of the mechanisms that facilitate Mφ infiltration in this disease. This study examined the expression of Mφ chemotactic molecules Mφ colony-stimulating factor (M-CSF) and Mφ migration inhibitory factor (MIF) and leukocyte adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) during the induction of glomerular Mφ infiltration in ExHC rats, a strain that is susceptible to lipid-induced glomerular injury. Methods Groups of five ExHC rats were fed a high-cholesterol diet (HCD) containing 3% cholesterol, 0.6% sodium cholate, and 15% olive oil and were killed after three days or one, two, or six weeks. Control animals were killed on day 0 or after six weeks on a normal diet. Results ExHC rats fed an HCD showed marked hypercholesterolemia in the absence of any increase in plasma triglyceride levels from day 3 and developed mild proteinuria and segmental glomerular lesions at week 6. Immunoperoxidase staining identified a significant increase in glomerular ED1 + Mφ at week 1, which was further increased at week 6, when Mφ-derived foam cells were seen in almost all glomeruli. Many of the infiltrating glomerular Mφ expressed lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4), which are ligands for ICAM-1 and VCAM-1, respectively. Coincident with the induction of hypercholesterolemia on day 3 and prior to significant Mφ infiltration, combined in situ hybridization and immunohistochemistry staining demonstrated a marked up-regulation of M-CSF and MIF mRNA expression by glomerular mesangial cells and podocytes. There was also a significant increase in ICAM-1 and VCAM-1 mRNA expression by intrinsic glomerular cells, including endothelial cells, on day 3 of the HCD. Conclusion These results suggest that hypercholesterolemia can induce a classic proinflammatory response within the kidney glomerulus, involving production of well-described Mφ chemotactic and adhesion molecules, which results in Mφ recruitment and the development of glomerular injury.

To clarify the therapeutic role of plasmapheresis (PP) for patients with Henoch-Schönlein purpura (HSP) nephritis, the clinical courses of nine children with a rapidly progressive type of HSP nephritis, who were treated with PP as the sole therapy, were retrospectively evaluated. All patients had nephrotic-range proteinuria (4.9 +/- 2.5 g/m2/d, mean +/- SD) and decreased glomerular filtration rate (GFR) (46.5 +/- 9.5 mL/min/1.73 m2) at the time of the initiation of PP. Biopsy specimens taken before PP showed large crescents involving more than 50% of the glomerular circumference in 56.8 +/- 6.9% of the glomeruli examined. The mean interval between disease onset and initiation of PP was 39.1 +/- 22.1 days. The PP regimen consisted of thrice-weekly treatment for 2 weeks, then weekly treatment for 6 weeks. No patients received any steroids or cytotoxic drugs, except for the use of steroids to manage severe abdominal pain. All patients responded promptly to PP with improvement in renal function, reduction of proteinuria, and subsidence of purpuric rash and abdominal pain. Six of nine patients showed further improvements without any other treatments; four had complete recovery, and two had only microscopic hematuria at the latest observation (follow-up period, 9.6 +/- 4.3 years). The remaining three patients showed a rebound increase of proteinuria after completion of PP; two of whom progressed to end-stage renal failure at 14.1 years and 1.8 years after disease onset. Because all patients had the most severe forms of nephritis, reported to carry a grave prognosis, this study suggests that PP as the sole therapy is effective in improving the prognosis of patients with rapidly progressive HSP nephritis, particularly if instituted early in the course of the disease. The role of PP in treating HSP nephritis deserves to be assessed further in larger randomized controlled trials.

低体重の末期腎不全児に対する血液透析を困難にしている最大の原因は, ブラッドアクセスの問題である. 我々は, ブラッドアクセスとして, ダクロンカフ付シリコン性カテーテルであるHickman catheter® (Bard, Utah, USA) を使用し, 以下の知見を得た.対象は, カテーテル挿入時年齢15か月から84か月, 体重7.8kgから13.8kgの小児. 血液透析の適応理由は, 腹膜炎の反復, 生体肝移植後, 膀胱拡大術後, 嚢胞腎による低腹腔容積であった. カテーテル留置に伴う合併症としては, 70か月間血液透析を継続した例の敗血症一度のみであった. また, 生体肝移植後の女児は5時間の血液濾過透析, 他の3例は通常の4時間透析を行い, 透析効率はKt/Vで1.06から1.41であった. 管腔内の血栓形成の予防は, 毎日のheparin sodium注入と一例にのみaspirin少量投与により可能であった.今後, 腎不全小児の病態の多様化により腹膜透析の困難な症例が増加してくると思われるが, Hickman catheter®を使用することにより血液透析も容易に施行できるものと思われる.

The characteristic pathological feature of collapsing glomerulopathy (CG) is marked cell hyperplasia and hypertrophy within the glomeruli. The present study investigated the phenotypic alteration of hyperplastic epithelial cells in CG to determine their origin. Renal biopsy specimens from two patients with CG were analyzed by immunohistochemical staining, using markers for podocytes (PHM-5), parietal epithelial cells (PECs; cytokeratin), and cell proliferation (Ki-67). In collapsed glomeruli, hyperplastic and hypertrophic epithelial cells were frequently connected to PECs and collapsed glomerular basement membranes (GBMs). These epithelial cells were more often Ki-67 positive and expressed cytokeratin, whereas PHM-5 was almost invariably negative. Serial section analysis showed that a small number of hyperplastic epithelial cells expressed both PHM-5 and cytokeratin, suggesting phenotypic conversion between podocytes and PECs. Moreover, cytokeratin-positive cells were associated with the sclerotic glomerular segments. Thus, we suggest that the majority of hyperplastic and hypertrophic epithelial cells in CG are of PEC origin. These epithelial features may participate in the development of characteristic tuft collapse and glomerulosclerosis in CG.

A teenage girl with crescentic glomerulonephritis had antineutrophil cytoplasmic antibody (ANCA) detected after she had received propylthiouracil (PTU) for hyperthyroidism without cutaneous vasculitis. ANCA was detected on admission; renal biopsy showed crescentic glomerulonephritis with focal necrotizing glomerulonephritis but no immune deposits. Administration of steroid and decreasing the dose of PTU produced a good clinical response and the ANCA disappeared. It was concluded that ANCA is closely related to the pathogenesis of crescentic glomerulonephritis and that treatment with PTU appeared to induce ANCA.

Recombinant human growth hormone (rhGH) has been widely used to improve growth in children with chronic renal failure (CRF). However, there has been great concern that GH may aggravate renal disease and hasten the progression to end-stage renal failure. We therefore investigated the effect of prolonged administration of rhGH at various doses on somatic growth and renal function and structure in rats with CRF, divided into four groups based on rhGH dose (vehicle, 0.4, 2.0, and 10.0 IU/day). rhGH was administered subcutaneously daily for 8 weeks. The mean growth was significantly greater in rats treated with high-dose rhGH (10.0 IU) than those treated with low-dose rhGH (P = 0.0089) or vehicle (P = 0.0011). Body weight gain increased in parallel with body length (Creatinine clearance at the end of the experiment was significantly lower in rats on high or medium-dose rhGH than those on low-dose rhGH and controls (P

SUMMARY Although macrophages play an important role in lipid-induced glomerular injury, we know little of the mechanisms by which hyperlipidaemia induces monocyte recruitment. This study investigated the role of M-CSF and macrophage MIF in monocyte recruitment during the development of lipid-induced glomerular injury in the susceptible ExHC rat strain. Groups of five ExHC rats were fed a high cholesterol diet (HCD) containing 3% cholesterol, 0.6% sodium cholate and 15% olive oil, and killed after 3 days, 1, 2 or 6 weeks. Control animals were killed on day 0 or after 6 weeks on a normal diet. Animals were hypercholesterolaemic 3 days after the induction of the HCD, but showed no change in plasma triglycerides over the 6-week period. Glomerular macrophage accumulation was first evident at 1–2 weeks and increased up to week 6, when macrophage-derived foam cells were seen in almost all glomeruli, and segmental lesions and mild proteinuria were also evident. Combined in situ hybridization and immunohistochemistry staining demonstrated that, coincident with the induction of hypercholesterolaemia on day 3, there was marked up-regulation of M-CSF and MIF mRNA expression by intrinsic glomerular cells (mostly mesangial cells and podocytes) which preceded monocyte recruitment. There was a highly significant correlation between the number of M-CSF and MIF-positive cells and glomerular macrophage accumulation over the 6-week period. Although some glomerular macrophages and foam cells exhibited M-CSF and MIF expression, the major source of these molecules was intrinsic glomerular cells. No local macrophage proliferation was observed during the development of glomerular lesions. In conclusion, hypercholesterolaemia caused marked up-regulation of M-CSF and MIF expression by intrinsic glomerular cells, which correlated with monocyte recruitment and the development of lipid-induced glomerular injury. This is the first study to implicate local synthesis of MIF in the pathogenesis of lipid-induced lesions.

高脂血症 (脂質代謝異常) は腎障害惹起・進展因子の一つとして位置づけられ，その治療上の意義が認識されつつある。最近の多くの基礎的研究により，高脂血症 (脂質代謝異常) による腎障害惹起・進展過程では単球・マクロファージが中心的な役割を果たしていること，またその浸潤機序として，酸化リポ蛋白，接着分子，MCP-1，M-CSFなどが関与していること，さらに浸潤マクロファージによる糸球体障害機序についても部分的ではあるが明らかにされた。高脂血症 (脂質代謝異常) と腎障害との関連性については，未だ不明な点や検討しなければならない事項も多いため，今後とも精力的な研究が必要な分野である。

1. It has become possible to perform apheresis in small children owing to the development and clinical application of specialized blood purification devices and equipment, such as vascular catheters for small children and small-volume extracorporeal circuits and modules. 2. Technical considerations include ensuring vascular access, reducing extracorporeal volume, preventing hypothermia, and providing proper anti-coagulant treatment.

In kidney transplantation, it is essential to avoid acute vascular complications, such as hemorrhage and renal vascular thrombosis, which may often lead to allograft loss. Inherited dysfibrinogenemia is a rare coagulation disorder with a wide spectrum of clinical manifestations, such as excessive bleeding and thrombosis. A 12-yr-old boy, previously diagnosed with renal hypodysplasia, was found to have reduced fibrinogen concentrations. Coagulation tests assessing surgical risk during kidney transplantation showed a discrepancy between functional and immunologic fibrinogen concentrations. Gene analysis confirmed inherited dysfibrinogenemia, with a heterozygous mutation in FGA (Aα Arg16His) in the patient and his mother. Based on the molecular and functional properties of the mutation, and a familial phenotype, in which his aunt had experienced a previous bleeding episode, the patient was considered at greater risk of bleeding than of thrombosis. The patient was administered fibrinogen concentrate before surgery, and kidney transplantation was performed with his father as the organ donor. The patient received additional prophylactic infusions of fibrinogen concentrate postoperatively, and his postoperative course was uneventful. Accurate diagnosis of dysfibrinogenemia, including gene analysis, is important for correctly managing patients with this coagulation disorder who are undergoing kidney transplantation.

Background Chronic kidney disease (CKD) in children is a progressive and intractable condition that may severely impair the child's growth, development and quality of life. Epidemiological information on pediatric CKD, particularly in Asians, is scant. Methods We conducted a nationwide, population-based survey of Japanese children aged 3 months to 15 years with pre-dialysis CKD to examine the prevalence of pediatric CKD in Japan. CKD was classified according to newly established criteria derived from reference serum creatinine levels in Japanese children. Surveys were sent to 1190 institutions across Japan to report on cases of pediatric CKD managed as of 1 April 2010. Results A total of 925 institutions (77.7%) responded. Information on 447 children was collected. When subdivided according to our diagnostic criteria, 70.5% of children had stage 3 CKD, 23.9% stage 4 and 5.6% stage 5. The estimated prevalence of Japanese children with CKD was 2.98 cases/100,000 children. Of 407 CKD cases with non-glomerular disease, 278 (68.3%) had congenital anomalies of the kidney and urinary tract (CAKUT). The newly established criteria showed good validity compared with existing criteria, including the abbreviated Schwartz equation. Conclusions Findings from the first nationwide survey of pre-dialysis CKD in Asian children indicate that the prevalence of stage 3-5 CKD in children in Japan aged 3 months to 15 years is 2.98 cases/100,000 children. Most children with CKD presented with non-glomerular disease, most frequently CAKUT. Improved management of CAKUT, including renoprotective treatment and urological intervention, is required.

Hyperlipidemia is not merely a complication but a major exacerbating factor in longstanding nephrotic syndrome (NS). Low-density lipoprotein apheresis (LDL-A) has been reported to ameliorate dyslipidemia and induce rapid remission of NS. Several clinical studies have suggested the therapeutic efficacy of LDL-A, but the level of clinical evidence is insufficient. Therefore, a multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome), was initiated in Japan.Patients with drug-resistant NS were prospectively recruited into the study and treated with LDL-A in facilities that were registered in advance. In the POLARIS study design, the clinical data are to be followed up for 2 years. In the current study, we aimed at evaluating the short-term efficacy based on the treatment outcome of LDL-A immediately after completion of treatment.Along with rapid improvement of hyperlipidemia, LDL-A significantly improved proteinuria and hypoproteinemia after treatment. More than half of the patients showed remission of NS based on the urinary protein level at the completion of LDL-A. The duration of NS before the start of treatment was significantly shorter in patients who responded to LDL-A.An analysis of patients registered in the POLARIS study indicated that LDL-A has short-term efficacy for drug-resistant NS. Rapid relief of dyslipidemia by LDL-A may provide early remission in about half of the NS patients who are resistant to conventional medication. Completion of the POLARIS study may reveal additional long-term effects of LDL-A in these patients.

We evaluated the safety and efficacy of darbepoetin alfa (DA), an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia, in Japanese children with chronic kidney disease (CKD) on peritoneal dialysis (PD) and hemodialysis (HD), and not on dialysis (ND). A total of 31 pediatric CKD patients (13 PD, 2 HD, and 16 ND) were enrolled. DA was administered bi-weekly intravenously (IV) or subcutaneously (SC) for PD or ND patients, and weekly IV for HD patients for 24 weeks. The target Hb was defined as 11.0 to ≤13.0 g/dl. In patients receiving rHuEPO, the initial DA dose was calculated at 1 μg DA for 200 IU rHuEPO. The initial DA dose for naive patients was determined by body weight, and intended not to exceed 0.5 μg/kg per administration. For some PD or ND patients, the dosing frequency was subsequently changed to once every 4 weeks. Mean Hb values increased from 10.5 ± 1.1 to 11.1 ± 1.1 g/dl after 4 weeks of DA treatment. The target Hb was achieved in all patients, 64.5 % of whom maintained the value at completion of the study. Hb responses were similar between IV and SC. The dosing frequency was extended to once every 4 weeks in 37.9 % of PD or ND patients. Eighty-seven adverse events were noted in 27 (87.1 %) of 31 patients, none of which were associated with DA. These results suggest that IV or SC administration of DA is an effective and safe treatment for renal anemia in Japanese children with CKD.

Background Hyperhomocysteinemia (hyper-Hcy) is an important and reversible cardiovascular disease risk factor. We examined the prevalence of hyper-Hcy, plasma folate levels, and dietary folate intake in adolescents and young adults who had undergone kidney transplantation during childhood to assess the necessity for managing dietary folate. Methods This cross-sectional study was performed in 89 kidney transplant recipients (age at kidney transplantation: 12.6 ± 4.1 years; age during study: 21.2 ± 5.5 years). Hyper-Hcy and plasma folate deficiency were defined as plasma homocysteine (Hcy) [15 nmol/ml and plasma folate \3.0 ng/ml, respectively. Results Of the patients, 60 (67.4 %) had hyper-Hcy and 14 (15.7 %) had plasma folate deficiency. Plasma homocysteine levels correlated negatively with estimated glomerular filtration rate (eGFR; r =- 0.565, p \ 0.01) and plasma folate levels (r =- 0.434, p \ 0.01). For determinants of plasma homocysteine levels, a priori selected variables included kind of calcineurin inhibitor, age at kidney transplantation, pretransplant duration of dialysis, time since transplantation, age at examination, eGFR, and plasma folate. Stepwise multiple linear regression analysis revealed eGFR and plasma folate levels as significant independent variables influencing plasma homocysteine levels. Dietary folate intake in 11 of 16 patients (66.8 %) with eGFR C60 ml/min/1.73 m 2 was below the recommended dietary allowance for Japanese. Conclusions The prevalence of hyper-Hcy and plasma folate deficiency, as well as the low dietary folate intake, suggest that dietary management of folate is necessary for adolescents and young adults who have undergone kidney transplantation during childhood.

膜性増殖性糸球体腎炎 (MPGN) に特徴的な組織病変がfocal，segmentalに認められるfocal MPGN例に対する治療・管理方法については未だ一定の見解は得られていない。本研究では，focal MPGN例に対するステロイド治療の有用性を検討する目的で，小児focal MGPN 5例を対象として，ステロイド治療の効果を尿所見，血清補体価，病理組織所見の点から，またその副作用を主に成長障害の点から検討した。その結果，全例でステロイド治療に伴って尿所見，血清補体価，そして病理組織所見の改善がみられ，一方，成長障害を始めとする重篤な副作用は認められなかった。以上の結果より，小児期focal MGPN例に対するステロイド治療は有用であると考えられた。

Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Approximately 10% of cases are classified as atypical due to the absence of Shiga toxin-producing bacteria as a trigger. Uncontrolled activation of the complement system plays a role in the pathogenesis of atypical HUS (aHUS). Although many genetic studies on aHUS have been published in recent years, only limited data has been gathered in Asian countries. We analyzed the genetic variants of 6 candidate genes and the gene deletion in complement factor H (CFH) and CFH-related genes, examined the prevalence of CFH autoantibodies and evaluated the genotype-phenotype relationship in 10 Japanese patients with aHUS. We identified 7 causative or potentially causative mutations in CFH (p.R1215Q), C3 (p.R425C, p.S562L, and p.I1157T), membrane cofactor protein (p.Y189D and p.A359V) and thrombomodulin (p.T500M) in 8 out of 10 patients. All 7 of the mutations were heterozygous and four of them were novel. Two patients carried CFH p.R1215Q and 3 other patients carried C3 p.I1157T. One patient had 2 causative mutations in different genes. One patient was a compound heterozygote of the 2 MCP mutations. The patients carrying mutations in CFH or C3 had a high frequency of relapse and a worse prognosis. One patient had CFH autoantibodies. The present study identified the cause of aHUS in 9 out of 10 Japanese patients. Since the phenotype-genotype correlation of aHUS has clinical significance in predicting renal recovery and transplant outcome, a comprehensively accurate assessment of molecular variation would be necessary for the proper management of aHUS patients in Japan.

Summary: A number of studies have demonstrated an important role for macrophages (Mo) in lipid induced glomerular injury; however, little is known of the mechanisms which facilitate Mo infiltration in this disease. the present study examined the expression of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) during the development of glomerular Mo infiltration in ExHC rats; a strain which is susceptible to lipid induced glomerular injury. Twenty-five male 6 week old ExHC rats were placed on a normal diet supplemented with 3% cholesterol, 0.6% sodium cholate and 15% olive oil (high-cholesterol diet, HCD). Groups of five rats were killed prior to the beginning of the HCD or after 3 days, 1, 2 and 6 weeks on a HCD. A group of five matched ExHC rats on a normal diet served as a control. ExHC rats fed a HCD showed marked hypercholesterolaemia in the absence of any increase in plasma triglyceride levels from day 3 (190 ± 14 vs 42 ± 2 mg/dL in control; mean ± s.e.m., P

小児特発性ネフローゼ症候群 (NS) では大部分の症例がグルココルチコイド療法により寛解するが，NSの発症病理に関するグルココルチコイドの役割は十分に解明されておらず，また治療抵抗性を認める症例の原因も明らかではない。我々はNS患者を中心にステロイド感受性に関するグルココルチコイドの分子作用機序についてその遺伝子転写調節の細胞内メッセンジャーであるグルココルチコイドレセプター (GR) とその発現制御因子についての解析を行った。その結果，頻回再発型ならびにステロイド抵抗性ネフローゼ症候群にGR発現量の低下を高頻度に認め，これらの症例ではGR Down regulationによるステロイド依存性転写調節障害が示唆された。またレセプタ一結合蛋白である熱ショック蛋白はGR発現量と相関することよりグルココルチコイドーGR系の情報伝達が阻害されステロイド抵抗性の原因となることが示唆された。

Darbepoetin alfa (DA) is an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia. Since DA has not been approved by the appropriate Japanese drug regulatory agencies for the indication of renal anemia in children in Japan, we have conducted a multicenter prospective study to determine the efficacy and safety of DA in Japanese children undergoing peritoneal dialysis (PD).Pediatric patients subcutaneously receiving rHuEPO were switched to DA treatment for a period of 28 weeks. The conversion to the initial dose of DA was calculated as 1 μg DA for 200 IU rHuEPO, and DA was administered intravenously once every 2 weeks. The target hemoglobin (Hb) concentration was defined as 11.0 to ≤13.0 g/dL. In some patients, the dose of DA was adjusted appropriately to achieve this target level, and/or the dosing frequency changed to once every 4 weeks.In the 25 patients switched from rHuEPO to DA the mean Hb concentration increased from 9.9 ± 1.0 to 11.1 ± 1.0 g/dL at 8 weeks following commencement of the DA treatment. The target Hb concentration was achieved in 88 % of these patients, and 60 % maintained this target value on completion of the study. The dosing frequency was extended to once every 4 weeks in 60 % of patients. Twenty-four adverse events were noted in 11 of 25 patients (44 %); however, there was no causality between DA and adverse events.The results of this study suggest that intravenous administration of DA once every 2 or 4 weeks is an effective and safe treatment for renal anemia in Japanese children undergoing PD.

The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1 %) by the J-RBR and 680 (16.9 %) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7 %) and 575 other cases (12.3 %) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9 %) and 171 renal grafts (5.1 %) and 3,869 native kidneys (94.2 %) and 237 renal grafts (5.8 %) were registered in 2009 and 2010, respectively. Patients younger than 20 years of age comprised 12.1 % of the registered cases, and those 65 years and over comprised 24.5 % of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4 % and 50.0 % in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4 % and 27.0 %); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6 % and 30.4 %), followed by primary glomerular diseases (except IgA nephropathy) (27.2 % and 28.1 %). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3 %) and minor glomerular abnormalities (50.0 %) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.

The first case of kidney transplantation at our institution was carried out in 1971, and this first renal transplant recipient is still living with a functioning kidney. From 1971 through the end of 2011, more than 3000 cases of kidney transplantation have been carried out at our institution. Since 1983, cyclosporine-based immunosuppression has been employed at our center. During this period, most of the patients were treated with cyclosporine- or tacrolimus-based immunosuppression. The latest outcomes of kidney transplantation seem to have significantly improved compared to earlier periods. Since 2000, 10 year-graft survival is more than 90% in living donor kidney transplantation and 82% in deceased donor kidney transplantation. To resolve the serious problem of donor organ shortage, expansion of the donor pool by various options such as transplantation using extended criteria donation, donation after cardiac death, ABO-incompatible (ABO-ILKT) donors, or crossmatch-positive donors, has been carried out at our institution over the last decade. We performed the first case of ABO-ILKT in 1989, and have performed more than 400 cases at our institution as of 2011. We will describe our experience of kidney transplantation, including ABO-ILKT, sensitized recipients, pathological analysis, pediatric renal transplantation, laparoscopic donor nephrectomy, and recurrent glomerulonephritis. The data shows good outcomes, however, we still have many issues to resolve to improve long-term renal transplant outcome and to reduce complications.

The slit diaphragm (SD) is an intercellular junction between renal glomerular epithelial cells (podocytes) that is essential for permselectivity in glomerular ultrafiltration. The SD components, nephrin and Neph1, assemble a signaling complex in a tyrosine phosphorylation dependent manner, and regulate the unique actin cytoskeleton of podocytes. Mutations in the NPHS1 gene that encodes nephrin cause congenital nephrotic syndrome (CNS), which is characterized by the loss of the SD and massive proteinuria. Recently, we have identified the expression of the transmembrane glycoprotein signal regulatory protein α (SIRPα) at the SD. In the present study, we analyzed the expression of SIRPα in developing kidneys, in kidneys from CNS patients and in proteinuric rat models. The possibility that SIRPα interacts with known SD proteins was also investigated. SIRPα was concentrated at the SD junction during the maturation of intercellular junctions. In the glomeruli of CNS patients carrying mutations in NPHS1, where SD formation is disrupted, the expression of SIRPα as well as Neph1 and nephrin was significantly decreased, indicating that SIRPα is closely associated with the nephrin complex. Indeed, SIRPα formed hetero-oligomers with nephrin in cultured cells and in glomeruli. Furthermore, the cytoplasmic domain of SIRPα was highly phosphorylated in normal glomeruli, and its phosphorylation was dramatically decreased upon podocyte injury in vivo. Thus, SIRPα interacts with nephrin at the SD, and its phosphorylation is dynamically regulated in proteinuric states. Our data provide new molecular insights into the phosphorylation events triggered by podocyte injury.