In most cases, children with idiopathic nephrotic syndrome (INS) are first treated with prednisolone according to the International Study of Kidney Disease in Children (ISKDC) induction protocol (prednisolone at 60 mg/m²/day for 4 weeks, followed by 40 mg/m²/day for 4 weeks). Steroid sensitive nephrotic syndrome (SSNS) is experienced by approximately 90 percent of all patients with INS. We conducted a retrospective analysis of the association between duration of the steroid therapy until the first remission, relapse occurrence in a two year period following the remission and early-stage relapse within six months following the remission. Twenty five patients with SSNS having two or more years of treatment history were enrolled in our study, who were initially treated with prednisolone according to the ISKDC induction protocol, achieved remission within 4 weeks and were able to stop prednisolone therapy in 8 weeks from the start of the steroid therapy. Receiver operating characteristic (ROC) analysis of the association between duration before the first remission and progression to steroid dependent nephrotic syndrome (SDNS) was statistically significant (p=0.027). The best cut-off value was eight days with a sensitivity of 75.0% and a specificity of 76.5%. Fifteen patients achieved remission within 7 days (early remission group) and 10 patients required 8 or more days to achieve remission (remission group). Significantly fewer patients in the early remission group developed to SDNS within two years following the first remission compared to the remission group (13% vs. 60%; p=0.014, χ² test). No significant difference was seen between the duration of the steroid therapy until the first remission and an early-stage relapse (27% vs. 50%; p=0.234, χ² test). Guidelines outlining standardized early-stage indicators for steroid dependency of patients with SSNS are not yet to be established, but several studies have reported the association between the duration of the initial steroid therapy until remission and the possibility of steroid dependency. The results of our study showed that the duration of the initial steroid therapy until remission could be an useful early-stage indicator for long-term steroid dependency of patients with SSNS. If we stratify the risk of patients with SSNS according to the duration needed to achieve the first remission and organize treatment protocol according to the risk stratification, we may be able to improve the treatment outcome of SSNS.

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We often experience difficulty diagnosing upper urinary tract infections in patients without pyuria or typical clinical features, because of antibiotics prescribed by other physicians. We sometimes encounter adult patients with reflux nephropathy or chronic renal failure who have never undergone investigation for vesicoureteral reflux. We always order an ultrasound for pyrexic patients lacking clinical features or without pyuria. Thus, we diagnose upper urinary tract infection based on a positive urine culture or a hypovascular renal lesion using ultrasound and advanced dynamic flow (ADF). In this study, we divided our patients into three groups based on urine culture findings and ultrasonographic findings (defined as having hypovascular lesions or not). The average age was significantly lower in the group with positive urine cultures and no hypovascular lesions than in the other two groups. Premedication with antibiotics was significantly more frequent in the group with negative urine cultures and hypovascular lesions than in the other two groups. The frequency of vesicoureteral reflux was significantly higher in groups with hypovascular lesions of the kidney than in group without hypovascular lesions. It is useful to evaluate renal blood flow with ultrasound and ADF when investigating the origin of a fever and estimating vesicoureteral reflux.

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Five primary school children suffering from remittent fever and abdominal pain were admitted to our hospital; of these children, 2 girls also had acute kidney injury (AKI). Yersinia pseudotuberculosis (Ypt) was detected in the stool samples of 2 patients, serum levels of anti-Ypt 5a antibodies increased in another 2 patients, and the anti-Yersinia pseudotuberculosis derived mitogen (YPM) antibody titer was significantly increased in 1 patient. Thus, all 5 patients were diagnosed with Ypt infection.Ypt infection is an important cause of AKI in healthy children, and tubulointerstitial nephritis (TIN) is the most common histological diagnosis. Ypt infection is known to cause not only AKI but also various conditions such as Kawasaki disease and mesenteric lymphadenitis. YPM, a superantigen produced by Ypt, stimulates many T cells and causes these symptoms. We studied the serum proinflammatory cytokines and the soluble receptors of patients with and without TIN. Levels of serum soluble tumor necrosis factor receptor (sTNFR)-1, sTNFR-2, interleukin (IL)-6, IL-17, and sIL-2Rα were higher in patients with TIN than in patients without TIN. The high levels of sIL2-Rα and IL-17 suggested that the T lymphocytes were activated by YPM. The levels of sTNFR-1 and sTNFR-2 were markedly higher in TIN patients. The tumor necrosis factor alpha (TNF-α) levels in patients with TIN higher than the levels in patients without TIN, but the difference was slight. Although the exact physiological role of sTNFRs remains unknown, the circulatory forms of TNFRs may function as decoys for TNF-α or their concentrations may reflect long-term exposure to this proinflammatory cytokine. Cleavage of TNF-α and TNFRs from the cell surface by a disintegrin and metalloproteinase-17 results in the soluble forms. The regulatory mechanisms of sTNFRs have not been clarified thus far. Some studies have suggested that TNF-α is the main regulator, as it induces TNFR shedding. Thus high levels of sTNFRs in patients with TIN suggest that TNF-α is associated with AKI.

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Renal ultrasonography and screening with a urine dipstick test for leucocytes and nitrite in 3-year-old children have been performed in Chiba City since 1991. We studied the efficacy of this screening for detecting congenital anomalies of the kidney and urinary tract (CAKUT). Screening with a urine dipstick test for leucocytes, nitrite, proteinuria, hematuria, and glucosuria was performed among 154,456 3-year-olds from April 1991 to March 2012 in Chiba City. In the second screening, a urine dipstick test and urinary sediments were detected, and renal ultrasonography was performed among 11,346 children. Children with a positive second screening for urine or renal abnormalities on ultrasonography were referred to hospital. Ultrasound findings included a renal pelvis anteroposterior diameter greater than 5–7 mm, a renal length less than 60 mm, and a difference in bilateral renal length of more than 1 cm. A total of 11,905 children (7.7%) at the first screening had positive urinary findings. Positive urinary findings were detected in 2,347 children (1.5%) referred to hospital. We observed vesicoureteral reflux (VUR) in 16 cases (5 with hematuria, and 11 with significant bacteriuria), Alport syndrome in 6, nephrotic syndrome in 5, focal segmental glomerulosclerosis in 5, chronic glomerulonephritis in 7, and bilateral renal hypoplasia in 1. Positive ultrasound findings were detected in 714 children (6.3%) at the second screening. CAKUT were detected in 92 children (0.8%); 17 of these cases were surgically corrected. Among 27 children with VUR, 3 had only positive urinary findings (1 hematuria and 2 bacteriuria), 13 had positive urinary (4 hematuria and 9 bacteriuria) and ultrasound findings, and 11 had only positive ultrasound findings. Reflux greater than grade III was detected in children with bacteriuria more than in children without bacteriuria (p<0.05). Ultrasound findings associated with renal size were useful for detecting multiple renal scars associated with high-grade VUR. Overall, 1 case with FSGS progressed to end-stage renal failure at 5 years after the first screening. A positive urine dipstick test for leucocytes and/or nitrite and ultrasound findings associated with renal size appear to be useful for detection of CAKUT.

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In 2010, AUA (American Urological Association) revised VUR guideline after more than 10-year interval. Although the guideline was initially supposed not so practical as had been expected, it clearly demonstrated that evidence is still lacking in recent clinical approach to primary VUR. Relevant issues such as CAKUT concept, urodynamics, prenatal diagnosis, and RI study, have been evolving and strongly influenced the approach. One might be able to say that VUR is a medical disease rather than surgical one. At present, large scale RCT has been progressing in north America for the purpose of documenting significance of continuous antibiotic prophylaxis. In young childhood, particularly in girls, voiding dysfunction has been shown to be related deeply and contributory to primary VUR for which medical approach including voiding instruction is essential. Of course, there are special cases with grade 5 VUR for which anti-reflux surgery is mandatory, but such cases are not common. High grade VUR has also been shown not exceptional to spontaneous resolution after as long as 10-year follow-up. However, if not resolved, persistent VUR bears a risk for UTI recurrence in women, especially later in pregnancy. The introduction of endoscopic injection therapy has provided good opportunity for us to decrease invasiveness of anti-reflux surgery. However, long term result after more than 3 years is still unknown. In this review article, the true character of primary VUR is investigated and optimal approach is discussed as well.

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Since 2007, Japanese Society of Nephrology (JSN) started the registration of renal biopsy cases, i.e. Japan Renal Biopsy Registry/J-RBR, which was constructed on the web page of University Hospital Medical Information Network (UMIN) Center. Based on J-RBR experience, JSN reorganized the system including 130 centers and expanded the registration to not only renal biopsied subjects, but also non-renal biopsied refractory renal disease subjects, such as nephrotic syndrome, rapidly progressive glomerulonephritis (RPGN), polycystic kidney diseases (PKD), pediatric kidney disease, and chronic kidney disease, as Japan Kidney Disease Registry/J-KDR. The registered cases were 21,483 at the end of May 2013. The clinical and pathological diagnoses, and clinical data were analyzed every term. In addition, the epidemiological and clinicopathological prospective studies based on J-RBR/J-KDR data of nephrotic syndrome, RPGN, IgA nephropathy, PKD and diabetic nephropathy were promoted to make the qualified clinical evidence of Japanese renal diseases, and to prevent these refractory and chronic kidney diseases in the future.

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Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease and the most important risk factor for cardiovascular events in the world. Microalbuminuria (MA) has been used as a key diagnosis marker for early phase DN, however, there are several problems for sensitivity and specificity for detecting early phase DN. Recent studies suggest that the glomerular structure in diabetic patients with or without MA failed to find a significant difference in the structural changes, even though MA definitely shows a key factor for cardiovascular events. DN is characterized by both mesangial matrix hyperplasia and thickening of glomerular basement membrane. The former finding has a strong correlation with decline of renal function, therefore, it is important to clarify the pathogenetic mechanism of mesangial matrix hyperplasia in DN. We have first shown that Smad1 is a transcription factor for α1 & 2 of type IV collagen (Col4), which is a major component of mesangial matrix hyperplasia. We have also identified Smad1 is a critical responsible molecule for developing mesangial matrix hyperplasia in rat DN. We also have found the good correlation between mesangial matrix hyperplasia and urinary Smad1 but not between mesangial matrix hyperplasia and urine albumin. The study also implicates that both bone morphogenic protein4 (BMP4)-Smad1 signaling pathway as well as angiotensin II (AngII)-Src-Smad1 signaling pathway have played a key role for development of DN. These suggest that it is necessary to clarify the whole mechanism related to Smad1 signaling to identify the pathogenesis of DN.

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Since the discovery of renin 100 or more years ago, the renin-angiotensin system (RAS) has been characterized as the circulating system regulating sodium balance and blood pressure, therefore leads to the application for antihypertensive agents. There is increasing evidence that local RAS is situated in many organs, including kidney where it is involved in renal development, renal function and the progression of chronic kidney disease. This article briefly reviews the new development of RAS in renal issues and points the critical role of RAS in life cycle from prenatal to adulthood.

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In this review, I introduce the strategy developed by our laboratory to explore the mechanisms of progressive glomerulosclerosis leading to renal death, including the animal model of irreversible glomerulosclerosis, imaging analysis of glomerular hemodynamics and therapeutic approach. In particular, I stress that our imaging system allows us to evaluate the progression of disease and the therapeutic effects of renoprotection as a diagnostic tool in the chronic kidney disease resulting in cardiovascular events.

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It is well known that many pediatric kidney diseases are caused by genetic abnormalities. Genetic approach is important for confirmation of diagnosis, precise genetic counseling, better understanding of pathophysiology and supporting clinical management. As diagnostic technologies for genetic approach, we can utilize chromosomal karyotyping, Sanger DNA sequencing, microarray-based comparative genomic hybridization (array CGH), multiplex ligation-dependent probe amplification (MLPA) and next generation sequencing technology. The array CGH and MLPA were recently developed, and are useful for detecting copy-number variation such as deletions and duplications. The next generation sequencing, another recently developed technology, was useful for genome-wide search for gene mutations. In this review, a few cases of childhood genetic renal diseases, mainly congenital anomalies of kidney and urinary tract (CAKUT), whose genetic abnormalities were detected by relatively new techniques, were presented. The study group for rare intractable diseases in kidney and urinary tract funded by the Health and Labour Sciences Research Grants for Research on Rare and Intractable Diseases was set up in 2012 in Japan. In this review, researches in this study group were also introduced.

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Since viral infections may trigger the development of inflammatory renal disease or worsening of preexisting renal disease, recent studies have focused on the involvement of toll-like receptors and their signaling pathways in the inflammatory processes of glomerular cells. Based on our recent experimental studies using human mesangial cells treated with polyinosinic-polycytidylic acid (poly IC), a synthetic analogue of viral dsRNA, we hypothesize that mRNA expression of proinflammatory cytokines/chemokines induced by poly IC in urinary sediment in patients with IgA immunocomplexmediated glomerulonephritis may reflect regional inflammation in the inflamed kidney. Twenty children with newly diagnosed IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (PN) were enrolled in this pilot study. We examined mRNA expression of poly IC-inducible proinflammatory cytokines/chemokines in urinary sediment obtained from study participants. As a result, mRNA expression of presumptive functional molecule, fractalkine/CX3CL1, in urinary sediment significantly reflected regional inflammation in selected patients with IgAN and PN. We therefore believe that measurement of mRNA expressions of cytokines/chemokines in urinary sediment could be used as a noninvasive method to predicate disease activity of glomerulonephritis in children, although this remains to be determined in future studies.

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The hypothesis of ‘Developmental Origins of Health and Disease (DOHaD),’ which proposes that the risk of developing some chronic non-communicable diseases in adulthood is influenced not only by genetic and adult life-style factors but also by environmental factors acting in fetal and infantile life, has been supported by a lot of epidemiological and animal studies. The risk of chronic kidney disease (CKD) is also affected by fetal and infantile environment. It is speculated that the reduction of nephron number caused by the poor environment during fetal and infantile life is involved in the pathogenesis of CKD. Many epidemiological observations have revealed that low birth weight increases the risk of developing CKD in adulthood. We recently reported that some extremely low birth weight infant developed CKD linked to DOHaD hypothesis even in childhood. It is important to know the fetal and infantile environment to make an accurate diagnosis of CKD in childhood. The average of birth weight continues to decrease and the incidence of low birth weight infant (less than 2.5 kg) continues to increase in Japan. It means that big medical and socioeconomic problems are supposed to be occurred in near future. It is important to implement health education perspective on the life cycle.

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Mycoplasma pneumoniae infection is responsible for both respiratory and extra respiratory symptoms, but renal involvement is rare. We here report a 15-year-old girl with gross hematuria appeared 5 days after the onset of low-grade fever and cough. Because of her proteinuria and moderate renal dysfunction, she was referred to our hospital. She was diagnosed as Mycoplasma pneumoniae pneumonia. But hypertension, oliguria and hypocomplementemia were absent, which are often seen in case of acute nephritis. Because her proteinuria and hematuria persisted even after her pneumonia improved, and tubular dysfunction was detected, a percutaneous renal biopsy was performed. The main histopathological finding was acute interstitial nephritis associated with mild IgA nephropathy. Her renal dysfunction was self-limiting, and subsequently she made a full recovery, except for microscopic hematuria. We conclude that Mycoplasma pneumoniae infection had an influence on the development of acute interstitial nephritis.

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We report a 5-month-old boy with megacystis-megaureter syndrome who developed urosepsis after bladder catheterization. Bilateral hydronephrosis, megaureter, and megalocystis were found by prenatal ultrasonography. After birth, bilateral grade V vesicourethral reflux (VUR) was detected by voiding cystourethrogram. Prophylaxis with cefaclor 5 mg/kg/day was initiated. At age 5 months, intravenous pyelography (IVP) with bladder catheterization was performed for preoperative assessment. On the next day, he developed fever and urinalysis showed leukocyturia. Gram-negative rods were detected in his urine, and antibiotic treatment was started. Subsequently, both urine and blood culture grew P. aeruginosa. After 2 weeks of treatment, he was scheduled for the surgery to correct VUR and discharged. Given that he developed fever on the next day of IVP, we think that bladder catheterization triggered the infection. We propose that bag urine culture before bladder catheterlization and prophylactic antibiotics for the cultured bacteria, if needed, are useful.

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In this report, we discussed about an 8-year-old girl with mental retardation and spastic paralysis of the lower limbs who was diagnosed with focal segmental glomerulosclerosis. Her past medical record indicated heavy proteinuria at the age of three, so we suspected that her proteinuria had been continued from early in her life. The cause of her mental retardation and spastic paralysis was unknown, and we suspected that her clinical symptoms are caused by some sort of congenital syndrome or mitochondrial cytopathy, but no diagnosis had been made. We also reviewed literature about patients with central nervous involvement and FSGS. According to previous reports of FSGS associated with psychomotor retardation and epilepsy, there are various types of syndromes or diseases that cause secondary FSGS. We are undertaking further research, such as gene analysis, to clarify her underlying disease and its pathology.

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We report on a 13-year-old boy with Down syndrome and recurrent bacterial infections such as otitis media who developed hematuria,proteinuria, and persistent hypocomplementemia due to C3 glomerulopathy. The histology on first renal biopsy showed MPGN type 2. The patient was intravenously treated with methylpredonisolone pulses followed by cyclosporine and showed remarkable improvement in the urinary abnormalities. Two years after initial treatment, a second renal biopsy was performed and the histology revealed C3 glomerulopathy. We conclude that urinalysis should be regularly performed in children with Down syndrome who had repeated episodes of bacterial infections.

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We report a case of poststreptococcal acute glomerulonephritis with an unusual clinical course, showing nephrotic syndrome, prolonged proteinuria, and recurrent gross hematuria. An 11-year-old male patient suffered transient gross hematuria, when three months later, he again developed gross hematuria which was associated with streptococcal pharyngitis. His serum complement levels were normal. This episode of gross hematuria lasted for a few days.About 3 weeks after diagnosis of streptococcal pharyngitis, he developed acute nephritis with gross hematuria, heavy proteinuria, hypoalubminemia, and hypocomplementemia. His first renal biopsy showed diffuse endocapillary proliferation with cellular crescent formation in some glomeruli, and remarkable inflammatory cell infiltration in the tubulointerstitium. Immunofluorescence (IF) showed C3 deposition along capillary walls. Electron microscopy showed intramembranous deposits. Hump was not observed. Staining for nephritis-associated plasmin receptor (NAPlr) and plasmin-like activity were positive in the glomeruli. We diagnosed this case as an acute phase of atypical PSAGN with severe inflammation from these pathological evidences. Serum albumin and complement levels returned to normal after a month. However, his mild proteinuria and microscopic hematuria persisted. He was then treated with intravenous methylpredonisolone pulse therapy (MPT) followed by oral predonisolone, mizoribine, warfarin, and dipyridamole. In spite of this therapy, his hematuria and proteinuria persisted. His second renal biopsy was performed at 5 months after MPT, and this showed diffuse and global mesangial proliferation with several segmental and global sclerosis. Immunofluorescence showed that both IgA and C3 were negative in glomeruli. The second histology indicated recovery phase of PSAGN. His proteinuria and hematuria disappeared 1 year and 9 months following the start of the above therapy respectively, at this point, we discontinued his multidrug therapy, and since, there has been no recurrence.This presentation of gross hematuria simultaneously with respiratory infection may be concluded as a typical presentation of IgA nephritis. However, these pathological findings suggested a severe presentation of PSAGN with an unusual clinical course, since there were no pathological findings suggesting other co-existing nephritides. Although we are currently unable to reach a definitive explanation for his complicated clinical course, we suggest a diagnosis of PSAGN superimposed by IgA nephritis.

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Hemolytic uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia and renal dysfunction. Approximately 10% of all cases are classified as atypical HUS because they are not caused by either verotoxin or streptococci. More than half of the patients with atypical HUS have complement abnormalities. DEAP-HUS (deficiency of CFHR proteins and CFH autoantibody positive) is characterized by an acquired factor which is an autoantibody against the complement factor H, and a genetic factor which is a homozygous deletion of CFHR1 and CFHR3 genes. A 4-year-old boy developed vomiting and diarrhea. Laboratory examinations at a local physician’s office revealed anemia, thrombocytopenia and renal dysfunction. After referral, he was found to have a low complement level (C3 50 mg/dl). No verotoxin was detected in his stool. We diagnosed him as having atypical HUS and started the administration of fresh frozen plasma. He received 3 plasma infusions and 5 plasma exchanges, and his anemia, thrombocytopenia and renal dysfunction resolved in 30 days. The patient is now 6 years old, and has not experienced any recurrence of HUS. We detected CFH autoantibodies in his serum by an ELISA method. We then investigated the expression of CFHR proteins by a Western blot analysis, which detected CFHR3 but not CFHR1. Furthermore, the copy number variation of CFH, CFHR3 and CFHR1 genes as detected by a MLPA method revealed the homozygous deletion of the CFHR1 gene. The diagnosis of DEAP-HUS was made.

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Urolithiasis rarely develops in children and is often associated with underlying conditions, such as idiopathic hypercalciuria, renal tubular acidosis, hypervitaminosis, and congenital metabolic disorders. Henoch-Schönlein purpura (HSP) is characterized by systemic small vessel vasculitis and is frequently complicated by colicky abdominal pain for which corticosteroid is very effective. We present unusual case of an 8-year-old boy with HSP complicated by bilateral ureteral obstruction due to urolithiasis. He was referred to us because of severe abdominal pain and bloody stool with the diagnosis of HSP on the 7th day of illness. As his abdominal pain was intractable, prednisolone had been administered for 2 weeks. At this point, vitamin D (alpfacalcidol) supplementation was initiated to prevent steroid induced osteoporosis. Eighteen days after the addition of vitamin D, he suffered backache, presented hematuria and anuria: based on the laboratory findings and imaging studies, the diagnosis of acute kidney injury (AKI) due to bilateral ureteral obstruction caused by urolithiasis was made. AKI improved rapidly by unilateral nephrostomy and ureteral stenting and he was discharged on the 59th day of illness without any sequelae. It is well known that vitamin D promotes intestinal absorption of calcium and increases its urinary excretion. In fact, our patient demonstrated the increased urinary levels of calcium since initiation of vitamin D supplementation. It is also reported that ureteritis due to periureteral vasculitis occasionally develops in patients with HSP. Taken together, we considerd that ureteral obstruction caused by urolithiasis in this boy was strongly associated with vitamin D supplementation as well as ureteral stenosis due to HSP. Therefore, lithogenic agents, such as vitamin D should be administered with caution in children with HSP.

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Dent disease is X-linked and characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis/nephrolithiasis, renal insufficiency in adulthood and is caused mainly by inactivating mutations in the chloride channel 5 gene (CLCN5). Although rickets is often observed in British patients, it is rather rarely reported in Japanese patients. Therapy and management have not yet been established for Japanese Dent disease patients with rickets. A 1-year-old boy whose brother had already been diagnosed with Dent disease had a very high level of urine β2 microglobulin and findings of nephrocalcinosis on ultrasound. He had bandy legs at age 2 years and X-ray findings of the knee joints were characteristic of rickets. The blood examination demonstrated a high serum alkaline phosphatase level and low serum phosphate level. He had a nonsense mutation of the CLCN5 gene similar to that of his brother. Phosphate supplementation improved his X-ray findings in the knee joints. We must pay attention to emerging rickets in patients with Dent disease. Furthermore, it is necessary to confirm the frequency of rickets in Japanese patients of Dent disease and to establish optimal therapeutic and management strategies.

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[in Japanese]

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