Hiro Matsukura

Influence of Prolonged Corticosteroid Therapy on the Outcome of Steroid-Responsive Nephrotic Syndrome

Eighty-six patients (59 males and 27 females) diagnosed with steroid-responsive nephrotic syndrome during childhood were identified. The patients were 20–40 years of age (mean 27.0 ± 5.0) with a mean follow-up period of 19.5 ± 5.9 years. All patients had been treated with a long-term tapering corticosteroid therapy. Thirty patients had also received a course of cyclophosphamide (2 mg/kg/day for 12 weeks). Sixty-six had achieved sustained remission off corticosteroids, while 20 were still receiving corticosteroids to maintain remission. None of the 86 patients had proteinuria or renal insufficiency at the time of the study. Mean final heights in males and females were similar (–0.51 ± 1.21 and –0.23 ± 1.16 standard deviation score). Mean final height of 20 steroid-dependent patients was significantly less than that of 66 in remission off corticosteroids (p < 0.005). Ten cyclophosphamide-treated patients got married and 9 had at least 1 healthy child. In children with steroid-responsive nephrotic syndrome, the need for corticosteroid therapy to maintain remission may be associated with decreased adult height. Patients who received a 12-week course of cyclophosphamide are likely to be normally fertile as adults.

Nutcracker phenomenon in two siblings of a Japanese family

Sirs, Compression of the left renal vein (LRV) between the aorta and the superior mesenteric artery (SMA), known as the nutcracker phenomenon (NCP), can cause gross or microscopic hematuria, flank pain, proteinuria, or a combination of these clinical features [1, 2, 3]. The phenomenon causes hypertension of the LRV, consequently causing LRV compression, left gonadal vein varices, and unilateral hematuria [2, 4]. A recent report documented orthostatic proteinuria associated with the NCP [1, 5, 6, 7]. We describe two siblings with microscopic hematuria caused by NCP. These patients were a 3-year-old brother and a 5-year-old sister born to healthy non-consanguineous parents. Their family history manifested no renal diseases. Microscopic hematuria was first indicated in both patients by an annual screening urinalysis at their kindergarten. Their respective blood chemistries and urinary calcium/creatinine ratios were normal. Urine was normal except for sediment containing 5–20 red cells per high-power field. Repeated urine cultures showed no pathological organisms. Urinary red cell morphology revealed predominantly (>90%) isomorphic cells. Serum complement, IgA, IgG, and IgM concentrations, as well as antistreptolysin O titer, antinuclear antibody, antidouble-stranded DNA antibody, and rheumatoid factor were in the normal range. Ultrasonography of the kidneys showed marked dilatation of the LRV in the hilar portion and severe compression of the LRV between the aorta and the SMA, which was an indirect finding that is typical of NCP. Entrapment of the LRV is not easily detectable using conventional means. Selective renal venography, with the measurement of the gradient pressure between the LRV and the inferior vena cava, or intra-arterial digital subtraction angiography has been used for the diagnosis of NCP [8]. Doppler ultrasonography, three-dimensional helical computed tomography, and magnetic resonance angiography have been employed recently as useful noninvasive diagnostic tools [1, 3, 4, 5]. Abnormal branching of the SMA from the aorta is suggestive of the fundamental pathophysiology of NCP [1]. Nevertheless, it remains unclear why so few patients have experienced compression of the LRV and why LRV hypertension causes hematuria. Additional studies have demonstrated a new variant of NCP with different anatomical details [9]. The urinary red cell morphology is not sufficiently reliable to distinguish a glomerular source of bleeding from a non-glomerular source [2]. Clarification of non-glomerular hematuria in patients with NCP, who also have other co-existing renal disorders causing hematuria, is more complicated. Concomitant IgA nephropathy or membranous nephropathy associated with the NCP has been reported [2]. NCP is not a hereditary disease: occurrence of NCP within the same family or in close relatives is rare. NCP may have occurred coincidentally, causing hematuria in both siblings. Alternatively, they may have had underlying familial benign hematuria in association with NCP despite a negative family history. Further evaluation is necessary to elucidate the etiology of non-glomerular hematuria of these siblings.

Acute tubulointerstitial nephritis: possible association with cytomegalovirus infection

Sirs, A previously healthy 14-year-old boy presented with mild acute renal dysfunction with proteinuria and glucosuria. His past history and family history were unremarkable. The ophthalmologic examinations were normal. The patient was taking no medicines. Blood urea nitrogen of 18 mg/dl, creatinine of 1.3 mg/dl and creatinine clearance of 107.4 ml/min/1.73 m 2 were all measured. An autoantibody screen was negative. Urinary excretion of N-acetyl-beta-glucosaminidase (NAG) was 63.2 U/l (normal 0.3–11.5 U/l), and b2-microglobulin (b2-MG) was 37,079 �g/l (normal 30–340 �g/l). Serological tests for Epstein-Barr virus (EBV) showed the following: EBVviral capsid antigen (VCA) IgG 80x (negative <10x); VCA IgM <10x; early antigen-diffuse and restricted antibody (EA-DR) IgG <10x; EBV-nuclear antigen (EBNA) <10x. A cytomegalovirus (CMV)-specific IgM antibody showed a 1.27 index (negative <0.49 index) and a CMVspecific IgG avidity of 152 arbitrary units/ml (AU/ml; negative <14.9 AU/ml). Other serological results for hepatitis B, C, mycoplasmal pneumonia and syphilis were negative. Serial urine cultures showed no pathogens. A renal biopsy specimen showed marked lymphocytic tubulointerstitial nephritis (TIN) with tubular epithelial lesions and intratubular hyaline casts. The 30 glomeruli evaluated were completely normal, as were the blood vessels without granulomas and interstitial fibrosis. Immunofluorescent studies were negative. Immunohistochemical tests for CMV and EBV were negative. Mononuclear infiltration consisted mainly of CD3-positive lymphocytes with some CD8-positive T-cells and in small numbers of B-cells. Electron microscopy showed no evidence of viral inclusions. A CMV polymerase chain reaction (PCR) assay on peripheral blood was negative. Virus isolation from urine was not performed. The patient was given oral prednisolone (40 mg/day, 1 mg/kg/day, daily) with imidapril hydrochloride (5 mg/day) and showed a complete recovery. After rapid improvement of the clinical and laboratory signs of TIN, prednisone was tapered off over a period of 6 months without a flare-up of TIN. Acute TIN is a heterogeneous disorder that is caused by infectious agents, immunological disorders and idiopathic type. The patient had not taken nonsteroidal antiinflammatory drugs or any herbal or alternative medicines. The autoimmune screen and complement concentrations were normal, excluding autoimmune systemic

Discordant phenotypic expression of Alport syndrome in monozygotic twins

BACKGROUND Alport syndrome is a genetically heterogeneous disorder, but most patients showed the X-linked form resulting from mutations in the COL4A5 gene. A few cases of mosaicism in Alport syndrome have been reported. METHODS We describe the case of an 8-year-old boy with mosaicism in Alport syndrome. Punch skin biopsies were obtained from the patients mother and monozygotic twin brother. Five biopsy specimens from non-Alport patients were used as controls. Immunohistochemical analysis was performed using rat monoclonal antibodies towards individual collagen IV(NC) domains. RESULTS Kidney tissue of the patient showed: mosaic expression of alpha3(IV), alpha4(IV) and alpha5(IV) in the glomerular basement membrane (GBM), distal tubular basement membrane (TBM) and Bowmans capsule; mosaic alpha6(IV) expression in the Bowmans capsule and distal TBM; and well-preserved expression of alpha1(IV) and alpha2(IV). The patients skin exhibited mosaic alpha5(IV) expression. His mother and monozygotic twin brother disclosed a normal linear staining of alpha5(IV) in their epidermal basement membranes. This unusual mosaicism of alpha3(IV), alpha4(IV), alpha5(IV) and alpha6(IV) is consistent with a pattern of female heterozygotes of Alport syndrome. CONCLUSION This discordant phenotypic expression of Alport syndrome in monozygotic twins with unaffected parents suggests possible somatic mosaicism in the COL4A5 gene.

Secondary erythrocytosis associated with distal renal tubular acidosis

AIMS Diagnosis and classification of renal tubular acidosis (RTA) have traditionally been made on the basis of functional studies. Despite recent expanding knowledge about the molecular abnormalities involved in renal bicarbonate (HCO3-) and H+ transport, the pathophysiology of secondary erythrocytosis in association with distal RTA remains obscure. CASE HISTORY A 2-month-old boy with severe hyperchloremic metabolic acidosis with positive urine anion gap was diagnosed with distal RTA. Replacement therapy with sodium bicarbonate and potassium citrate succeeded in improving his metabolic acidosis and growth. His renal function remained normal. He had persistent erythrocytosis. CONCLUSION Secondary erythrocytosis is a rarely reported association of distal RTA. It may increase the risk of thromboembolism.

Vesicoureteral junction obstruction associated with unilateral renal agenesis.

A 7-month-old boy with a solitary kidney showed recurrent urinary tract infection. Magnetic resonance urography helps in the identification of vesicoureteral junction obstruction associated with unilateral renal agenesis.

MODY3, renal cysts, and Dandy-Walker variants with a microdeletion spanning the HNF1A gene

Heterozygous hepatocyte nuclear factor-1-α gene (<italic>HNF1A</italic>) mutations are the most common cause of maturity-onset diabetes of the young (MODY), but they rarely involve extrahepatic manifestations. Renal cysts and diabetes syndrome can be caused by <italic>HNF1B</italic> mutations. No association between MODY3 and Dandy-Walker variants (DWV) has been reported. <italic>HNF1A</italic> mutations might be responsible for renal malformations. In a Japanese girl with glycosuria, developmental delay, mental retardation, renal cysts, and DWV, the <italic>HNF1B</italic> gene had no mutations. Array comparative genomic hybridization analysis identified a de-novo interstitial 12q24.22-q24.31 deletion of 5.6 Mb encompassing the <italic>HNF1A</italic> gene, which is compatible with a diagnosis of MODY3. The variety of phenotypes suggests a novel microdeletion syndrome spanning the <italic>HNF1A</italic> gene. Because <italic>HNF1B</italic> functions as an <italic>HNF1A/HNF1B</italic> heterodimer, haploinsufficient <italic>HNF1A</italic> interacts with a certain <italic>HNF1B</italic> haplotype. The resulting truncated heterodimer might engender renal cysts. More patients with well-defined deletion within 12q.24.31 must be evaluated to produce a detailed genotype-phenotype correlation and to elucidate this emerging microdeletion syndrome.
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Intracranial calcification in a uremic infant with Wilms’ tumor in a solitary kidney

Wilms’ tumor (WT), also called nephroblastoma, is an embryonic neoplasm of the developing kidney. A previously healthy Japanese female infant had WT in a single kidney without associated congenital malformations. Preoperative chemotherapy was started for the preservation of renal tissue and function. Tumor lysis syndrome, disseminated intravascular coagulopathy, and acute renal failure were accompanying. The infant needed surgical intervention and permanent replacement therapy. At the start of emergency hemodialysis, the infant had posterior reversible leukoencephalopathy syndrome because of severe hypertension. During ongoing peritoneal dialysis, the infant suffered from anemia, dietary and fluid restriction, and restriction of time and mobility. Despite alfacalcidol and calcium supplementation, the infant had secondary hyperparathyroidism and remarkably short stature. After waiting for the completion of chemotherapy, renal transplantation from the mother was completed. Successful kidney transplantation promptly corrected preexisting metabolic abnormalities causing secondary hyperparathyroidism. Subsequently, the infant often complained of headache. Computed tomographic scanning revealed calcification in the cerebellum. Refractory secondary hyperparathyroidism was inferred as the cause. A well-functioning graft provided the infant with a greater sense of well-being and enabled her to enjoy a lifestyle free of dialysis, although the infant must continue taking transplant medications and has retained unresolved issues of short stature and ectopic intracranial calcification.

Gross hematuria and detection of nephrotic syndrome after an athletics event

Sirs, We read with great interest the article by Butani in Pediatric Nephrology [1]. The author described an infant presenting with gross hematuria (GH) at the onset of minimal-change disease nephrotic syndrome (MCNS) [1]. We recently experienced a similar case in which hematuria and nephrotic syndrome (NS) were detected in a child after an athletics, raising the question of whether the exercise induced or augmented the signs or primary renal disease. A 7-year-old Japanese girl participated in a shortdistance foot race (2 km) as a member of a selected athletics team. After completing the race, the girl was observed with prominent facial edema, GH, and proteinuria. Urinalysis showed cola-like urine with 4+ proteinuria (urine proteinto-creatinine ratio 5.49) containing numerous blood cells per high-powered field with casts. Serum total protein was 3.9 g/dl; albumin, 1.8 g/dl; total cholesterol, 410 mg/dl; creatinine, 0.3 mg/dl. Platelet counts and coagulation studies were normal. Serological tests, including those for anti-nuclear and anti-double-stranded DNA antibodies, complements C3 and C4, antistreptolysin O titers, myeloperoxidase-antineutrophil cytoplasmic antibody, and hepatitis B antigens, were all negative/normal. Renal biopsy was performed because persistent GH is unusual in MCNS. All 18 of the glomeruli obtained showed widely open patent capillary walls without mesangial proliferation. Immunofluorescence studies were negative and showed a diffuse linear staining of the alpha 5(IV)NC domain of collagen IV along the glomerular basement membrane (GBM). Electron microscopy studies revealed that the glomeruli were normal with a fusion of foot processes. The GBMs were of a normal thickness with no electrondense deposits. The profound proteinuria failed to respond to initial prednisolone therapy (dose 60 mg/m/day, orally administered each day for 4 weeks, followed by 4 weeks of the same dose on alternate days) [2]. The GH subsided 3 weeks after the athletics event concomitant with 3 weeks of oral prednisolone therapy. Weekly methylprednisolone pulse therapy combined with oral prednisolone and cyclophosphamide (2 mg/kg per day for 12 weeks) achieved an initial complete remission [3]. However, soon after prednisolone tapering, relapses accompanied with GH occurred. The manifestation of multiple relapses led to the addition of oral cyclosporin with a trough level of 80–100 ng/ml to her pharmacotherapeutic regimen. The patient continued to show frequently relapsing steroid-dependent NS even when treated with a combination of oral prednisolone and cyclosporin. Her renal function has remained normal with normotension at 6 years after diagnosis. Pediatr Nephrol (2009) 24:2463–2464 DOI 10.1007/s00467-009-1212-z