Long‐term clinicopathologic observation in a case of steroid‐resistant nephrotic syndrome caused by a novel Crumbs homolog 2 mutation

Recent advances in high‐throughput sequencing for clinical genetic testing have revealed novel disease‐causing genes, such as Crumbs homolog 2 (CRB2) for early‐onset steroid‐resistant nephrotic syndrome (SRNS). We report the long‐term clinicopathologic observation of a Japanese female patient with SRNS caused by a newly identified compound heterozygous mutation of CRB2 (p.Arg628Cys and p.Gly839Trp located in the 10th and 11th epidermal growth factor‐like domains, respectively). She was initially examined during a mass urinary screening for 3.5‐year‐old children in Japan. Although she developed long‐standing SRNS without any extrarenal clinical signs thereafter, her renal function was well‐preserved over the next 17 years. In total, six sequential renal biopsy specimens revealed histologic alterations ranging from minor glomerular abnormalities to advanced focal segmental glomerulosclerosis (FSGS). A genetic analysis for SRNS performed at 19 years of age revealed a newly identified compound heterozygous mutation in CRB2. Glomerular CRB2 immunoreactivity in biopsy specimens from the patient was scanty, whereas intense expression was observed in those from patients with idiopathic FSGS or in controls. To our knowledge, this is the first report regarding a long‐term outcome in a case of SRNS due to an identified CRB2 mutation. Although the phenotype of CRB2 mutation‐related syndrome is now expanding, we believe that this case might provide a novel clinicopathologic aspect of this syndrome.     

Clinical,pathological, and genetic characteristics of cases with asymptomatic proteinuria not manifesting nephrotic syndrome at onset: a single-center retrospective study

Clinical and Experimental Nephrology - Cases with asymptomatic proteinuria (ASP) not manifesting nephrotic syndrome often pathologically show focal segmental glomerulosclerosis (FSGS). However,...     

Clinical time course of pediatric acute disseminated encephalomyelitis

The detailed clinical time course in acute disseminated encephalomyelitis (ADEM) from initial symptoms, through exacerbation, to remission has not been widely reported. Hence, this study aimed to investigate the clinical time course of pediatric ADEM. This was a multicenter retrospective study based on registry data from medical chart reviews. The study included children who met the international consensus diagnostic criteria for ADEM. The patients comprised 18 boys and 6 girls, with a mean age of 5.5?±?3.3?years at onset. From onset, the time until peak neurological symptoms, time until initial improvement, and time until full recovery was 3.1?±?3.7?days, 6.0?±?4.5?days, and 26?±?34?days, respectively. Twenty-three (96%) patients were treated with high-dose methylprednisolone (mPSL) with a mean duration of 4.1?±?4.0?days from onset. The condition of 15 patients (65%) improved within 3?days of high-dose mPSL initiation, whereas, that of four patients began to improve after >5?days of high-dose mPSL initiation. Only one patient (4%) did not achieve full recovery despite treatment with high-dose mPSL, intravenous immunoglobulin, and plasma exchange. This study presents the detailed clinical time course in pediatric ADEM in Japan. Progression of neurologic deficits typically lasts a few days, with initial improvement in 1?week leading to full recovery within 1?month.     

Fosphenytoin vs. continuous midazolam for pediatric febrile status epilepticus

Background

Fosphenytoin (fPHT) and continuous intravenous midazolam (cMDL) had commonly been used as second-line treatments for pediatric status epilepticus (SE) in Japan. However, there is no comparative study of these two treatments.

The effect of aldosterone blockade in patients with Alport syndrome

Recent studies indicate that adding the mineralocorticoid receptor antagonist spironolactone (SP) to angiotensin converting enzyme inhibitors (ACEI) or ACEI and angiotensin receptor blocker (ARB), which is known as a triple blockade, enhances the more beneficial effects on urinary protein excretion of patients with chronic kidney diseases. In this study, we explored the effects of SP on urinary protein excretion in patients with Alport syndrome featuring persistent proteinuria in spite of the long-term use of ACEI (lisinopril) or both ACEI and ARB (candesartan). Five patients with Alport syndrome were enrolled and SP treatment (25 mg/day) was started. At the start of SP administration, all patients showed good renal function and none of them suffered from hypertension. We decided to assess the effect of SP by determining the morning urinary protein/creatinine ratio (U-P/C) and estimated glomerular filtration rate (EGFR). After SP treatment was started, U-P/C was significantly reduced at 3, 6, 12 and 18 months, while EGFR did not change. The drop in systolic and diastolic blood pressure was statistically significant and serum potassium level was slightly elevated. None of the patients showed signs of severe hyperkalemia (>5.0 mEq/l). These results suggest that aldosterone receptor blockade combined with ACEI and ARB therapy offers a valuable adjuvant treatment for the reduction of proteinuria in patients with Alport syndrome as in those with other chronic kidney diseases. SP can thus be expected to constitute a good renoprotective agent for Alport syndrome. These preliminary data indicate that large-scale trials of this therapy should be done.     

Risk factors for cyclosporine-induced tubulointerstitial lesions in children with minimal change nephrotic syndrome

BACKGROUND: Cyclosporine (CsA) is effective for the treatment of children with steroid-dependent and -resistant nephrotic syndrome (NS), but it can result in chronic CsA nephrotoxicity including CsA-induced tubulointerstitial lesions. The factors responsible for the development of CsA-induced tubulointerstitial lesions are unknown. METHODS: To identify the risk factors for the development of CsA-induced tubulointerstitial lesions in children with minimal change NS who had been treated with long-term moderate-dose CsA, we compared several clinical and laboratory factors of 37 patients with and without CsA-induced tubulointerstitial lesions by the Mann-Whitney U test, Fisher's exact test, and stepwise logistic-regression analysis. RESULTS: Thirteen patients had CsA-induced tubulointerstitial lesions and 24 patients had none. Among clinical and laboratory factors, the duration of CsA treatment (P = 0.003) and the duration of heavy proteinuria during CsA treatment (P = 0.024) were related to the development of CsA-induced tubulointerstitial lesions as determined by the univariate analyses. Indeed, CsA-induced tubulointerstitial lesions were found in 2 of 18 (11%) patients who had been treated with CsA for less than 24 months, but in 11 of 19 patients (58%) who had been treated for more than 24 months (P = 0.005). They were also found in 4 of 23 patients (17%) who had heavy proteinuria for less than 30 days during CsA treatment, but in 9 of 14 patients (64%) who had heavy proteinuria for more than 30 days (P = 0.006). Stepwise logistic-regression analysis revealed that the duration of CsA treatment for more than 24 months (chi2 = 6.203, P = 0.013) and the duration of heavy proteinuria during CsA treatment for more than 30 days (chi2 = 5.871, P = 0.015) were independent risk factors for the development of CsA-induced tubulointerstitial lesions. CONCLUSIONS: Duration of the CsA treatment and the duration of heavy proteinuria during CsA treatment were independent significant risk factors for the development of CsA-induced tubulointerstitial lesions in children with MCNS who had been treated with long-term moderate-dose CsA.     

Risk factors for developing severe clinical course in HUS patients: a national survey in Japan

Background: Hemolytic uremic syndrome (HUS) is characterized by acute renal failure, thrombocytopenia and hemolytic anemia. Cases accompanied by prodromal gastrointestinal tract symptoms are referred to as typical HUS. Some severe HUS patients require dialysis or develop central nervous system (CNS) disorders after the onset of HUS.
Methods: Patients who developed typical HUS in 2001 and 2002 in Japan, 127 in all, were the study subjects. To identify the risk factors for the development of a severe clinical course, clinical and laboratory data were analyzed on logistic regression.
Results: Two of the 127 patients died (1.6%): one from acute cardiac failure and the other from a CNS disorder. Thirty-five patients required dialysis (28%) and 30 had CNS symptoms (24%). Multivariate analysis indicated that the risk factors for need for dialysis were serum sodium and alanine aminotransferase (ALT) levels of ≤130 mEq/L and ≥70 IU/L, respectively, at the onset of HUS and those for developing CNS disorders were dialysis and C-reactive protein (CRP) ≥5.0 mg/dL at the onset of HUS.
Conclusions: Because patients with these risk factors, such as low serum sodium, high ALT or high CRP levels, may require dialysis or develop CNS disorders, they should be treated carefully in the early stage of HUS.     

Early steroid pulse therapy for children with suspected acute encephalopathy: An observational study

Steroid pulse therapy is widely used to treat virus-associated acute encephalopathy, especially the cytokine storm type; however, its effectiveness remains unknown. We sought to investigate the effectiveness of early steroid pulse therapy for suspected acute encephalopathy in the presence of elevated aspartate aminotransferase (AST) levels.We enrolled children admitted to Hyogo Children''s Hospital between 2003 and 2017 with convulsions or impaired consciousness accompanied by fever (temperature >38°C). The inclusion criteria were: refractory status epilepticus or prolonged neurological abnormality or hemiplegia at 6 hours from onset, and AST elevation >90 IU/L within 6 hours of onset. We excluded patients with a neurological history. We compared the prognosis between the groups with or without steroid pulse therapy within 24 hours. A good prognosis was defined as a Pediatric Cerebral Performance Category Scale (PCPC) score of 1-2 at the last evaluation, within 30 months of onset. Moreover, we analyzed the relationship between prognosis and time from onset to steroid pulse therapy.Fifteen patients with acute encephalopathy and 5 patients with febrile seizures were included in this study. Thirteen patients received steroid pulse therapy within 24 hours. There was no between-group difference in the proportion with a good prognosis. There was no significant correlation between PCPC and timing of steroid pulse therapy (rs = 0.253, P = .405). Even after excluding 2 patients with brainstem lesions, no significant correlation between PCPC and steroid pulse therapy timing (rs = 0.583, P = .060) was noted. However, the prognosis tended to be better in patients who received steroid pulse therapy earlier.Steroid pulse therapy within 24 hours did not improve the prognosis in children with suspected acute encephalopathy associated with elevated AST. Still, even earlier administration of treatment could prevent the possible neurological sequelae of this condition.     

Clinical characteristics and long-term outcome of diarrhea-associated hemolytic uremic syndrome: a single center experience

Objectives

To clarify the clinical characteristics and long-term outcomes of patients with diarrhea-associated hemolytic uremic syndrome (D?+?HUS) with a particular focus on time course.

Methods

We retrospectively analyzed the medical records of 61 patients with D?+?HUS who were admitted to Kobe University Hospital between 1995 and 2015. The onset of D?+?HUS was defined as day 1 of diarrhea.

Results

The age of onset was 4.1 (1.5–13.4) years, and the period between onset and diagnosis of D?+?HUS was 5 (3–18) days. The platelet count was lowest on day 7 (4–24), and the lactase dehydrogenase level was maximal on day 8 (4–25). Twenty-three patients required dialysis for 13 (2–37) days, starting at day 5–9. Seventeen patients showed central nervous system (CNS) symptoms at day 4–18. They were followed up for 3.7 (0–18.4) years. At the final follow-up, estimated glomerular filtration rate was 113.7 (57.9–159.9) ml/min/1.73 m² with five patients having chronic kidney disease. Three patients developed CNS sequelae. The time to diagnosis was significantly shorter in the group of patients receiving dialysis than without dialysis (p?=?0.018) and in the group with CNS complications than without (p?=?0.013).

Conclusion

CNS complications were often apparent after blood examination results improved. Moreover, a shorter period between the onset of diarrhea and a diagnosis of D?+?HUS indicated a more severe clinical course or long-term sequelae, and it should be considered as a risk factor for poor prognosis.

     

Identification of mutations in <Emphasis Type="Italic">FN1</Emphasis> leading to glomerulopathy with fibronectin deposits

Background

Glomerulopathy with fibronectin deposits (GFND) is a rare autosomal dominant disease characterized by massive fibronectin deposits, leading to end-stage renal failure. Although mutations within the heparin-binding domains of the fibronectin 1 gene (FN1) have been associated with GFND, no mutations have been reported within the integrin-binding domains.

Methods

In this study, FN1 mutational analysis was conducted in 12 families with GFND. Biochemical and functional features of mutated proteins were examined using recombinant fibronectin fragments encompassing both the integrin- and heparin-binding domains.

Results

We report six FN1 mutations from 12 families with GFND, including five that are novel (p.Pro969Leu, p.Pro1472del, p.Trp1925Cys, p.Lys1953_Ile1961del, and p.Leu1974Pro). p.Pro1472del is localized in the integrin-binding domain of fibronectin, while the others are in heparin-binding domains. We detected p.Tyr973Cys, p.Pro1472del, and p.Leu1974Pro mutations in multiple families, and haplotype analysis implied that p.Pro1472del and p.Leu1974Pro are founder mutations. The protein encoded by the novel integrin-binding domain mutation p.Pro1472del showed decreased cell binding ability via the integrin-binding site. Most affected patients developed urine abnormalities during the first or second decade of life, and some mutation carriers were completely asymptomatic.

Conclusions

This is the second large-scale analysis of GFND families and the first report of an integrin-binding domain mutation. These findings may help determine the pathogenesis of GFND.