ABSTRACT
Objective:To deepen our understanding of Methylmalonic aciduria (MMA) associated pulmonary hypertension (PH) by analyzing the characteristics of clinical presentation,pulmonary high resolusion CT(HRCT),treatment response and gene mutation.Methods:This study includes 15 cases of pediatric patients with MMA associated PH diagnosed and treated in Peking University First Hospital pediatric department between May 2012 and May 2016 with symptoms of PH as their leading presentation.Clinical symptoms and signs were recorded,Routine blood laboratory examinations was done including arterial blood gas analysis.Plasma total homocysteine (Hcy) and brain natriuretic peptide (BNP) level were measured.MMA gene mutation was analyzed.Chest HRCT was done in most of the patients.Standard treatment strategy to MMA and PH was given and follow up study was done,and the related literature was reviewed.Statistical analysis was done.The diagnosis of MMA was made by methylmalonic acid level ＞ 100 times the normal value in the urine.The diagnosis of PH was made by pulmonary arterial systolic pressure (PASP) ＞ 40 mmHg,which was estimated by the measurement of tricuspid regurgitation velocity through Doppler Echocardiography.Results:(1) Patient characteristics:There were 10 male and 5 female patients diagnosed as MMA associated PH,aged 0.5 to 13.8 years,with an average of (5.0 ± 4.3) years.The age of onset of PH was (3.7 ± 3.5) years,with an early onset type MMA in 5 cases and late-onset type in 10 cases.(2) Clinical presentation:Among the 15 cases of MMA,the first symptoms were associated with PH in 10 cases,so PH and MMA were diagnosed at the same time,and PH was diagnosed 3 to 72 months post MMA presentation in the other 5 cases.The main presentations of PH were techypnea/dyspnea and cyanosis in 11 cases each,weakness and fatigue on exertion in 6 cases,and edema in 4 cases.PH WHO functional classification (WHO FC) was Class Ⅱ in 4,Class Ⅲ in 5 and Class Ⅵ in 6 cases,with an average of Class 3.1 ± 0.8.Multi-system involvements were common with the highest frequency in the kidney (14 cases).Macrocytic anemia was present in 8 cases and subclinical hypothyroidism in 5 cases,and mild to moderate mental retardation in 4 cases.(3) Laboratory examination:PASP of the 15 patients was from 49 to 135 mmHg,with an average of (90.3 ±23.9) mm Hg.Total blood Hcy level was severely elevated to (121.2 ± 48.2) μmol/L (range:35.0-221.0 μmol/L),and Hcy ＞ 100 μmoL/L within 11 cases.Plasma BNP level was also elevated,median 794 ng/ L (range:21.0-4 995.0 ng/L) with 12 cases ＞ 300 ng/L.Blood gas analysis showed low arterial blood oxygen saturation between 70％ and 94％,with an average of 81.4％ ±8.4％.(4) Chest HRCT:chest HRCT showed a diffuse ground-glass centrilobular nodular opacities with septal line thickening in the lungs in 9 cases,and with associated mediastinal lymph node enlargement in 1 case,which indicated pulmonary veno-occlusive disease (PVOD),a rare type of pulmonary arterial hypertension (PAH).There was lung infection or edema in 3 cases,and interstitial infiltration and mesh-like feature in other 3 cases,which was inferred to interstitial lung disease.(5) Gene mutation:Genetic testing was done in 10 cases,totally 5 reported disease-causing mutations were found.There were 100％ presence of MMACHC c.80A ＞ G mutation in all the 10 patients tested,with the allelic genes of c.609G ＞ A mutation in 6 patients,including a sister and a brother from the same parents.(6).Treatment and follow up:Intramus cular hydroxocobalamin or vitamin B12 was given to all of the patients,together with betaine,levocarnidtine,folinic acid and vitamin B6.According to the severity of PH,single or combined PAH targeted drugs was given to 11 cases.By an average of (20.0 ± 13.5) days of in-hospital treatment in 13 patients (excepting 1 case treated as outpatient),symptoms remarkably resolved,WHO FC reduced to an average of Class 2.4 ±0.9,PASP dropped to (69.4 ±21.3) mmHg,and plasma Hcy and BNP level were decreased to (74.9 ± 25.9) μmol/L and (341.6 ± 180.2) ng/L,respectively.The above values all reached statistical significance (P ＜ 0.05) compared with each related value before treatment.Therewere 2 patients who expired during hospitalization despite of treatment.At the end of 3 months' follow up,all of the 13 patients disposed oxygen,and PASP significantly dropped to 38.7 ± 7.9 mmHg,and plasma BNP returned to normal,but plasma Hcy level showed no further decline.At the last follow up of 27.5 ± 19.0 (range:11-64) months,all the patients' PASP remained normal except for the 13.8-year-old boy with 6 years-long history of MMA and almost 3.6 years' history of PH still having PASP 58 mmHg.Conclusion:PH is a severe complication of MMA combined type,especially cblC type,it is more often happens in late-onset type of male patients and can be the first and leading manifestations of MMA.Its clinical symptoms are urgent and severe,characterized by tachypnea/dyspnea and cyanosis,and sometimes right heart failure,hypoxemia is usually present,chest HRCT is often indicative of PVOD,lung edema and interstitial lung disease may occur.Rapid diagnosis and targeted treatment of MMA with appropriate anti-PAH mcdication can reverse PH and save life.MMACHC gene c.80A ＞ G mutation may be the hot point of MMA cblC type associated PH.
ABSTRACT
Objective:To assess the correlation and consistency between continuous noninvasive hemo globin detection and venous blood hemoglobin detection in children with kidney disease,and try to analyze the affecting factors.Try to provide a reference for the monitoring of hemoglobin in children with kid ney disease by continuous noninvasive hemoglobin detection technique.Methods:Eighty-five inpatient children with kidney disease,50 boys (58.8％) and 35 girls (41.2％),aged from 3 years old to 18 years old (9.35 ± 4.29) were included finally.Noninvasive hemoglobin monitoring by spectrophotometry (SpHb) was stably read by PRONTO-7,selecting the ring finger of the non handedness as the detection site.And then the venous blood hemoglobin of the same patient was collected in 5 minutes as the true hemoglobin (tHb) by Beckman coulter DXH-800.The data of SpHb and tHb were compared and analyzed using SPSS 17.0 and MedCalc.Results:Correlation analysis showed data of SpHb and tHb were with significant correlation,the correlation coefficient between SpHb and tHb was 0.85 (P ＜ 0.05).BlandAltman plot points suggested that the mean of differences between SpHb and tHb was-1.3 g/dL.The 95％ CI of agreement of SpHb-tHb was-4.2-1.5 g/dL,suggesting that the average measurement re sult of SpHb was lower than that of tHb.The mean of differences as percent between SpHb and tHb was -9.8％,95％ CI of agreement was (-35.9％,16.2％) exceeding the acceptable range of true value ± 6％.The consistent rate of non-invasive hemoglobin detection and venous blood hemoglobin detection was 31.8％,the 95％ CI of consistent rate was (21.7％,41.9％).The chi square test of the fourfold table showed that the diagnosis of anemia with SpHb was of high sensitivity,but the specificity was low,the false positive rate was high,and the difference was statistically significant (P =0.000).Conclusion:There was a significant correlation between SpHb and tHb in the children with kidney disease.Noninvasive hemoglobin measurement can be used for monitoring of changes of hemoglobin in children with kidney diseases.But the consistency between SpHb and tHb needs to be improved.Noninvasive hemoglobin measurement could not replace the venous hemoglobin measurement.It could not be used for the diagnosis of anemia,and the accuracy of hemoglobin concentration measurement in children with kidney disease should be further explored.
ABSTRACT
Objective:To investigate the clinical features and side effects,with regard to glucocorticoid-induced ocular hypertension,glaucoma or cataract in children with primary nephrotic syndrome.Methods:Clinical data were collected and analyzed from 71 cases of primary nephrotic syndrome with glucocorticoid-induced ocular hypertension,glaucoma or cataract from Jun.2014 to Jun.2016.These children were hospitalized in Peking University First Hospital.Results:Totally 1 580 children with primary nephrotic syndrome were collected,glucocorticoid-induced complications in eyes were found in 71 cases,and the incidence was 4.5％.There were 66 cases with ocular hypertension,2 cases with glucocorticoid glaucoma,2 cases with glucocorticoid glaucoma combined with cataract,1 case with high intraocular pressure combined with cataract.There were 41 boys and 30 girls with eye-related side effects caused by glucocorticoid.The average age of onset of glucocorticoid-induced eye adverse reactions in children with primary nephrotic syndrome in our research were 8 (2,16) years.The average duration or interval time from glucocorticoid medication use to eye adverse effects was 157 (6,420) days.No statistical significance was found in intraocular pressure between different genders,types of glucocorticoid,different route of glucocorticoid and whether methylprednisolone pulse treatment (P ＞ 0.05).There was no significant correlation between age,body mass index,blood pressure,cumulative dosage,duration time of glucocorticoid,mean daily dosage and glucocorticoid-induced ocular hypertension (P ＞ 0.05).The ocular hypertension was controlled after treatment.Conclusion:Children with nephrotic syndrome after treatment of glucocorticoid are susceptible to ocular complications,and the occurrence of ocular hypertension is closely related to glucocorticoid susceptibility of the nephrotic children.Regular eye monitor is indispensable for the children suffering from primary nephrotic syndrome.
ABSTRACT
Objective:Tacrolimus prolonged-release(PR) formulation is a new once-daily formulation of the calcineurin inhibitor tacrolimus,which is currently used in adult liver or kidney transplant patients,and is also gradually widely used in children with nephrotic syndrome.The present study was undertaken to preliminarily investigate the pharmacokinetic characteristics of tacrolimus PR in pediatric nephrotic syndrome recipients.Methods:This single-center open-label prospective study was performed in pediatric nephrotic syndrome recipients.Pharmacokinetic samples were collected from eight pediatric subjects with nephrotic syndrome from Department of Pediatric Nephrology in Peking University First Hospital between June and August 2011.They followed administration of single oral doses of tacrolimus PR formulation at 0.02 mg/kg (n =2),0.05 mg/kg (n =2) and 0.10 mg/kg (n =4).Blood samples were taken before the dose and 1,2,4,6,8,10,12 and 24 h after drug intake.No other medicines or interacting food or drinks were taken during the study period.Blood concentrations were measured using an enzyme multiplied immunoassay technique.Pharmacokinetic analysis was performed using WinNolin Phoenix software Version 6.0 (Pharsight,Cary,NC,USA).Results:The pharmacokinetic data were best described by a non-compartment model.Pharmacokinetic parameters of tacrolimus PR formulation in the 3 ascending doses groups (0.02 mg/kg,0.05 mg/kg and 0.10 mg/kg) were as follows:the maxi mum drug concentrations (Cm=/D) were (1.7 ± 1.0) μg/L,(3.1 ± 1.9) μg/L,(8.0 ± 3.5) μg/L,respectively;Areas under the drug concentration-time curve (AUCo-∞/D) were (47.2 ± 47.1) h · μg/ L,(84.0 ± 13.1) h · μg/L,(175.6 ± 107.1) h · μg/L,respectively;Oral clearance rates were (0.8±0.9) L/(h·kg),(0.4±0.1) L/(h · kg),(1.9 ±1.3) L/(h · kg),respectively;Body weight normalized distribution volumes were (7.0 ± 3.4) L/kg,(12.4 ± 8.4) L/kg and (73.6 ± 68.6) L/kg,respectively.Both mean Cmax normalized level for the administered dose (Cmax/D) and mean AUC0-∞ normalized level for the administered dose (AUC0-∞/D) were higher in the 0.05 mg/kg dosage group than in the 0.02 and 0.10 mg/kg dosage group.There were two peaks in the drug concentrations in every dose group;a primary peak appeared at the end of about 2 h followed by a small secondary peak at h 12,which was more noticeable in the 0.10 mg/kg dose group than in the two lower dosages.Conclusion:The pharmacokinetic characteristics of tacrolimus PR formulation were initially explored in pediatric patients with nephritic syndrome.The data presented form a basis for subsequent larger scale studies on pharmacokinetics of tacrolimus PR formulation in nephritic syndrome children.