Hyogo Nakakura

TWO CASES OF HYPONATREMIC-HYPERTENSIVE SYNDROME IN CHILDHOOD WITH RENOVASCULAR HYPERTENSION

We report two children with renovascular hypertension and fibromuscular dysplasia. They initially presented with severe hyponatremia, hypokalemia, polyuria, and transient proteinuria. This combination of symptoms is known to occur in patients with renovascular and malignant hypertension, and is known as hyponatremic-hypertensive syndrome (HHS), although it is considered rare in children. Since in both of our patients, the renal arterial stenosis was very severely or almost totally occlusive, we could not perform percutaneous transluminal renal artery angioplasty, and therefore nephrectomy was the only option. A histological study showed partial or complete occlusion with intimal hyperplasia and medial fibroplasia of intrarenal arteries such as the interlobular arteries. Conclusion: Both patients showed rapidly progressive renovascular hypertension and loss of function of the affected kidney. In order to preserve renal function in such cases, early invasive intervention appears to be necessary.

Clinical characteristics of obstructive uropathy associated with rotavirus gastroenteritis in Japan.

AIMS Rotavirus gastroenteritis is severe and often results in dehydration and pre-renal azotemia. However, we have encountered four children with acute obstructive uropathy associated with acute rotavirus gastroenteritis, and several similar cases have been reported. Therefore, the aim of the present study was to clarify the epidemiology and clinical features of acute obstructive uropathy associated with acute rotavirus gastroenteritis in Japanese children. PATIENTS AND METHODS We sent questionnaires to all members of the Japanese Society for Nephrology and all authors who had published case reports of this disease in Japan, inquiring about patient age at diagnosis, sex, the type of stones, laboratory data and other factors. RESULTS 21 reported patients were evaluable, ranging from 0.4 to 3 years. The sex distribution showed a strong male prevalence. Oliguria had appeared about 7 days after the onset of gastroenteritis. Most of the patients showed hyperuricemia and hyponatremia. The stones consisted mainly of ammonium acid urate. The patients were discharged with normal renal function. CONCLUSION Although obstructive uropathy associated with rotavirus gastroenteritis is very rare, this disease condition should be explored when anuria is refractory to sufficient fluid replacement therapy or when oliguria persists despite recovery of the gastrointestinal symptoms.

Oxidative stress in a rat model of nephrosis can be quantified by electron spin resonance

The pathogenesis of nephrotic syndrome is not clear. In this study, we used electron spin resonance (ESR) to evaluate levels of reactive oxygen species in rats with puromycin aminonucleoside (PAN)-induced nephrosis. Twenty-six Wistar rats were divided into four groups: (1) PAN treated, (2) PAN treated and α-tocopherol supplemented, (3) supplemented with α-tocopherol only, (4) control. On day 9, urinary protein excretion was measured. On day 10, all animals were sacrificed with retrograde perfusion via the aorta to obtain renal venous perfusates. The signal intensities of ascorbate radicals in the perfusates were determined by ESR. After perfusion, the kidneys were isolated and sieved to obtain glomeruli for determination of glomerular thiobarbituric acid-reactive substance (TBArs) and α-tocopherol. Urinary protein excretion by PAN-treated rats increased significantly on day 9 and was reduced by α-tocopherol supplementation. The ascorbate radical intensity and glomerular TBArs level were higher in PAN-treated than in control rats and were both suppressed to control levels by α-tocopherol supplementation. There were positive correlations between ascorbate radical intensity and the daily urinary protein, as well as between ascorbate radical intensity and the glomerular TBArs level. Hence, it is possible to quantify oxidative stress due to PAN nephrosis by ESR. Our findings suggest that lipid peroxidation plays an important role in the pathogenesis of proteinuria in PAN-treated rats.

A case report of successful treatment with plasma exchange for hemophagocytic syndrome associated with severe systemic juvenile idiopathic arthritis in an infant girl.

Abstract:  An infantile case of hemophagocytic syndrome (HPS) with systemic juvenile idiopathic arthritis (s‐JIA), refractory to methylprednisolone pulse therapy and cyclosporine A administration, was successfully treated by plasma exchange. The patient was a one‐year‐old Japanese girl who had developed recurrent steroid‐dependent signs, including fever, skin eruption, and hepatopathy, while in France, where she had been diagnosed as having s‐JIA at eight months of age. As a high fever and rheumatoid rash were evident on arrival at our hospital, she was admitted and given intravenous methylprednisolone pulse therapy and cyclosporine A. She developed pancytopenia with a generalized clonic seizure, high fever, and liver dysfunction after her cytomegalovirus (CMV) titer became positive during the course of treatment; therefore, she was treated with ganciclovir. She was subsequently diagnosed as having HPS complicating s‐JIA from the findings of a bone marrow aspirate. At this time, her blood examination data including a high level of C‐reactive protein and hyperferritinemia, suggested that her s‐JIA was very active, and the pancytopenia continued after her CMV titer became negative. Therefore, CMV infection against a background of active s‐JIA could have triggered the HPS in this case. Because the HPS was resistant to an immunosuppressive regime of methylprednisolone pulse therapy and cyclosporine A, plasma exchange therapy was started. After three sessions of this therapy, the patients symptoms and laboratory data were markedly improved. Our experience suggests that plasma exchange should be considered as a therapeutic tool for HPS refractory to conventional therapy.

Clinical features and mutational survey of NPHS2 (podocin) in Japanese children with focal segmental glomerulosclerosis who underwent renal transplantation

Abstract:  Recurrent FSGS is a major challenge in the field of nephrology. To clarify the role of NPHS2 defects in the pathogenesis of FSGS recurrence, we sequenced all eight exons of NPHS2 in 11 Japanese pediatric FSGS patients with or without post‐transplant recurrence. All patients had biopsy‐proven primary FSGS, had no family history of renal diseases or consanguinity, were steroid‐resistant, and received living‐related renal transplantation. The mean age at onset was 5.0 ± 3.1 yr and mean age at renal transplantation was 10.4 ± 4.1 yr. Mutational analysis of NPHS2 was performed using polymerase chain reaction and direct sequencing. We found a synonymous T/C polymorphism at alanine 318 (GCC to GCT) in seven of 11 patients but no other causative NPHS2 mutations. FSGS recurred immediately after transplant in seven patients, while the remaining four patients had no recurrence for 3.2–5.8 yr. There were no differences between recurrent and non‐recurrent patients in the onset age and the interval from onset to ESRD. In conclusion, we detected no causative NPHS2 mutations in Japanese pediatric FSGS patients with or without post‐transplant recurrence. Further studies on the involvement of other genes are required to better understand recurrent FSGS.

Protective effect of radical scavenger edaravone against puromycin nephrosis.

AIM Recent studies have indicated that reactive oxygen species (ROS) play a role in the pathogenesis of glomerular injury leading to proteinuria in nephrotic syndrome. In the present investigation, we examined the effects of the radical scavenger edaravone administered at various time points to rats with puromycin nephrosis. MATERIALS AND METHODS 35 Wistar rats were divided into five groups: treatment with puromycin aminonucleoside (PAN) alone, treatment with PAN followed by edaravone in the early period, treatment with PAN followed by edaravone administration in the late period, treatment with PAN and administration of edaravone for the whole experimental period, and untreated controls. On Days 3, 6 and 9, urinary protein excretion was measured. The levels of glomerular thiobarbituric acid-reactive substance (TBArs) were determined in all animals on Day 10. RESULTS On Day 9, rats that had been administered edaravone showed reduced urinary protein excretion and reduced glomerular TBArs. In particular, edaravone administration in the late period, during which proteinuria was most acute, had the effect of reducing the severity of proteinuria. Glomerular TBArs were suppressed to the control level. Our results indicate that edaravone exerts a protective effect in the acute phase of PAN nephrosis when administered as antioxidant therapy at the onset of proteinuria. CONCLUSIONS Edaravone can ameliorate urinary protein excretion after the onset of proteinuria in nephrotic syndrome.

Clinical characteristics of rotavirus gastroenteritis with urinary crystals

Rotavirus gastroenteritis is severe and often results in dehydration and pre‐renal azotemia. In addition, some patients with acute obstructive uropathy due to ammonium acid urate stones, developing approximately 6–7 days after the onset of rotavirus gastroenteritis, have been reported, mainly in Japan. The pathophysiological mechanism responsible for stone formation has not been clarified. In the present study, we investigated the clinical characteristics of these patients, and analyzed the pathophysiology underlying the formation of urinary stones.

Molecular effect of a novel missense mutation, L266V, on function of ClC-5 protein in a Japanese patient with Dent's disease.

UNLABELLED We report the use of three dimensional computational analysis of chloride channel 5 (ClC-5) based on a novel mutation, L266V, identified in a 15-year-old Japanese boy with Dents disease. Since both leucine and valine are branched-chain amino acids, it has not been proved conclusively whether L266V mutation is actually responsible for the development of Dents disease. In the present study using molecular analysis, we investigated the mechanism for loss of function of the ClC-5 protein resulting from the L266V mutation. Structural analysis of the normal ClC-5 transmembrane region using molecular modeling showed that the two respective Leu266 residues were located at the interface of the dimer formed by the aligned ClC-5 monomers. The Leu266 side-chains were positioned close to each other through hydrophobic interaction, resembling two interconnecting hooks. When Leu266 was replaced by a valine residue, the hydrophobic interaction between the CLC-5 monomers was reduced, and dimer formation was impaired. This computer simulation analysis has thus provided strong evidence for the important role of Leu266 in the dimerization of human ClC-5 in membranes. CONCLUSION The finding of the present study suggest that computational modeling and molecular analysis could be an alternative to labor-intensive in vitro functional studies.

Clinical features in a series of 258 Japanese pediatric patients with thrombotic microangiopathy

BackgroundThrombotic microangiopathy (TMA) includes hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). This study examined the epidemiological characteristics of pediatric patients with TMA classified according to etiology.MethodsThe survey evaluated 258 Japanese pediatric patients diagnosed with TMA between 2012 and 2015.ResultsThe primary diseases responsible for TMA were categorized as TTP (15 cases), Shiga toxin-producing Escherichia coli-associated HUS (STEC-HUS) (166 cases), atypical HUS (aHUS) (40 cases), and secondary TMA (27 cases). The remaining 10 cases were unable to be classified to one of the four categories of the primary disease. Renal replacement therapy was required in the acute phase in 103 patients with TMA, including 65 with STEC-HUS, 22 with aHUS, two with TTP, 10 with secondary TMA, and four unclassified cases. The last observational findings were normal renal function in 95 patients and chronic kidney disease (CKD) stage 1 in 62. For 31 patients, chronic renal insufficiency (CKD stage 2-5) persisted, including four patients with end-stage kidney disease (CKD stage 5). Seventeen patients suffered recurrence of TMA, and eight patients died.ConclusionThis study clarified differences in the relative proportions of primary diseases between patients from Japan and North America and Europe. The difference may be attributable to the lower estimated incidence of STEC-HUS in Japan.

A clinicopathological study of recurrent IgA nephropathy following renal transplantation in children

(1) The mean age at onset was 10.1 years (range, 6.2– 12.9 years) and the mean interval between disease onset and the progression to end-stage renal failure was 3.8 years (range, 0.1–9.7 years). After dialysis therapy with a mean period of 1.1 years (range, 0.3–1.6 years), patients underwent kidney transplantation with a mean age at transplantation of 14.8 years (range, 8.0– 17.8 years). (2) Of seven patients, recurrence of IgAN was observed in six, and haematuria and proteinuria were appeared after a mean of 1.2 years (range, 0.3–2.5 years) and of 1.7 years (range, 0.5–4.4 years) post-transplantation, respectively. (3) Extra-capillary glomerular lesion including crescent was observed in five out of six patients with recurrent IgAN following renal transplantation, and the mean percentage of glomeruli with crescent was 13.0% (range, 5–38%). These lesions seemed to be associated with the deterioration of the renal allograft function in a portion of patients with recurrent IgAN. (4) Allograft biopsies showed some pathological findings including an increase of glomerular size, ischemia-related lesions, and thickening of endothelium other than IgAN-specific findings.