Emerging drugs for the treatment of hepatic fibrosis on nonalcoholic steatohepatitis.

INTRODUCTION: Approved drug therapies for nonalcoholic steatohepatitis (NASH) are lacking, for which various agents are currently being tested in clinical trials. Effective drugs for liver fibrosis, the factor most associated with prognosis in NASH, are important. AREAS COVERED: This study reviewed the treatment of NASH with a focus on the effects of existing drugs and new drugs on liver fibrosis. EXPERT OPINION: Considering the complex pathophysiology of fibrosis in NASH, drug therapy may target multiple pathways. The method of assessing fibrosis is important when considering treatment for liver fibrosis in NASH. The Food and Drug Administration considers an important fibrosis endpoint to be histological improvement in at least one fibrosis stage while preventing worsening of fatty hepatitis. To obtain approval as a drug for NASH, efficacy needs to be demonstrated on endpoints such as liver-related events and myocardial infarction. Among the current therapeutic agents for NASH, thiazolidinedione, sodium-glucose co-transporter 2, and selective peroxisome proliferator-activated receptors α modulator have been reported to be effective against fibrosis, although further evidence is required. The effects of pan-peroxisome proliferator-activated receptors, obeticholic acid, and fibroblast growth factor-21 analogs on liver fibrosis in the development stage therapeutics for NASH are of particular interest.

Mortality associated with the development of acute liver failure after a single dose of nivolumab.

AIM: Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors are reported in all organs; however, the frequency of liver injury is low compared to irAEs in other organs. We describe a case of fulminant hepatitis after administration of the first dose of nivolumab for the management of esophageal cancer. METHODS: A man in his 80s was treated with nivolumab as a second-line therapy after his overall health worsened during preoperative chemotherapy for esophageal cancer. He was admitted to the hospital as an emergency case 30 days later with complaints of vomiting, following which acute liver failure was diagnosed. RESULTS: The patient developed hepatic encephalopathy on the third day after admission and died on the seventh day. The pathological results showed sub-extensive spread hepatocellular necrosis throughout the liver, and immunostaining confirmed the presence of CD8-positive cells, which is consistent with irAEs. CONCLUSIONS: Immune checkpoint inhibitors have proven to be effective for the treatment of malignant tumors, and although fatalities due to acute liver failure are extremely rare, such cases have been reported previously. Among the immune checkpoint inhibitors, anti-programmed death-1 receptor is associated with less hepatotoxicity. However, even a single dose of this treatment can cause acute liver failure, which could be fatal.

Urine alpha 1-microglobulin-to-creatinine ratio and beta 2-microglobulin-to-creatinine ratio for detecting CAKUT with kidney dysfunction in children.

BACKGROUND: The leading cause of advanced chronic kidney disease (CKD) in children is congenital anomalies of the kidney and urinary tract (CAKUT). However, the most appropriate parameters of biochemical urine analysis for detecting CAKUT with kidney dysfunction are not known. METHODS: The present observational study analyzed data on children with CAKUT (stage 2-4 CKD) and the general pediatric population obtained from school urine screenings. The sensitivity and specificity of urine alpha 1-microglobulin-, beta 2-microglobulin-, protein-, and the albumin-to-creatinine ratios (AMCR, BMCR, PCR, ACR, respectively) in detecting CAKUT with kidney dysfunction were compared with those of the conventional urine dipstick, and the most appropriate of these four parameters were evaluated. RESULTS: In total, 77 children with CAKUT and 1712 subjects in the general pediatric population fulfilled the eligibility criteria. Conventional dipstick urinalysis was insufficient due to its low sensitivity; even when the threshold of proteinuria was +/-, its sensitivity was only 29.7% for stage 2 and 44.1% for stage 3 CKD. Among the four parameters assessed, the AMCR and BMCR were adequate for detecting CAKUT in children with stage 3-4 CKD (the respective sensitivity and specificity of the AMCR for detecting CAKUT in stage 3 CKD was 79.4% and 97.5% while that of BMCR was 82.4% and 97.5%). These data were validated using national cohort data. CONCLUSION: AMCR and BMCR are superior to dipstick urinalysis, PCR, and ACR in detecting CAKUT with kidney dysfunction, particularly stage 3 CKD. However, for AMCR, external validation is required. A higher resolution version of the Graphical abstract is available as Supplementary information.

ß2-microglobulin measurement with dried urine spots for congenital anomalies of the kidney and urinary tract screening in 3-year-old children.

BACKGROUND: Screening using dipstick urinalysis has long been performed in 3-year-old children; however, it is ineffective in detecting congenital anomalies of the kidney and urinary tract (CAKUT). Measurement of the urinary ß2-microglobulin (ß2MG)/creatinine (Cr) ratio may be more effective for this purpose. Analysis of dried urine spots (DUS) on filter paper is suitable for mass screening since operational costs are low and samples are easy to collect and transport. We examined the accuracy of measuring the urinary ß2MG/Cr ratio in DUS on filter paper. METHODS: We collected 2,623 urine samples from 3-year-old children. ß2MG and Cr levels were measured in DUS on filter paper. We examined the correlation between the ß2MG/Cr ratios measured in DUS and using the conventional method in 640 samples using the coefficient of determination test. Children with high ß2MG/Cr ratios (>0.6 µg/mg Cr) in DUS samples were further examined to establish a definitive diagnosis. RESULTS: There was strong correlation between the two methods for determination of ß2MG levels (r2 = 0.68; P < 0.001) and ß2MG/Cr ratios (r2 = 0.69; P < 0.001). Of the 2,623 children, 38 (1.45%) had ß2MG/Cr ratios >0.6. Thirty-five children were subsequently examined, resulting in findings of renal hypodysplasia (n = 2, 0.08%), horseshoe kidney (n = 1, 0.04%), renal tubular dysfunction with hepatoblastoma (n = 1, 0.04%), data abnormality (high urine ß2MG level, n = 6, 0.23%; high serum Cr level, n = 1, 0.04%), and normal values (n = 24, 0.91%). CONCLUSIONS: We evaluated a practical method for measuring ß2MG/Cr ratios in DUS as a screening method to detect CAKUT in 3-year-old children.

The true distribution volume and bioavailability of mizoribine in children with chronic kidney disease.

BACKGROUND: Mizoribine (MZR) is used kidney transplant and various kidney diseases. However, few studies reported the association between pharmacokinetics and pharmacodynamics. The Pharmacokinetics Study Group for Pediatric Kidney Disease (PSPKD) used population pharmacokinetics (PPK) analysis and Bayesian analysis to investigate the usefulness of MZR. In this study, the fact that almost all MZR are excreted unchanged in urine was used to calculate its bioavailability (F) and true distribution volume (V d), and analyzed these correlation with age. METHODS: Ishida et al. reported a PPK analysis by the PSPKD. In the present study, 71 samples extracted from their study population of 105 pediatric chronic kidney disease patients aged between 1 and 20 years were investigated. The bioavailability was calculated by measuring total excreted MZR in 24 h urine samples, and this was compared to the oral dosage. The apparent distribution volume (V d/F) obtained from Bayesian analysis was then used to calculate true distribution volume (V d), and the correlation of each parameter with age was investigated. RESULTS: The median dose of MZR per weight was 5.17 mg/kg/day. Median bioavailability was 32.02%. Median V d per weight was 0.46 L/kg. There was a significant, weakly positive correlation between bioavailability and age (p = 0.026). There was also a significant, weakly negative correlation between V d per weight and age (p = 0.003). CONCLUSION: Bioavailability and V d per weight tended to decrease depending on age. The younger patient required larger dose required to obtain the maximum effect from MZR, and this is important for immunosuppressive therapy.

Effects of financial support on treatment of adolescents with growth hormone deficiency: a retrospective study in Japan.

BACKGROUND: Treatment costs for children with growth hormone (GH) deficiency are subsidized by the government in Japan if the children meet clinical criteria, including height limits (boys: 156.4 cm; girls: 145.4 cm). However, several funding programs, such as a subsidy provided by local governments, can be used by those who exceed the height limits. In this study, we explored the impacts of financial support on GH treatment using this natural allocation. METHODS: A retrospective analysis of 696 adolescent patients (451 boys and 245 girls) who reached the height limits was conducted. Associations between financial support and continuing treatment were assessed using multiple logistic regression analyses adjusting for age, sex, height, growth velocity, bone age, and adverse effects. RESULTS: Of the 696 children in the analysis, 108 (15.5 %) were still eligible for financial support. The proportion of children who continued GH treatment was higher among those who were eligible for support than among those who were not (75.9 % vs. 52.0 %, P < 0.001). The odds ratios of financial support to continuing treatment were 4.04 (95 % confidence interval [CI]: 1.86-8.78) in boys and 1.72 (95 % CI: 0.80-3.70) in girls, after adjusting for demographic characteristics and clinical factors. CONCLUSIONS: Financial support affected decisions on treatment continuation for children with GH deficiency. Geographic variations in eligibility for financial support pose an ethical problem that needs policy attention. An appropriate balance between public spending on continuation of therapy and improved quality of life derived from it should be explored.

Association between low birth weight and childhood-onset chronic kidney disease in Japan: a combined analysis of a nationwide survey for paediatric chronic kidney disease and the National Vital Statistics Report.

BACKGROUND: Although numerous epidemiological surveys performed across several continents and ethnic groups have linked low birth weight (LBW) to increased risk of chronic kidney disease (CKD) in adulthood, the effects of birth weight and prematurity on development of CKD in childhood have not been clearly established. METHODS: Data on sex, LBW incidence and gestational age were compared between paediatric CKD cases and a control group. Paediatric CKD cases were obtained from a nationwide survey conducted by the Pediatric CKD Study Group in Japan. The population attributable fraction was calculated to evaluate the effects of reducing the prevalence of LBW infants (LBWI). RESULTS: Of 447 individuals born between 1993 and 2010 that fulfilled the eligibility criteria, birth weight data were obtained for 381 (85.2%) (231 boys and 150 girls), 106 (27.8%) of whom were LBWI. The proportion of LBWI in the general population during the same period was much lower (8.6%). Therefore, the risk ratio (RR) for paediatric CKD was significantly higher in the LBW group [crude RR: 4.10; 95% confidence interval (CI) 3.62-5.01], and the overall impact on paediatric CKD for removal of LBW amounted to 21.1% (95% CI 16.0-26.1%). In addition, 82 patients (21.9%) with paediatric CKD were born prematurely (before 37 weeks of gestation), and as with LBW, a strong correlation was observed between prematurity and CKD (RR: 4.73; 95% CI 3.91-5.73). CONCLUSIONS: Both birth weight and gestational age were strongly associated with childhood-onset CKD in this study.

A Case of Juxtaglomerular Cell Tumor, or Reninoma, of the Kidney Treated by Retroperitoneoscopy-Assisted Nephron-Sparing Partial Nephrectomy Through a Small Pararectal Incision.

A 15-year-old girl was found to be hypertensive (230-270/140-170 mm Hg) without any subjective symptoms. Magnetic resonance imaging confirmed the presence of a well-defined 22 mm hypodense lesion in the lower pole of the left kidney, located close to the renal hilum. Plasma rennin activity was elevated (75 ng/mL/h), and reninoma was diagnosed. Retroperitoneoscopy-assisted nephron-sparing surgery was planned. The retroperitoneum was accessed through a 4 cm left pararectal upper abdominal incision. Following blunt dissection, the abdominal wall was elevated with a lifting bar and lifting retractor, inserted below the 12th rib in the anterior axillary line to create sufficient working space in the retroperitoneal cavity without the need for pneumoperitoneum. Three 5 mm trocars were introduced above the superior iliac crest for the camera and the assistant. Gerota's fascia was opened and the kidney exposed. The surgeon dissected the left kidney through the minilaparotomy incision under both direct vision and using the magnified view on the monitor, which was particularly effective for the lateral and posterior sides of the kidney. The posterior peritoneum was incised intentionally next to the diaphragm to allow further mobilization of the kidney. Diathermy was used to remove the tumor and a layer of surrounding normal parenchymal tissue at least 0.5 cm thick. The histopathologic diagnosis was reninoma. Ischemia time was 14 minutes. Postoperatively, both plasma rennin activity and blood pressure were normal (1.9 ng/mL/h and 90-110/70-80 mm Hg, respectively). After follow-up of 12 months, there is no evidence of recurrence.

Population pharmacokinetics of mizoribine in pediatric patients with kidney disease.

BACKGROUND: The present study aimed to obtain information enabling optimisation of the clinical effect of mizoribine (MZR) in pediatric patients with kidney disease. METHODS: A total of 105 pediatric patients with kidney disease treated at our institutions were enrolled. Kidney transplant patients were excluded. Population pharmacokinetic analysis of MZR was performed based on serum concentration data. Area under the curve from time zero to infinity (AUC∞) and maximal concentration (C max) were calculated by Bayesian analysis. RESULTS: In children, the appearance of MZR in the blood tended to be slower and the subsequent rise in blood concentration tended to be more sluggish, compared to healthy adults. Apparent volume of distribution and oral clearance were also higher in children compared to adults. A significant positive correlation was observed between patient age and AUC∞. There were significant differences of AUC∞ and C max by age group. No relationship was observed between the administration method of MZR and serum concentration. CONCLUSION: The pharmacokinetics of MZR was different in children compared to adults. To obtain the expected clinical efficacy, the regular MZR dosage schedule (2-3 mg/kg/day) might be insufficient for pediatric patients. In particular, younger patients might require a higher dosage of MZR per unit body weight.

Growth impairment in children with pre-dialysis chronic kidney disease in Japan.

BACKGROUND: Growth impairment is a major complication of chronic kidney disease (CKD) in children. However, no cohort studies have examined the growth of Asian children with pre-dialysis CKD. METHODS: We sent cross-sectional surveys to 113 Japanese medical institutions that were treating 447 children with CKD stages 3-5 in 2010 and 2011. Of 447 children included in our survey conducted in 2010, height and CKD stage were evaluable for 297 children in 2011, and height standard deviation score (height SDS) was calculated in these children. RESULTS: Height SDS decreased with increasing CKD stage (P < 0.001) in boys and girls. Height SDS also decreased significantly with increasing CKD stage among patients with congenital anomalies of the kidney and urinary tract (P < 0.001). Risk factors for growth impairment included CKD stages 4 and 5 (relative to stage 3), being small-for-date, and asphyxia at birth. Among children with a height SDS ≤-2.0, growth hormone was used in 19.5, 31.0, and 25.0 % of children with CKD stages 3, 4, and 5, respectively. CONCLUSIONS: This prospective cohort study revealed marked growth impairment in Japanese children with CKD stages 3-5 relative to healthy children. CKD-related risk factors for growth impairment included advanced CKD (stages 4 and 5), being small-for-date, and asphyxia at birth. Growth hormone was infrequently used in this cohort of children with pre-dialysis CKD.

Secondary pseudohypoaldosteronism causing cardiopulmonary arrest and cholelithiasis.

A 4-month-old boy presented with cardiopulmonary arrest on arrival after a brief period of lethargy. Laboratory examination indicated severe hyperkalemia, hyponatremia, metabolic acidosis, and slightly elevated C-reactive protein. Whole body computed tomography identified left-dominant hydronephrosis, hydroureter and cholelithiasis. Despite cardiac arrest >30 min, he was successfully resuscitated and treated with therapeutic hypothermia. Escherichia coli was detected on urine culture. Renal ultrasound showed bilateral hydronephrosis, grade II in the right and grade IV in the left. Retrospective analysis of the blood sample at admission indicated a high level of aldosterone. The patient recovered almost fully with no electrolyte imbalance and normal plasma renin and aldosterone, leading to the diagnosis of secondary pseudohypoaldosteronism associated with bilateral infected hydronephrosis. In this case, cholelithiasis, which may account for chronic dehydration, was a diagnostic clue in the absence of information of pre-existing situations.

Progression to end-stage kidney disease in Japanese children with chronic kidney disease: results of a nationwide prospective cohort study.

BACKGROUND: The risk of progressing to end-stage kidney disease (ESKD) and factors associated with progression in children with chronic kidney disease (CKD) are unclear, especially in Asian children. METHODS: We started a nationwide, prospective cohort study of 447 Japanese children with pre-dialysis CKD in 2010, with follow-up in 2011. Progression to ESKD was analyzed by Kaplan-Meier analysis according to CKD stage. Cox regression analysis was used to identify risk factors for progression. RESULTS: Data were analyzed for 429/447 children. Five patients died, of which four died before progression to ESKD. Fifty-two patients progressed to ESKD (median follow-up 1.49 years), including 9/315 patients with stage 3 CKD, 29/107 with Stage 4 CKD and 14/25 with Stage 5 CKD. One-year renal survival rates were 98.3, 80.0 and 40.9%, for Stages 3, 4 and 5 CKD, respectively. Risk factors for progression to ESKD included CKD stage [versus Stage 3; Stage 4: hazard ratio (HR) 11.12, 95% confidence interval (CI) 4.22-29.28, P < 0.001; Stage 5: HR 26.95, 95% CI 7.71-94.17, P < 0.001], heavy proteinuria (>2.0 g/g urine creatinine; HR 7.56, 95% CI 3.22-17.77, P < 0.001) and age ( < 2 years: HR 9.06; 95% CI 2.29-35.84, P = 0.002; after starting puberty: HR 4.88; 95% CI 1.85-12.85, P = 0.001). CONCLUSIONS: In this cohort, 12.5% of children with pre-dialysis CKD progressed to ESKD with a median-follow-up of 1.49 years. Children with advanced (Stage 4/5) CKD were particularly likely to progress. To our knowledge, this is the first, nationwide, prospective cohort study of children with pre-dialysis CKD in Asia.

Pre-dialysis chronic kidney disease in children: results of a nationwide survey in Japan.

BACKGROUND: Chronic kidney disease (CKD) in children is a progressive and intractable condition that may severely impair the child's growth, development and quality of life. Epidemiological information on pediatric CKD, particularly in Asians, is scant. METHODS: We conducted a nationwide, population-based survey of Japanese children aged 3 months to 15 years with pre-dialysis CKD to examine the prevalence of pediatric CKD in Japan. CKD was classified according to newly established criteria derived from reference serum creatinine levels in Japanese children. Surveys were sent to 1190 institutions across Japan to report on cases of pediatric CKD managed as of 1 April 2010. RESULTS: A total of 925 institutions (77.7%) responded. Information on 447 children was collected. When subdivided according to our diagnostic criteria, 70.5% of children had stage 3 CKD, 23.9% stage 4 and 5.6% stage 5. The estimated prevalence of Japanese children with CKD was 2.98 cases/100,000 children. Of 407 CKD cases with non-glomerular disease, 278 (68.3%) had congenital anomalies of the kidney and urinary tract (CAKUT). The newly established criteria showed good validity compared with existing criteria, including the abbreviated Schwartz equation. CONCLUSIONS: Findings from the first nationwide survey of pre-dialysis CKD in Asian children indicate that the prevalence of stage 3-5 CKD in children in Japan aged 3 months to 15 years is 2.98 cases/100,000 children. Most children with CKD presented with non-glomerular disease, most frequently CAKUT. Improved management of CAKUT, including renoprotective treatment and urological intervention, is required.

Evaluation of limited sampling designs to estimate maximal concentration and area under the curve of mizoribine in pediatric patients with renal disease.

The aim of this study was to evaluate limited sampling designs to estimate the maximal concentration (C(max)) and area under the curve (AUC) of mizoribine in pediatric patients with renal disease. We utilized 48 serum mizoribine concentration profiles obtained from the full (6-point) sampling pharmacokinetic test, and estimated 48 individual C(max) and AUC values accurately with Bayesian analysis using the full sampling data. We then developed limited sampling models (LSM) for C(max) and AUC using 1-4 serum mizoribine concentration data points. The C(max) and AUC estimation performance of the Bayesian and LSM analysis was fairly good in the 3-point (2, 3, and 6 hr after the dose) sampling design. In addition, the C(max) estimation performance of the Bayesian and LSM analysis deteriorated only marginally even in the 1-point (3 hr) sampling design. On the other hand, the AUC estimation performance seemed to be inadequate in the 1-point (3 hr) sampling design; however, it improved markedly in the 2-point (3 and 6 hr) sampling design. These findings suggested that the 1-point (3 hr) sampling design is promising for approximate C(max) estimation, but that the 2-point (3 and 6 hr) sampling design is preferable to estimate the AUC of mizoribine.

A case of Epstein-Barr virus-associated pulmonary leiomyosarcoma arising five yr after a pediatric renal transplant.

EBV-associated SMTs in immuno-compromised patients have recently been reported. We report on a case of EBV-associated pulmonary leiomyosarcoma arising five yr after renal transplantation. The patient was an eight-yr-old girl, who received a living related kidney transplant from her mother. She had had bilateral giant Wilm's tumors as an infant and underwent bilateral nephrectomy at one and two yr of age. At the age of seven, she suffered from bronchitis several times, and a year later, two nodules were detected in her left lung by X-ray and computed tomography. We suspected a recurrence of Wilm's tumor and performed surgical resection. The pathological finding was SMT with moderate mitosis and no evidence of Wilm's tumor. The fact that the tumors were positive for EBER suggested an association with the EBV. Six months later, there was a recurrence in her left lung. Surgical resection was performed, and immunosuppressive agents were reduced. Two yr after the second operation, she is well with no recurrence. We report the first case of EBV-associated pulmonary leiomyosarcoma in a pediatric patient after renal transplantation owing to a malignant tumor.

Multiple drug-resistant gene 1 in children with steroid-sensitive nephrotic syndrome.

BACKGROUND: A full dose of corticosteroid is required to induce complete remission (CR) in steroid-sensitive nephrotic syndrome (SSNS), unless it is possible to taper and discontinue along with the course after CR. But the mechanism of this change in steroid sensitivity remains unknown. P-glycoprotein (PGP) can eliminate given corticosteroids from cytoplasm, which results in corticosteroid resistance. Therefore, drug delivery was analyzed using real-time polymerase chain reaction (PCR) of multiple drug-resistant gene 1 (MDR1; encoding PGP) mRNA expression. METHODS: Fourteen patients with SSNS (male/female: 14/0; age: 1-23 years; mean 10.4 years) were enrolled in the study. MDR1 mRNA gene expression of peripheral blood nucleated cells (PBNC), before and after CR (19 sets of blood samples), was quantified using real-time PCR. RESULTS: The MDR1 mRNA levels before CR were variable in each patient, but there was an apparent decrease in the MDR1 gene expression of PBNC after CR (P < 0.003). CONCLUSION: PGP may play a role in the tapering of corticosteroids after CR in SSNS.

Immunoadsorbent apheresis eliminates pathogenic IgG in childhood lupus nephritis.

BACKGROUND: It is suggested that the highly cation-charged fraction of the IgG and IgG3 subclasses may play a pathogenic role in lupus nephritis. In contrast, immunoadsorbent therapy using a sodium dextransulfate fixed cellulose gel column-low invasive selective immunoadsorbent apheresis therapy (SDSC-IAT) has been applied to lupus nephritis with favorable results. However, elimination using pathogenic IgG by SDSC-IAT has never been investigated. METHOD: Two patients with diffuse proliferative lupus nephritis were treated using SDSC-IAT concomitant with immunosuppressive therapy. The eluates from the SDSC, and the patients' serum obtained before and just after SDSC-IAT were subjected to an IgG charge analysis using isoelectric focusing and immunoblotting, and also to laser nephelometry assay, which is used for measuring IgG subclass concentration. Indirect immunofluorescence staining was performed to detect IgG subclass deposition in the glomerulus. RESULTS: Both of the patients had an immediate decrease in anti-double-strand DNA antibody and in the circulating immune complex with a following clinical improvement. Repeated biopsies demonstrated improvement of glomerular lesions with a marked reduction of IgG and C3 deposition. The IgG of the SDSC eluates consisted of highly cation charged (isoelectric points: 9-10) fractions. In addition, IgG3 was specifically removed from the patients' serum using an SDSC among the IgG subclasses. The subclass of deposited IgG in the glomeruli showed IgG3 predominance. CONCLUSION: SDSC-IAT specifically removed the highly cation charged fractions of IgG and IgG3 from the patients' serum and the elimination of these fractions may have resulted in clinical improvement.

Triggers of relapse in steroid-dependent and frequently relapsing nephrotic syndrome.

An awareness of the triggers of relapse is critical for the control of steroid-dependent, frequently relapsing nephrotic syndrome (SDFRNS). We have investigated the triggers, usually described as 'episodes', to such relapses within a temporal context. Thirty-five patients with SDFRNS were analyzed retrospectively. A total of 442 relapses occurred in 2499 patient-months. The relapses were classified into two groups: those with episodes (E+) and those without episodes (E-). There were 135 E+ relapses and 296 E- relapses. The common cold was the most common episode (52%) of E+ relapse, followed by school events (18%). These E+ relapses occurred almost evenly throughout the 4 weeks between each follow-up visit. Conversely, 161 (55%) of the 296 E-z relapses occurred within the 3-day period preceding the patient's appointment (relapse-related hospital visit, RRHV). McNemar's test revealed that the concentration of relapses in this period was statistically significant (P < 0.00011). In addition, 15 out of 26 RRHV without additional therapy showed a spontaneous remission. From a chronological perspective, the common cold and school events as well as up-coming hospital visits may trigger relapses in SDFRNS patients.