Proinflammatory cytokines are related to the pathogenesis of EHEC infection and hemolytic-uremic syndrome (HUS). We assessed the kinetics of the release of cytokines such as neopterin, interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)-α and the soluble forms of type I and II TNF receptors during EHEC-induced HUS. Twenty one patients with EHEC-induced HUS were enrolled in this study. Serum concentrations of all cytokines were significantly elevated in patients with severe HUS compared with those in patients with mild HUS. Serum concentrations of these cytokines rapidly and markedly increased, and massive hypercytokinaemia developed in a short time after the onset of HUS in patients with severe HUS. Changes in the number of white blood cells and concentration of serum lactate dehydrogenase were significantly larger between the onset of hemorrhagic colitis and the time of the diagnosis of HUS in patients with severe HUS compared with those in patients with mild HUS. Proinflammatory cytokines play an important role in the pathogenesis of EHEC infection and development of severe complications, including HUS and encephalopathy. Monitoring the cytokine profile may be useful for assessing disease activity of EHEC infections.

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We examined 10 pediatric heavy proteinuria cases of Henoch-Schönlein purpura nephritis (HSPN). They all showed good clinical course by using combination therapy including steroid, ACEI and ARB. Eight patients continuously showed heavy proteinuria (urinary protein excretion of >1.0 g/day/m² body surface area or urine protein-creatinine ratio in the first morning urine of >1.0 g/g) for longer than 1–2 months, and 2 patient showed hypoalbuminemia of < 3.0 g/dL at the onset. Their proteinuria disappeared relatively smoothly after the introduction of treatment. The pathological findings on second renal biopsy revealed improvement in all cases. The close observation for longer than 18 months has been carried out after the cessation of steroid administration. No proteinuria has appeared since then. This study indicates a possibility of effectiveness of combination therapy including steroid, ACEI and ARB for HSPN patients with severe proteinuria.

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Background: Kidney transplant recipients are recognized as patients harboring risk factors for cardiovascular disease (CVD). Therefore, early identification and management of risk factors associated with CVD is important after kidney transplantation. In this study, we measured brachial-ankle pulse wave velocity (baPWV) for evaluating arterial wall stiffness and investigated risk factors associated with CVD in young adult recipients who underwent kidney transplantation during childhood.
Methods: We assessed 33 young adult recipients who underwent kidney transplantation during childhood (mean age at kidney transplantation was 13.1±4.2 years and mean age at the baPWV measurement was 24.4±4.6 years). The baPWV value of more than 1400cm/sec was designated as a cut off value of screening high CVD risk patient with arterial wall stiffness in this study.
Results: Eight of 33 patients (24.3%) had more than 1400cm/sec of baPWV, and were diagnosed as having a CVD risk associated with arterial wall stiffness. According to the cut off value of baPWV, patients were divided into two groups; those were the high baPWV group (baPWV>1400cm/sec.) and the low baPWV group (baPWV≤1400cm/sec.). Blood pressure, frequency in the use of cyclosporine, duration after the kidney transplantation and plasma homocysteine levels were significantly higher or longer in the high baPWV group compared to the low baPWV group. The estimated glomerular filtration rate (eGFR) was significantly lower in the high baPWV group compared to the low baPWV group.
Conclusion: This study suggests that early identification and management of several risk factors associated with CVD is important in young adult recipients who underwent kidney transplantation during childhood.

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Intrarenal renin-angiotensin system activation plays a pivotal role in the pathogenesis of hypertension and chronic kidney disease. Recently, the focus of interest in the renin-angiotensin system has shifted toward the role of the local/tissue renin-angiotensin system in specific tissues. Angiotensinogen is the only known substrate for renin, which in the rate limiting enzyme of the renin-angiotensin system. Because the levels of angiotensinogen are close to the Michaelis-Menten constant values for renin, angiotensinogen levels as well as renin levels can control the renin-angiotensin system activity, and thus, up-regulation of angiotensinogen leads to an increase in the angiotensin II. While most circulating angiotensinogen is synthesized in the liver, the kidneys also produce angiotensinogen. Recent studies using experimental animal models have documented that involvement of angiotensinogen in the intrarenal renin-angiotensin system activation and development of hypertension and chronic kidney disease. Enhanced intrarenal angiotensinogen mRNA and/or protein levels were observed in those experimental models, supported the important roles of angiotensinogen in the development and the progression of the disease. Urinary excretion rates of angiotensinogen provide a specific index of the intrarenal renin-angiotensin system status. Using newly developed human angiotensinogen ELISA, we measured urinary angiotensinogen levels in chronic glomerulonephritis patients and patients with type 1 diabetes in childhood. Urinary angiotensinogen level was positively correlated with diastolic blood pressure, urinary albumin, urinary protein levels, and urinary occult blood in chronic glomerulonephritis patients. Furthermore, urinary angiotensinogen level was significantly increased in chronic glomerulonephritis patients not treated with renin-angiotensin system blockers compared with control subjects. Importantly, patients treated with renin-angiotensin blockers had a marked attenuation of this increase. Also, urinary angiotensinogen level was significantly higher in patients with diabetic nephropathy in the pre-micro albuminuric phase than in control subjects. These results suggest that urinary angiotensinogen reflects intrarenal renin-angiotensin system status in chronic glomerulonephritis and may be an early marker of diabetic nephropathy.

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Cilia arise from basal bodies, which are formed from centrioles, complex microtubule-based structures located within the cytoplasm. Ciliopathies comprise a group of disorders associated with mutations in genes encoding proteins related to formation or function of cilia. As cilia are a component of almost all vertebrate cells, cilia dysfunction can manifest as a constellation of features that include characteristically, retinal degeneration, renal disease and cerebral anomalies. Diverse developmental and degenerative single-gene disorders such as polycystic kidney disease(PKD), nephronophthisis, the Bardet-Biedl syndrome, the Joubert syndrome, and the Meckel syndrome are categorized as ciliopathies.
The PKD are transmitted as autosomal-dominant(ADPKD)or autosomal-recessive(ARPKD)traits. Although both forms of PKD initiate early in life, ARPKD rapidly progresses to kidney failure shortly after birth whereas ADPKD can take many years to reach end-stage renal disease(ESRD). Although both forms of the disease are characterized by the development and expansion of numerous fluid-filled cysts in the kidney as well as defects in multiple other tissues, the distribution of the renal cysts and the other body organs affected vary. Significantly, ADPKD is one of the most common human monogenic diseases with an incidence of 1:200–1,000; it is a systemic disorder, characterized by fluid-filled cysts not only in the kidneys but also in liver, pancreas, and other organs as well as cardiovascular defects and aneurysm. Although the incidence of ARPKD is lower at 1:10,000–40,000 it is associated with a high level of mortality in affected newborns. Most cases manifest in utero or at birth with renal enlargement and biliary dysgenesis. In ADPKD the causative genes are PKD1 and PKD2 that encode polycystin-1 and polycystin-2, respectively, whereas mutations in a single gene, PKHD1, cause ARPKD.
Nephronophthisis is the most common genetic cause of chronic kidney disease within the first three decades of life. Patients usually present with symptoms of polyuria and polydipsia, secondary enuresis and anemia. Presentation may occur during infancy, but more typically in late childhood with progressive renal failure manifesting during early puberty. Ultrasound features demonstrate normal sized kidneys with loss of cortico-medullary differentiation and increased echogenicity. Histologically, nephronophthisis kidneys are characterised by the presence of cortico-medullary cysts, tubular basement membrane disruption and tubulointerstitial nephropathy. Extra-renal involvement has been described in over 10% of cases and primarily involves retinal disease, fibrocystic liver disease, cerebellar vermis hypoplasia and skeletal dysplasia.

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The kidney is susceptible to hypoxia due to a large amount of oxygen consumption and arterial-venous oxygen shunt with subsequent low efficiency of oxygen uptake. Thus, chronic hypoxia of the kidney induced by various mechanisms serves as a final common pathway to end stage kidney disease. Previous studies utilized different methods and demonstrated hypoxia of the kidney in experimental models of various kidney diseases. Recently BOLD-MRI showed hypoxia of the human kidney. Cells are endowed with a defensive mechanism against hypoxia, and hypoxia inducible factor (HIF) serves as a master transcriptional regulator of adaptive genes to hypoxia. Current therapeutic modalities show improvements of hypoxia in the kidney, and development of HIF activators is awaited. Hypoxia changes histone modifications and may induce gene expression in a long term. Epigenetic aspects of hypoxia are a very important issue to be pursued.

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The pathogenesis of idiopathic nephrotic syndrome (INS) has not been clearly understood. Most of the pediatric nephrologists currently considered that immune mediated factor derived from T cell is related in some way to INS. Some clinical findings supporting this hypothesis were shown as follows: the response of the disease to corticosteroids and to alkylating agents, the remission which is occurring in association with measles, and occurance of minimal change nephrotic syndrome (MCNS) in patients with Hodgkin’s disease. Reguratory T cell (Treg) is one of T cell component, which function to maintain the balance between self-tolerance and autoimmunity. It is known that Treg is responsible for the pathogenesis of many autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and myasthenia gravis. Recent reports also suggested the relationship between Treg and INS. We experienced two cases of INS which were thought to be due to reduction of Treg or impaired Treg function. First case was immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome complicated by MCNS. IPEX syndrome is caused by mutations in the FOXP3 gene that result in the defective development of Treg. After bone marrow transplantation, INS in this patients were achieved complete remission. This case imply that reduction of Treg may be cruicial for development of MCNS. Second case was polyglandular autoimmune syndrome (PGA) complicated by INS. The etiology of PGA is currently unknown, however, one of the most leading hypothesis is dysfunction of Treg. This case also imply that impaired Treg may be cruicial for development of INS. Together with previous reports, it is of much interest to consider Treg as one of the pathogenesis of INS. Further studies are needed to define a precise relationship between INS and Treg.

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The efficacy of rituximab (RTX) as the sole therapy for preventing relapses of nephrotic syndrome (NS) is transient in most patients; therefore, the optimal therapy required for maintaining a successful response to a biological agent remains a challenge. We conducted a prospective study to compare the efficacy of cyclosporine (CsA) with that of mycophenolate mofetil (MMF) as maintenance therapy after a single infusion of RTX. Despite the mean number of relapses before RTX treatment being significantly lower in the MMF group than in the CsA group, the rate of sustained remission was significantly higher in the CsA group than in the MMF group. Our study also showed that a single infusion of RTX allowed a decrease in both CsA dose and NS relapse rate; therefore, it may be effective for preventing the progression of CsA nephrotoxicity. We recommend the early initiation of RTX treatment before increasing the dose of CsA in patients with secondary CsA-resistant /severe steroid-dependent NS to avoid the development of chronic nephrotoxicity.

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A 4-year-old girl presented with proteinuria, gross hematuria and renal insufficiency. Laboratory studies revealed normal serum titers of complement and absences of anti-neutrophil cytoplasmic autoantibody (ANCA) and anti- glomerular basement membrane (GBM) antibody. A renal biopsy showed crescentic glomerulonephritis with diffuse tubule-interstitial injury and C3 deposition along the capillary walls of the glomeruli alone in immunofluorescence (IF), so she was diagnosed with idiopathic crescentic glomerulonephritis. Although she required a temporary hemodialysis, urinary findings and renal function gradually improved by intravenously with 9 pulses of methylprednisolone, followed by combinations of prednisolone (PSL), mizoribine (MZB), dipyridamole and warfarin. At 6 years old, the second renal biopsy showed no active lesions in the glomeruli and prednisolone was discontinued. Four months after that, however, hematuria and proteinuria recurred with decreased C3 levels. They do not improve with conservative therapy. As with the first, the third renal biopsy showed the image of severe segmental necrotizing glomerulonephritis, also found Hump. Since electron-dense deposits have been observed in the basement membrane on electron microscopy of the first renal biopsy, it was diagnosed with dense deposit disease (DDD). As during initial, steroid pulse therapy was very effective. Currently, she was treated with PSL and MZB as prevention of recurrence, and angiotensin converting enzyme inhibitor (ACEI)/ angiotensin receptor blocker (ARB) as renal protective effect.

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We experienced a 10-year-old boy with steroid-resistant nephrotic syndrome accompanied with collaptic glomeruli and tubulointerstitial change such as tubules filled with urinary casts, interstitial fibrosis and inflammatory cells in interstitium. In the beginning, it was greatly difficult to wean this patient from full dosage of prednisolone. The introduction of cyclosporine treatment enabled maintaining the remission and weaning steroid. The second renal biopsy was performed one year after combination therapy including cyclosporine treatment, which revealed no remarkable findings. The patient was finally diagnosed with minimal change nephrotic syndrome based on these results, and then prednisolone was stopped. To date, the single use of cyclosporine has been successfully keeping the remission.

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[in Japanese]

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