Eculizumab for paediatric patients with atypical haemolytic uraemic syndrome: full dataset analysis of post-marketing surveillance in Japan.

BACKGROUND: Eculizumab was approved for atypical haemolytic uraemic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in a real-world setting. METHODS: Paediatric patients in the PMS cohort who were <18 years of age at the first administration of eculizumab and diagnosed with aHUS [excluding Shiga toxin-producing Escherichia coli HUS, thrombotic thrombocytopaenic purpura and secondary thrombotic microangiopathy (TMA)] were included in the effectiveness and safety analysis. Clinical endpoints of effectiveness [complete TMA response, TMA event-free status, platelet (PLT) count and lactate dehydrogenase (LDH) normalization, serum creatinine (sCr) decrease and estimated glomerular filtration rate (eGFR) improvement] were analysed in patients treated with at least one dose of eculizumab. Serious adverse events (SAEs) were also evaluated. RESULTS: A total of 40 paediatric patients (median age 5 years) were included. The median eculizumab treatment duration was 66 weeks. PLT count, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3% and 77.5% of patients, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation and 5 patients, including 1 patient with aHUS relapse, continued the treatment but extended the treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. CONCLUSION: Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan.

Pathophysiological clinical features of an infant with hypertension secondary to multicystic dysplastic kidney: a case report.

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.

Nephrotic syndrome relapse in a boy with COVID-19.

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.

Early tonsillectomy for severe immunoglobulin A nephropathy significantly reduces proteinuria.

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.

Membranoproliferative glomerulonephritis related to a streptococcal infection in a girl with IgA deficiency: a case report.

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.

Pathologic tonsillar findings similar to IgA nephropathy and the role of tonsillectomy in a patient with nephrotic syndrome.

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.

An 18-Year-Old Male With X-linked Lymphoproliferative Syndrome Type 1 Who Developed Primary Central Nervous System Lymphoma 6 Months After Primary Epstein-Barr Virus Infection.

X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare congenital immunodeficiency disease. We report the case of an 18-year-old male who developed hemophagocytic lymphohistiocytosis (HLH) with neurologic complications after primary Epstein-Barr virus (EBV) infection and subsequently developed EBV-related central nervous system lymphoma (CNSL). Given the vulnerability to EBV, he was finally diagnosed with XLP1 and treated with whole-brain irradiation along with chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation from a SH2D1A wild-type sibling donor. Although the prognosis for CNSL is generally dismal, reconstitution of the immune system from a normal donor contributed to the patient remaining in remission for 30 months.

Three patients with Schaaf-Yang syndrome exhibiting arthrogryposis and endocrinological abnormalities.

MAGEL2 is the paternally expressed gene within Prader-Willi syndrome critical region at 15q11.2. We encountered three individuals in whom truncating mutations of MAGEL2 were identified. Patients 1 and 2, siblings born to healthy, non-consanguineous Japanese parents, showed generalized hypotonia, lethargy, severe respiratory difficulty, poor feeding, and multiple anomalies including arthrogryposis soon after birth. We carried out whole-exome sequencing, which detected a MAGEL2 mutation (c.1912C>T, p.Gln638*, heterozygous). The patients' father was heterozygous for the mutation. Patient 3 was a female infant, showed respiratory difficulty reflecting pulmonary hypoplasia, generalized hypotonia, feeding difficulty and multiple anomalies soon after birth. Targeted next-generation sequencing detected a novel heterozygous mutation in MAGEL2 (c.3131C>A, p.Ser1044*). This mutation was not found in the parents. MAGEL2 mutations, first reported to be the cause of the Prader-Willi like syndrome with autism by Schaaf et al. (2013) Nature Genetics, 45: 1405-1408 show the wide range of phenotypic spectrum from lethal arthrogryposis multiplex congenital to autism spectrum disorder (ASD) and mild intellectual disability (ID). Our results indicate that MAGEL2 mutations cause multiple congenital anomalies and intellectual disability accompanied by arthrogryposis multiplex congenita and various endocrinologic abnormalities, supporting that the view that clinical phenotypes of MAGEL2 mutations are variable.

ErbB4 deletion accelerates renal fibrosis following renal injury.

Tubulointerstitial fibrosis (TIF) is a prominent factor in the progression of chronic kidney disease regardless of etiology. Avian erythroblastic leukemia viral oncogene homolog 4 (ErbB4) expression levels were inversely correlated to renal fibrosis in human fibrotic kidneys. In both unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury followed by uninephrectomy (IRI/UNx) mouse models, expression levels of ErbB4 were elevated in the early stage of renal injury. Using mice with global ErbB4 deletion except for transgenic rescue in cardiac tissue ( ErbB4-/-ht+), we determined that UUO induced similar injury in proximal tubules compared with wild-type mice but more severe injury in distal nephrons. TIF was apparent earlier and was more pronounced following UUO in ErbB4-/-ht+ mice. With ErbB4 deletion, UUO injury inhibited protein kinase B phosphorylation and increased the percentage of cells in G2/M arrest. There was also increased nuclear immunostaining of yes-associated protein and increased expression of phospho-Mothers against decapentaplegic homolog 3, snail1, and vimentin. These results indicate that ErbB4 deletion accelerates the development and progression of renal fibrosis in obstructive nephropathy. Similar results were found in a mouse IRI/UNx model. In conclusion, increased expression of ErbB4 in the early stages of renal injury may reflect a compensatory effect to lessen tubulointerstitial injury.

Cyclosporine A induced histological changes of Cathepsin L and CD2AP expression in renal glomeruli and tubules.

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.

Minimal change nephrotic syndrome and prohibitin-2 gene polymorphism.

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.

Heterozygous p.S811F RET gene mutation associated with renal agenesis, oligomeganephronia and total colonic aganglionosis: a case report.

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.

Clinical and genetic characteristics of Japanese nephronophthisis patients.

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.

Tubulointerstitial nephritis complicating IVIG therapy for X-linked agammaglobulinemia.

BACKGROUND: Patients with X-linked agammaglobulinemia (XLA) develop immune-complex induced diseases such as nephropathy only rarely, presumably because their immunoglobulin (Ig) G concentration is low. We encountered a patient with XLA who developed tubulointerstitial nephritis during treatment with intravenous immunoglobulin (IVIG). CASE PRESENTATION: A 20-year-old man was diagnosed with XLA 3 months after birth and subsequently received periodic γ-globulin replacement therapy. Renal dysfunction developed at 19 years of age in association with high urinary ß2-microglobulin (MG) concentrations. A renal biopsy specimen showed dense CD3-positive lymphocytic infiltration in the tubulointerstitium and tubular atrophy, while no IgG4-bearing cell infiltration was found. Fibrosclerosis and crescent formation were evident in some glomeruli. Fluorescent antibody staining demonstrated deposition of IgG and complement component C3 in tubular basement membranes. After pulse steroid therapy was initiated, urinary ß2-MG and serum creatinine concentrations improved. CONCLUSION: Neither drug reactions nor collagen disease were likely causes of tubular interstitial disorder in this patient. Although BK virus was ruled out, IgG in the γ-globulin preparation might have reacted with a pathogen present in the patient to form low-molecular-weight immune complexes that were deposited in the tubular basement membrane.

Childhood Cogan syndrome with aortitis and anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

Cogan syndrome is a systemic disease manifesting interstitial keratitis, sensorineural hearing loss, tinnitus, and rotatory vertigo. Renal complications of this syndrome are very rare. We encountered an adolescent with Cogan syndrome complicated by aortitis and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. At the age of 14, the patient showed proteinuria in a screening urinalysis at school and was found to lack a right radial pulse. Magnetic resonance angiography disclosed right subclavian artery stenosis. Examination of a renal biopsy specimen showed ANCA-positive crescentic glomerulonephritis. Steroid and immunosuppressant treatment improved renal function and histopathology, but repeated recurrences followed. At 18, the patient developed rotatory vertigo, a sense of ear fullness, and sensorineural hearing loss. The patient was diagnosed with Cogan syndrome. We know of no previous description of ANCA-positive crescentic glomerulonephritis in children with Cogan syndrome. Accordingly, evaluation of aortitis in childhood should include not only otolaryngologic and ophthalmologic examinations, but also periodic urine examination and renal function tests.

A novel OCRL1 mutation in a patient with the mild phenotype of Lowe syndrome.

Oculocerebrorenal syndrome of Lowe (OCRL, OMIM 309000), also known as Lowe syndrome, is a rare X-linked multisystem disorder characterized by congenital cataracts, mental retardation, and Fanconi syndrome of the kidney proximal tubules. Lowe syndrome is caused by mutations in the gene encoding a member of the inositol polyphosphate-5-phosphatase protein family (OCRL1) on chromosome Xq26.1. OCRL1 contains 24 exons and encodes a 105-kDa phosphatidylinositol (4,5) bisphosphate 5-phosphatase. An OCRL1 isoform generated by alternative splicing is predominantly expressed in brain, and localizes to the trans-Golgi network, lysosomes, and endosomes. Impaired inositol polyphosphate-5-phosphatase activity elevates phosphatidylinositol (4,5) bisphosphate levels that are required for vesicle trafficking within the Golgi apparatus, actin cytoskeleton remodeling closely associated with Golgi, and endosomal membrane trafficking. Accordingly, abnormalities in the actin cytoskeleton may influence the function of renal epithelial cells in patients with Lowe syndrome. OCRL1 mutations exist in about 95% of patients with Lowe syndrome, and new mutations occur in 32% affected males. We here describe a Japanese male with the mild phenotype of Lowe syndrome. Physical examination revealed mild congenital bilateral cataracts, mild mental disability, and short stature. Proteinuria was also mild with a high ß2-microglobulinuria level. Nucleotide sequence analysis identified a hemizygous mutation (T-to-C transition) at nucleotide 2039 in exon 18 that substitutes Ser (TCT) for Phe (TTT) at amino acid position 680. This missense mutation is located outside the known catalytic domain that is encoded by exons 4 through 15. The present patient carries a novel OCRL1 mutation that is helpful for genetic counseling.

Deletion of ErbB4 accelerates polycystic kidney disease progression in cpk mice.

ErbB4 is highly expressed in the cystic kidneys with polycystic kidney diseases. To investigate its potential role in cystogenesis, cpk mice carrying a heart-rescued ErbB4 deletion were generated. Accelerated cyst progression and renal function deterioration were noted as early as 10 days postnatally in cpk mice with ErbB4 deletion compared to cpk mice, as indicated by increased cystic index, higher kidney weight to body weight ratios, and elevated BUN levels. No apparent defects in renal development were noted with ErbB4 deletion itself. Increased cell proliferation was predominately seen in the cortex of cystic kidneys with or without ErbB4 deletion. However, there was significantly more cell proliferation in the cyst-lining epithelial cells in cpk mice with ErbB4 deletion. TUNEL staining localized apoptotic cells mainly to the renal medulla. There were significantly more apoptotic cells in the cyst-lining epithelial cells in ErbB4-deleted cpk kidneys, with decreased levels of cyclin D1, increased levels of p21, p27, and cleaved caspase 3. Thus, lack of ErbB4 may contribute to elevated cell proliferation and unbalanced cell apoptosis, resulting in accelerated cyst formation and early renal function deterioration. These studies suggest that the high level of ErbB4 expression seen in cpk mice may exert relative cytoprotective effects in renal epithelia.

Cyclosporin A may cause injury to undifferentiated glomeruli persisting in patients with Alport syndrome.

BACKGROUND/AIMS: Alport syndrome (AS) is a renal disorder caused by a genetic abnormality of type IV collagen α3 and α4, or α5 genes and shows a poor prognosis. Since the defect of type IV collagen synthesis disturbs the maturation process of the glomerular capillary loop, residual immature glomeruli persist after birth. The therapeutic efficacy of cyclosporin A (CyA) for AS patients seems to be controversial. We recently noted that renal specimens obtained from a child with AS who was treated with CyA and then developed CyA nephropathy included an increased number of undifferentiated embryonic-type glomeruli. METHODS: We analyzed renal histologic and immunohistologic findings in children with AS who did (n = 3) or did not (n = 2) develop CyA-induced nephropathy despite appropriately low serum CyA concentrations (<100 ng/mL) being maintained over a period of 2 years. To discriminate embryonic-type from mature glomeruli, staining for type IV collagen α1, laminin ß1, and laminin ß2 accompanied by light microscopic observation were employed. Staining patterns were used to semiquantitatively assess glomerular immaturity (glomerular immaturity index, or GII). RESULTS: In initial biopsy specimens, residual embryonic-type glomeruli were observed in each patient. Patients with early-onset CyA nephropathy had a high GII (median value 2.91 vs 1.23 ± 0.62 normal kidney tissues). In the follow-up biopsy after CyA treatment, surviving embryonic-type, collapsing embryonic-type, and sclerotic glomeruli that had failed to differentiate were observed. Taken together, the number of these glomeruli essentially equaled the total number of embryonic-type glomeruli in specimens obtained before CyA treatment. CONCLUSIONS: Our findings indicate a need for caution in CyA therapy for patients with AS, even for a relatively short course of administration, because some patients may have an unexpected number of embryonic-type glomeruli that predispose to CyA nephropathy.

Low nitric oxide bioavailability upregulates renal heparin binding EGF-like growth factor expression.

Decreased nitric oxide bioavailability has an important role in the initiation and progression of diabetic nephropathy, but the underlying mechanisms remain unclear. Here, we found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression levels increased in the kidneys of both endothelial nitric oxide synthase (eNOS)-knockout and eNOS-knockout diabetic (Lepr(db/db)) mice as early as at 8 weeks of age. Further increases in expression were only seen in eNOS-knockout diabetic mice and paralleled the progression of glomerulopathy. HB-EGF expression increased in endothelium, podocytes, and tubular epithelial cells. In cultured glomerular endothelial cells, the nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) or L-N5-(1-iminoethyl) ornithine increased HB-EGF protein expression. Administration of L-NAME dramatically increased renal HB-EGF expression and urinary HB-EGF excretion in diabetic mice. On the other hand, replenishing nitric oxide with sodium nitrate in eNOS-knockout diabetic mice reduced urinary HB-EGF excretion and inhibited the progression of diabetic nephropathy. Furthermore, specific deletion of HB-EGF expression in the endothelium attenuated renal injury in diabetic eNOS-knockout mice. Thus, our results suggest that decreased nitric oxide bioavailability leads to increased HB-EGF expression, which may be an important mediator of the resulting progressive diabetic nephropathy in eNOS-knockout diabetic mice.