Yuki Abe

Secondary renal Fanconi syndrome caused by valproate therapy

Although renal Fanconi syndrome resulting from valproate (VPA) has occasionally been reported, the detailed clinical characteristics of this disease remain unclear. To clarify the clinical features of patients with VPA-induced Fanconi syndrome, we analyzed the clinical and laboratory data of seven affected patients. All patients were children, were severely disabled and required tube feeding. Five patients required treatment with multiple anticonvulsant agents. Hypophosphatemia and hypouricemia were found in all patients. Mild proteinuria, increased excretion of urinary β2-microglobulin (β2MG) and generalized hyperaminoaciduria were present in all patients. The renal biopsy of one patient exhibited tubulointerstitial nephritis without any structural abnormalities of the mitochondria in proximal renal tubular cells. All patients recovered from the Fanconi syndrome after the cessation of VPA therapy without any long-term renal sequellae. These results indicate that young age and being severely disabled with tube feeding and anticonvulsant polytherapy are contributory factors to the development of VPA-induced Fanconi syndrome. Serum phosphate and uric acid concentrations and urinary β2MG levels in addition to serum electrolytes and urinalysis should be examined regularly in patients receiving VPA therapy, especially in those with the contributory factors outlined above. Patients with Fanconi syndrome caused by VPA have a favorable renal outcome.

Sterile pyuria in patients with Kawasaki disease originates from both the urethra and the kidney.

To identify the origin of urinary leukocytes in Kawasaki disease (KD) patients with pyuria, we prospectively studied clinical and laboratory findings of 23 KD patients. Patients were divided into three groups: patients without pyuria, patients with pyuria in both voided urine and bladder urine obtained by transurethral catheterization (bladder pyuria) and patients with pyuria only in voided urine (urethral pyuria). Pyuria in voided urine was found in ten of 23 KD patients (43.5%), with subsequent urine cultures proving sterile. Five out of ten patients with pyuria in voided urine also exhibited pyuria in bladder urine, whilst the remaining patients did not have pyuria in bladder urine. Urinary protein levels were higher in patients with bladder pyuria and in patients with urethral pyuria than in patients without pyuria. Urinary β2-microglobulin concentrations and serum blood urea nitrogen (BUN) and creatinine levels were higher in patients with bladder pyuria than in patients with urethral pyuria or in patients without pyuria, although the serum BUN and creatinine levels of patients with bladder pyuria were within the normal ranges. These results suggest that some patients with KD develop sterile pyuria that originates from the urethra and/or the kidney as a result of mild and subclinical renal injury.

Renal involvement in children with influenza A virus infection.

Abstract.Renal involvement in influenza A virus infection has been rarely reported. To define the clinical characteristics and the factors contributing to the development of renal involvement in influenza A virus infection, we reviewed the clinical characteristics, laboratory data, pediatric risk of mortality (PRISM) score, and the number of systemic inflammatory response syndrome (SIRS) criteria and dysfunctional organs in 45 hospitalized children with influenza A virus infection. Eleven (24.4%) patients had renal involvement. All patients with renal involvement suffered from sepsis and multiple organ dysfunction syndrome (MODS) and 5 developed acute renal failure (ARF). The incidences of dehydration, hypotension, disseminated intravascular coagulation (DIC), and rhabdomyolysis were significantly higher in patients with renal involvement. PRISM scores, the numbers of SIRS criteria and dysfunctional organs, and mortality rate were also higher in patients with renal involvement. Influenza A RNA was absent in the renal tissues of 3 patients with ARF. These results suggested that renal involvement in influenza A virus infection occurred in patients with sepsis and MODS; dehydration, hypotension, DIC, and rhabdomyolysis were factors contributing to its development; direct viral injury to the kidney did not seem to occur in influenza A virus infection.

Lower Birth Weight Associated with Current Overweight Status Is Related with the Metabolic Syndrome in Obese Japanese Children

The purpose of this study was to clarify the relationship between lower birth weight and current overweight status and to examine the involvement of these factors in the development of the metabolic syndrome (MS) in obese Japanese children. We examined 97 obese boys (mean age 11.3 years; mean percentage overweight [POW] 52.4%) and 29 obese girls (mean age 11.1 years; mean POW 58.3%). The anthropometric measurements, blood pressure, fasting serum insulin and blood glucose, liver enzymes, lipids and lipoproteins were measured. Birth weight and gestational weeks were also recorded. The subjects were divided into either an MS group or a Non-MS group using criteria proposed for Japanese children. We compared the weight parameters (birth weight, current weight and current weight–to−birth weight ratio [WBWR]) between the two groups and analyzed the relationships between the weight parameters and metabolic derangements. There were no significant differences in age or anthropometric measurements between the two groups. However, birth weight in the MS group was lower than that in the Non-MS group, while WBWR of the MS group was higher than that in the Non-MS group. Blood pressure and serum insulin correlated positively with WBWR. These findings suggested that lower birth weight with current overweight status was associated with the MS in obese Japanese children. We were unable to clarify whether subjects with lower birth weight who achieved proper weight gains had the same risk as subjects with appropriate birth weight. However, they should be assisted to grow adequately to prevent future metabolic derangements.

A case of Rabson-Mendenhall syndrome with a novel mutation in the tyrosine kinase domain of the insulin receptor gene complicated by medullary sponge kidney

Abstract Rabson-Mendenhall syndrome (RMS) is a genetic disorder characterized by severe insulin resistance and somatic characteristics. Recombinant insulin-like growth factor 1 (r-IGF-1) is used to treat RMS, as the IGF-1 and insulin receptors share homology. However, the effect of r-IGF-1 varies in patients and it is difficult to manage metabolic status appropriately in r-IGF-1 resistant cases. We report a Japanese boy with RMS who showed resistance to r-IGF-1 therapy and a novel mutation in the insulin receptor in the tyrosine kinase domain. Mutations in this region disturb tyrosine kinase catalytic activity in IGF-1 receptors as a result of dominant negative effects. We consider this mutation to be the cause of resistance to r-IGF-1. The patient also exhibited radiographical features of medullary sponge kidney and had severe nephrocalcinosis and hypokalemia, indicating Bartter syndrome. However, analysis revealed no mutations in the responsible genes and the etiology of the renal abnormalities therefore remains unknown.

Association between Compound Heterozygous Mutations of SLC34A3 and Hypercalciuria

Background: Mutations in SLC34A3 have been shown to cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Patients with compound heterozygous or homozygous mutations develop skeletal lesions in addition to hypercalciuria, hypophosphatemia and/or elevated 1,25-dihydroxy vitamin D [1,25-(OH)2D] levels. Here, we report a case of hypercalciuria without skeletal lesions in a patient with compound heterozygous mutations of SLC34A3.Case Presentation: A 3-year-old girl presented with microscopic hematuria. Laboratory data revealed elevated 1,25-(OH)2D levels and serum calcium, reduced serum inorganic phosphorus and hypercalciuria. In addition, the ratio of maximal rate of renal tubular reabsorption of phosphate to glomerular filtration rate was reduced. Abdominal ultrasound revealed bilateral nephrocalcinosis. These data were consistent with HHRH, but the patient had no clinical features of rickets or any family history of skeletal disease. Genetic analysis revealed compound heterozygous mutations of c.175+1 G>A and c.1234 C>T in SLC34A3.Conclusions: This is the report of a patient with compound heterozygous mutations of SLC34A3 and normal skeletal features. Biallelic mutations in SLC34A3 can thus be associated with hypercalciuria not accompanied by rickets. Orally administered inorganic phosphate is predicted to improve symptoms in these patients, hence screening for SLC34A3 mutations should be considered in patients with hypercalciuria of unknown etiology.

Pertussis pneumonia complicated by a hyponatremic seizure.

We present the case of a 6-week-old male infant who had a convulsion due to pertussis pneumonia. He was admitted to our emergency department because of lethargy and hypothermia. He developed a generalized tonic-clonic convulsion, requiring various treatments, including artificial ventilation. A chest CT showed bilateral pneumonia and laboratory data revealed hyponatremia with other features of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Although SIADH has been recognized as a cause of hyponatremia in association with pneumonia, there is little in the literature regarding SIADH caused by pertussis. Hyponatremia caused by SIADH must be considered as a differential diagnosis of seizures in pertussis infection of infants.

Renal tubular dysfunction in patients with molecular defects of the insulin receptor gene.

To the editor, We readwith interest on a case of Donohue syndromewith renal tubular dysfunction (RTD) and amutation in the insulin receptor gene (INSR) written byHovnik et al. that was published recently in your journal [3]. The authors showed that although recombinant human insulin-like growth factor I (rh-IGF-I) therapy improved RTD, it did not improve the anabolic status of their patient. We recently reported on a case of Rabson–Mendenhall syndrome with INSR mutations and RTD [1]. Although the patient underwent rh-IGF-I therapy at the age of 4 months, his physical constitution continued to deteriorate, and RTD did not resolve. The therapeutic effect of rh-IGF-I varies between cases.We suggest that rh-IGF-I may have had an inadequate effect in the patient of the study of Hovnik et al. because anabolic status did not improve. Chin et al. showed that activation of phosphatidylinositol3-kinase (PI3K) stimulated endocytosis of the renal outer medullary potassium channel (ROMK) [2]. Insulin and IGFI can activate PI3K and therefore may inhibit renal potassium excretion by reducing the abundance of ROMK. However, our patient showed sustained RTD after administration of rhIGF-I, probably due to a poor response to rh-IGF-I. The patient in the study of Hovnik et al. appeared to be in a similar situation to our patient, because rh-IGF-I therapy did not improve their anabolic status. Therefore, recovery of RTD in their patient could not be fully explained by the effect of rhIGF-I. In our patient, RTD resolved spontaneously at the age of 18 months. The recovery of renal tubular function in Hovnik’s patient may have depended partially on rh-IGF-I treatment, although this may not have been the only mechanism. Some renal pathways other than the system mediated by IGF-I develop during infancy and may play a specific role in renal tubular function in patients with insulin receptor insufficiency.

Detection of early stage medullary thyroid carcinoma by measuring serum calcitonin using an electro chemiluminescence immuno-assay: A case report of a young Japanese woman with a high-risk RET mutation

Abstract. Medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder caused by the mutation of the RET proto-oncogene, that shows nearly complete penetration. The American Thyroid Association guidelines recommend prophylactic thyroidectomy for patients with high-risk RET mutations. However, in Japan, ethical and medical issues may preclude prophylactic treatment in young patients. Hence, an early diagnosis of MTC is necessary to ensure a favorable outcome. Here, we report the case of a young Japanese girl with a high-risk RET mutation, diagnosed with very early stage MTC using serum calcitonin (Ctn) values measured using an electro chemiluminescence immuno-assay (ECLIA). The Japanese girl with a family history of MEN2 had been followed at our hospital since she was 5-mo-old. RET analysis revealed that she displayed a Cys634Gly mutation. The patient underwent annual neck ultrasonography and calcium infusion testing. When she was 8-yr-old, the Ctn level, measured using ECLIA, dramatically increased with calcium stimulation, from a baseline of 11.3 pg/mL to 333 pg/mL. She subsequently underwent total thyroidectomy and was diagnosed with stage I MTC. Detecting early stage MTC by monitoring serum Ctn measured by ECLIA, may represent a useful strategy for patients with high-risk RET mutations.

Bartter-like syndrome in patients with molecular defects of the insulin receptor gene.

I read with interest the article entitled ‘‘Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR?’’ in this journal by Grasso et al. [1]. The authors described two patients with SIR who exhibited type II Bartter-like syndrome (BLS). Bartter syndrome type II is caused by molecular defects of the renal outer medullary potassium channel (ROMK) gene, and patients may develop transient hyperkalemic metabolic acidosis in the early postnatal period in contrast to type I Bartter syndrome [2]. We recently reported the case of a boy with Rabson– Mendenhall syndrome (RMS) with compound heterozygous INSR mutations (T937M/A1204T) who exhibited clinical features of type II BLS [3]. The patient showed transient normokalemic metabolic acidosis in the early postnatal period and subsequently developed hypokalemic metabolic alkalosis with nephrocalcinosis at 2 month of age, suggesting that the patient had type II Bartter syndrome. However, no mutations were found in SLC12A1, KCNJ1 or CLCNKB in this patient. The patient’s serum insulin level before treatment for SIR was 8,038.0 l U/mL (normal range: 2.6–31.6 l U/mL). Subcutaneous administrations of high-dose insulin and recombinant insulin-like growth factor-1 (rIGF-1) gradually improved the patient’s hyperinsulinemia, and clinical features of BLS disappeared at 18 months of age, with the patient having serum insulin level of 915.0 l U/mL. These findings suggest that type II BLS in our patient may have resulted from ROMK dysfunction secondary to extremely high insulin levels. A recent experimental study by Cheng et al. [4] using human embryonic kidney cells transfected with ROMK revealed that high-dose insulin activates phosphatidylinositol-3-kinase and then inhibits the function of ROMK by enhancing its endocytosis. This study indicated that highdose insulin can cause ROMK dysfunction. However, patients with complete loss of INSR function exhibit no insulin reaction on any organs and die in neonate or early infancy. Patients with RMS, like our patient, have some residual INSR function. Organ-specific variability of insulin reaction may induce ROMK dysfunction of the thick ascending limb of Henle’s loop in our patient with some residual INSR function. Taken together, the clinical and laboratory findings of our patient and the experimental study of Cheng et al. suggest that ROMK dysfunction secondary to extremely high concentration of insulin may contribute to the development of type II BLS in some patients with SIR associated with molecular defects of INSR.