非典型溶血性尿毒症症候群(atypical hemolytic uremic syndrome:aHUS)は補体制御因子の異常による血栓性微小血管症で,生命予後に影響する腎外病変に対する関心が集まっている.症例は3歳女児.血尿,蛋白尿,浮腫を主訴に当院へ紹介され,精査によりaHUSと診断された.臨床経過中に消化管出血,難治性高血圧,肺水腫,そして可逆性の脳萎縮といった多彩な腎外病変を呈し,特に重篤な消化管出血と難治性高血圧の管理に難渋した.病初期におけるaHUSに対する血漿交換療法とエクリズマブの併用療法に加えて,難治性高血圧に対してレニン・アンジオテンシン系阻害薬,そして虚血性腸炎の体液管理に酢酸オクトレオチドがそれぞれ奏功した.多臓器にわたる腎外病変を有するaHUSは重症例が多く,適切な治療を行わなければ致死的な経過をたどる可能性があるため,集学的治療による全身管理が生命予後の改善に重要である.(著者抄録)

非典型溶血性尿毒症症候群(atypical hemolytic uremic syndrome:aHUS)は補体制御因子の異常による血栓性微小血管症で,生命予後に影響する腎外病変に対する関心が集まっている.症例は3歳女児.血尿,蛋白尿,浮腫を主訴に当院へ紹介され,精査によりaHUSと診断された.臨床経過中に消化管出血,難治性高血圧,肺水腫,そして可逆性の脳萎縮といった多彩な腎外病変を呈し,特に重篤な消化管出血と難治性高血圧の管理に難渋した.病初期におけるaHUSに対する血漿交換療法とエクリズマブの併用療法に加えて,難治性高血圧に対してレニン・アンジオテンシン系阻害薬,そして虚血性腸炎の体液管理に酢酸オクトレオチドがそれぞれ奏功した.多臓器にわたる腎外病変を有するaHUSは重症例が多く,適切な治療を行わなければ致死的な経過をたどる可能性があるため,集学的治療による全身管理が生命予後の改善に重要である.(著者抄録)

BACKGROUND: Kimura's disease (KD) is a rare chronic inflammatory disease of unknown etiology. Clinically, KD is characterized by nodular subcutaneous masses, that are typically localized to the neck and head. Involvement of the lacrimal glands and limbs is uncommon and seldom reported. CASE PRESENTATION: We report a case of a 4-year-old Japanese boy presenting with bilateral upper eyelid swelling with nodular subcutaneous lesions and peripheral eosinophilia. Based on clinical, histopathological, and laboratory findings, the patient was diagnosed with KD. An itchy subcutaneous mass on the left arm developed at the age of 14 years. Treatment with steroids was effective. However, as the steroids were tapered after the patient developed side effects, the masses relapsed within a few months. Treatment with cyclosporine A was then initiated, which led to an improvement of clinical features and serial levels of cytokines. CONCLUSIONS: We report a rare case of KD with a peculiar clinical presentation. The patient responded well to treatment with cyclosporine A.

Clinical data on coronavirus disease-19 (COVID-19) in children during the management of nephrotic syndrome (NS) is lacking. Patients on prednisolone are compromised hosts at the risk of severe infections. Some infections may induce NS relapse. We describe the clinical course of a child with NS and COVID-19. A 3-year-old boy was admitted with clinical and laboratory findings indicative of NS. Induction therapy with prednisolone (2 mg/kg/day) induced complete remission. While tapering the dose, he was infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He developed a high fever and periorbital edema. Urinalysis revealed proteinuria (protein-creatinine ratio: 6.3 g/gCr). He was transferred to our hospital for the concurrent management of COVID-19 and NS relapse. As proteinuria worsened, the prednisolone dose was increased to 2 mg/kg/day. Proteinuria gradually improved, and remission was noted a week after initiating full-dose steroid treatment. The fever subsided after 2 days without treatment for COVID-19. Anti-SARS-CoV-2 antibody including IgG levels decreased in the early convalescent phase. To the best of our knowledge, this is the first reported case with the recurrence of NS triggered by the SARS-CoV-2 infection in Asia. SARS-CoV-2 infection may induce NS relapse. Daily administration of full-dose of prednisolone may be effective for managing the recurrence of NS associated with SARS-CoV-2 infection.

BACKGROUND: The association of hypertension with congenital renal hypoplasia has been established. We report a case of an infant who underwent nephrectomy for hypertension. CASE PRESENTATION: Magnetic resonance imaging for the mother revealed fetal renal masses, and fetal multicystic dysplastic kidney was suspected. Following birth, the baby developed hypertension. Numerous investigations revealed that the left kidney was non-functional, and she was initiated on benazepril hydrochloride. However, because the drug response was poor, the left kidney was removed at the age of 7 months. Examination of the renal specimen revealed abrupt transition from normal to atrophic cortex with lobar atrophy and cysts. Tubular atrophy, marked abnormal blood vessels with wall thickening, gathered immature glomeruli, and parenchymal destruction were observed. Renin was partially localized in the proximal tubules and the parietal epithelium of the Bowman's capsule in the immature glomeruli. We speculated that an abnormal vascular structure and irregular renin localizations may be the cause of hypertension. Serum renin and aldosterone levels gradually reduced post-surgery, reaching normal levels on the 90th postoperative day. A long follow-up is needed due to the possibility of the child developing hypertension in the future. CONCLUSION: This is a case of an infant with MCDK, which discusses the clinicopathological features based on the pathophysiological analysis, including renin evaluation.

Tonsils are located mainly at the gateway of the respiratory tract, and are reportedly one of the secondary lymphatic organs of the immune system. The development of several diseases including IgA nephropathy (IgAN) is associated with inflammatory stimulation and an aberrant immune response of the tonsils. Several studies have reported an improvement in and/or an increase in the stability of the clinicopathological findings of patients with IgAN post tonsillectomy. However, the efficacy in and precise mechanism of the alleviation of symptoms of other renal diseases by tonsillectomy remain unknown. We hypothesize that tonsillectomy may play a potentially therapeutic role in renal diseases apart from IgAN, which are thought to be caused by an impaired regulation of the immune system.

BACKGROUND: Early multiple-drug therapy for severe childhood immunoglobulin A (IgA) nephropathy prevents the progression of nephritis and improves the long-term prognosis. Recent studies have focused on the relationship between the pathophysiology of IgA nephropathy and tonsillar focal infection, and the efficacy of tonsillectomy with methylprednisolone pulse therapy in children has been demonstrated. However, no study has reported on the relationship between the period from diagnosis to tonsillectomy and the long-term prognosis of IgA nephropathy. METHODS: To clarify the long-term effects of an early tonsillectomy, 40 patients who were diagnosed with severe IgA nephropathy in childhood and underwent a tonsillectomy were divided into two groups based on the period from diagnosis to undergoing tonsillectomy: Group A, less than 3 years; and Group B, more than 3 years. The primary endpoint of this study was the change in the amount of proteinuria. Renal prognosis was evaluated 10 years after the diagnosis. RESULTS: This study enrolled 40 patients diagnosed with severe IgA nephropathy in childhood who underwent tonsillectomy after multiple-drug therapy with/without methylprednisolone pulse therapy at Kindai University Hospital; eight patients were excluded based on the exclusion criteria. Group A consisted of 18 patients and Group B, 14 patients. Proteinuria and hematuria levels were significantly reduced in the early surgery group (P < 0.01). No significant differences were found in serum creatinine, uric acid, and IgA/C3 ratio. CONCLUSIONS: High proteinuria levels worsen the renal prognosis in IgA nephropathy. Tonsillectomy in less than 3 years combined with multiple-drug therapy after the initial diagnosis could improve long-term prognosis.

Nephrotic syndrome (NS) is one of the most common glomerular diseases in children. Glomerular podocyte dysfunction can result in proteinuria, the presence of a large amount of protein in the urine. Podocytes are unique epithelial cells that divide into 3 separate structural and functional segments: a cell body, major processes, and foot processes. Since synaptopodin, dynamin, and actin are crucial components of the podocyte cytoskeleton, degradation of these proteins is associated with cytoskeleton instability, resulting in the development of proteinuria. Cathepsin L (CatL), a cysteine proteinase, plays a crucial role in various renal diseases. CatL expression is elevated in rats with puromycin aminonucleoside-induced nephropathy, which is used as a model of minimal change NS. In CatL-deficient mice, which do not develop proteinuria, dynamin is retained through the escape of CatL-mediated decomposition, resulting in no changes in the filtration barrier of podocytes. However, there is limited information on the roles of CatL in NS. Based on these data, CatL might play an important role in the development of proteinuria. Furthermore, identifying the functions of CatL may contribute to a better understanding of the pathogenesis of childhood-onset NS. We hypothesize that high levels of CatL can lead to cytoskeletal instability of podocytes, resulting in proteinuria in childhood-onset NS.

BACKGROUND: IgA deficiency associated with glomerulonephritis is rare. In particular, there is no prior report regarding the association between IgA deficiency and membranoproliferative glomerulonephritis (MPGN) in children. Herein, we describe the case of a 5-year-old girl with selective IgA deficiency and MPGN. CASE PRESENTATION: The patient presented with persisting urinary abnormality and hypocomplementemia following a group A treptococcal infection. Renal biopsy revealed the presence of diffuse mesangial hypercellularity, endocapillary proliferation, and focal thickening of the walls of the glomerular capillaries using light microscopy, with IgG and moderate C3 deposits observed using immunofluorescence. Electron microscopy images revealed nodular deposits in the subendothelial areas, with hump-shaped subepithelial deposits. The pathological diagnosis was confirmed as MPGN. Treatment using oral prednisolone (PSL), mizoribine (MZR), and angiotensin-converting enzyme inhibitors reduced the proteinuria. The PSL dose was gradually tapered, with the low dose of PSL and MZR continued for 4 years. Histological findings were improved on repeated renal biopsy, and PSL and MZR administration was discontinued. CONCLUSIONS: We report a rare case of MPGN related to a streptococcal infection in a child. The clinical presentation included selective IgAD, with several pathological findings and a clinical course typical of glomerulopathy. The patient was successfully treated using multidrug therapy.

BACKGROUND: The pathological findings of tonsils in IgA nephropathy include the expansion of T-cell nodules around lymphoid follicles and abnormal reticulation of the crypt epithelium in contrast to chronic tonsillitis. Recently, several studies have reported that regulatory T cells play an important role in the maintenance of self-tolerance, an abnormality that is involved in the onset of nephrotic syndrome (NS). We encountered a patient of 28-year-old male with frequently relapsing nephrotic syndrome (FRNS) and chronic tonsillitis whose tonsils demonstrated pathological findings similar to those of IgA nephropathy. CASE PRESENTATION: A patient had developed NS at the age of 5 years, and was pathologically diagnosed with minimal change disease (MCD), for which he received various immunosuppressive agents as treatment for recurrence. Because tonsillitis often triggers the recurrence of NS, a tonsillectomy was performed for chronic tonsillitis at the age of 25 years. Immunohistochemical staining of his tonsils showed the expansion of CD4 positive lymphocytes around the lymphoid follicles and abnormal reticulation of the crypt epithelium. The number of peripheral blood CD4+CD25+ regulatory T cells increased, and the frequency of relapses decreased after tonsillectomy. CONCLUSION: A similar self-tolerance abnormality exists in NS and IgA nephropathy; therefore, tonsillectomy might become a novel therapeutic approach for FRNS to redress the unbalanced self-tolerance and to remove the tonsillar focal infection. Further studies are necessary to verify the clinical efficiency of tonsillectomy for FRNS with recurrent episodes triggered by tonsillitis.

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

Background Cyclosporine A (CsA) is used globally as an immunosuppressant for the treatment of immune-mediated nephrotic syndrome (NS). However, its long-term use causes nephrotoxicity characterized by tubulointerstitial injury and glomerulosclerosis. The present study aimed to investigate the associations between histomorphological findings and immunohistological expression of Cathepsin L (CatL) and CD2-associated protein (CD2AP) in patients with NS mediated with CsA. Methods A total of 18 patients with child-onset NS were divided into two groups after treatment with CsA for 2 years (group A; n = 10) and more than 4 years (group B; n = 8), respectively. Analyses of relationships between tubulointerstitial disorders and expression of CatL and CD2AP proteins were performed using immunohistochemistry of paired renal specimens. Results Glomeruli with arteriole hyalinization were significantly increased in both groups depending on dosage periods, although degrees of tubule and interstitial injury did not differ between groups. CD2AP expression was significantly greater in podocytes (P = 0.046) and was significantly less in proximal tubule cells (P = 0.014) in patients of group B compared with those of group A. Moreover, CD2AP expression was significantly increased in lateral tubule cells in both groups (group A, P = 0.02; group B, P = 0.001), and CatL expression in glomeruli and tubule cells did not change with the duration of CsA treatment in either patient group. Conclusions CD2AP expression in renal tubules may histologically associate with tissue hypoxia and reflected recovery from CsA-mediated renal injury in patients, even with mild histological features of tubulointerstitial disorder.

BACKGROUND: Several shared common gene networks participate in development of interstinal ganglia and also nephron formation; the glial cell line-derived neurotrophic factor/Ret/glial cell line-derived neurotrophic factor receptor gene network is particularly important. CASE PRESENTATION: We encountered a patient with total colonic aganglionosis as well as right renal agenesis and oligomeganephronia. Gene analysis in this patient disclosed a heterozygous p.S811F mutation was in Ret gene exon 14, resulting in a substitution of phenylalanine for serine. The large side chain of phenylalanine obstructed the opening of the hydrophobic pocket of the Ret molecule causing interference with its interaction with adenosine triphosphate and consequent marked reduction in its enzyme activity. This could account for our patient's severe intestinal disease and renal dysplasia. We know of no previous reports of concomitant Hirschsprung's disease and oligomeganephronia. CONCLUSIONS: The patient's overall illness could be considered a novel Ret gene mutation syndrome.

BACKGROUND: Nephronophthisis (NPH) accounts for 4-5 % of end-stage renal disease occurring in childhood. METHOD: We investigated the clinical context and characteristics of renal and extrarenal symptoms, as well as the NPHP genes, in 35 Japanese patients with clinical and histologic features suggesting NPH. RESULTS: NPH occurred fairly uniformly throughout Japan irrespective of region or gender. In three families, NPH affected siblings. The median age of patients was 12.5 years. Renal abnormalities attributable to NPH discovered through mass screening, such as urine tests in school. However, NPH accounted for less than 50 % of children with abnormal findings, including incidentally discovered renal dysfunction during evaluation of extrarenal symptoms or during routine check-ups. Typical extrarenal manifestations leaded to discovery including anemia and delayed physical development. The urine often showed low gravity specific density and low molecular weight proteinuria. Frequent renal histologic findings included cystic dilation of tubules, mainly in the medulla, and irregularity of tubular basement membranes. Genetically abnormalities of NPHP1 were not common, with large deletions frequently noted. Compound heterozygotes showing single abnormalities in each of NPHP1, NPHP3, and NPHP4 were observed. CONCLUSIONS: Our findings resemble those reported in Western populations.

〈Abstract〉Patients with the disease entity termed acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE) manifests non-oliguric renal failure, usually accompanied by few urinary abnormalities such as hematuria and proteinuria. This condition, diagnosed by the demonstration of hypouricemia in addition to these features, usually responds well to conservative treatment. However, differentiation from other renal disorders occasionally proves difficult, which can lead to unnecessary steroid administration and renal biopsy. In the patient reported here, acute glomerulonephritis (AGN) was initially suspected based on his course and urinalysis findings, although typical AGN symptoms such as oliguria, edema, and hypertension were absent. After the detection of hypouricemia, renal hypouricemia was added to the clinical picture. URAT1 gene mutation (W258X, homozygote) was demonstrated by gene analysis. The patient's mother was heterozygous for mutation at the same site.

AIM: We investigated efficacy and therapeutic mechanisms of tonsillectomy for intractable childhood IgA nephropathy. Five patients refused tonsillectomy. Among 25 patients, 19 patients were able to evaluate histological findings before and after surgery. Patients with poor (n = 7) or relatively poor (n = 18) histologically determined prognosis and an age of at least 7 years, together with proteinuria of at least 0.3 g/day or severe persisting despite ongoing drug treatment, are candidates for surgery. Patients were grouped by interval between diagnosis of IgA nephropathy and tonsillectomy (within 3 years; early group vs 3 years or later; later group). Patients underwent kidney biopsy shortly before and 1 to 2 years after tonsillectomy. RESULTS: Proteinuria was reduced after tonsillectomy over 2 years of follow-up in both early and later groups compared with proteinuria in the 6 months preceding surgery. Complete remission was achieved in 10 patients, most often among those having surgery within 3 years, while patients refusing surgery failed to attain complete remission of urinary findings. Histological activity decreased in both groups, significantly when surgery was early. Complement component C3 deposition and activated macrophages in glomeruli decreased after tonsillectomy, especially with early surgery. CONCLUSION: Tonsillectomy improved clinicopathological features in relatively severe paediatric IgA nephropathy, especially with the early-surgery group. Therapeutic mechanisms may include inhibition of complement activity in glomeruli and glomerular infiltration by activated macrophages.

The complement system, the major component of the innate immune functions resisting microbial infection, includes the classical complement pathway, the alternate pathway, and the mannose-binding lectin pathway. All of these merge at the level of complement component (C) 3. Complement factor H (CFH), a soluble complement mediator in blood, regulates alternate pathway activation; a conformational change of C3 molecules by C3 convertases leads to an enzyme complex formation resulting in opsonization and cell lysis. Clinical manifestations arising from CFH gene (CFH) abnormalities include hemolytic uremic syndrome and membranoproliferative glomerulonephritis. We encountered a 24-year-old woman initially diagnosed with C3 glomerulonephritis associated with persistently low circulating C3. Definitive diagnosis of C3 glomerulonephritis was made from immunohistologic demonstration of isolated mesangial C3 deposits. The biopsy specimen showed moderately increased mesangial proliferation, without thickening of the glomerular capillary walls. Genetic analysis disclosed a homozygous CFH missense mutation, a G-to-T transversion at nucleotide 3,048 in exon 18, resulting in substitution of Asp for Glu at position 936. A low serum CFH concentration (110 mu g/mL) might reflect the consequences of this CFH mutation. C3 glomerulonephritis is associated with a CFH mutation, the mutation of which results in the unexpected activation of alternate pathway complement with clinical laboratory fluctuations, such as varying reduction of serum CFH and C3. The finding of a patient with a CFH mutation associated with C3 glomerulonephritis represents an opportunity to expand the phenotypic spectrum of the CFH mutations.

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

Introduction: We analyzed renal histologic and immunohistologic findings in children with nephrotic syndrome (NS) who did (n = 5) or did not (n = 17) develop cyclosporine A (CyA) nephropathy despite appropriately low serum CyA concentrations being maintained over 2 years. Methods: To discriminate embryonic-type from mature glomeruli, we performed staining for type IV collagen alpha 1, laminin beta 1 and laminin beta 2. Staining patterns were used to semiquantitatively assess glomerular immaturity (glomerular immaturity index, or GII). Results: In follow-up biopsy specimens, residual embryonic-type, collapsed embryonic-type and sclerotic glomeruli that had failed to differentiate were observed. Patients with early-onset CyA nephropathy had a high GII. In patients with a high GII, arteriopathy developed early in CyA treatment. Arteriopathy was observed mostly near embryonic-type glomeruli. Taken together, these glomeruli (surviving embryonic-type, collapsing embryonic-type, and sclerotic glomeruli) essentially equaled the total number of embryonic-type glomeruli in specimens obtained before CyA treatment. Conclusion: Our findings indicate a need for caution in CyA therapy for patients with NS, even for a relatively short course of administration, because some patients may have embryonic-type glomeruli or immature arterioles that predispose them to CyA nephropathy.

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

Tubulointerstitial nephritis antigen (TIN-ag), which has been localized to the renal tubular basement membrane, is a target antigen in some forms of TIN. Physiologically, TIN-ag is thought to be important in maintaining the structure of renal tubular basement membrane. Here we describe a child with chronic renal failure showing a human TIN-ag gene (hTIN-ag) deletion. Immunohistochemical examination using an antihuman TIN-ag monoclonal antibody showed attenuation or lack of TIN-ag staining along the renal tubular basement membrane, whereas nephrocystin staining was normal in renal tubules. Polymerase chain reaction detected no amplification band corresponding to hTIN-ag in this patient. Testing for a deletion in this gene showed nearly complete deletion. By using array-comparative genomic hybridization method, large deletion of a gene mapped on chromosome 6p11-6p12 was demonstrated, corresponding to the locus where hTIN-ag is located. Therefore, an hTIN-ag defect may be a potent cause of end-stage renal failure in childhood.