Research Progress of Monogenic Mutation in the Pathogenesis of Steroid-Resistant Nephrotic Syndrome / 罕见病研究

Steroid-resistant nephrotic syndrome (SRNS) is the second cause of chronic kidney disease in children. The SRNS has high risk of rapid progression to end-stage renal disease. With the advancement of high-throughput sequencing technology, more than 70 monogenic mutation having the Mendelian inheritance patterns are identified to be associated with SRNS. Most of these genes are involved in podocyte function. Accurate diagnosis of monogenic mutation in SRNS patients helps with guiding clinical treatment protocols and genetic counseling, avoiding the excessive use of steroids/immunosuppressive therapy, and opening up possibilities for targeted therapies in SRNS patients. In this article, our research team summarizes and generalizes the molecular mechanisms, genetic testing, and specific treatment for the major types of monogenic mutations associated with SRNS.

Outcomes of children with idiopathic steroid resistant nephrotic syndrome: a single centre observational study / Desfechos de crianças com síndrome nefrótica idiopática córtico-resistente: um estudo observacional de centro único

ABSTRACT Introduction: Idiopathic steroid resistant nephrotic syndrome (SRNS) has variable outcomes in children. The primary objective of the present study was to assess the cumulative remission rate and the secondary objectives were to assess factors affecting the remission status, kidney function survival, and adverse effects of medications. Methods: One hundred fourteen patients with SRNS were included. Calcineurin inhibitor-based treatment protocol along with prednisolone and angiotensin-converting enzyme inhibitor were used, and patients were followed over 5 years. Results: Median age was 4.5 years; 53.5% of cases were between 1 to 5 years of age. Sixty-two patients (54.4%) were at initial stage and 52 (45.6%) were at a late SRNS stage. Median eGFRcr was 83.5 mL/min/1.73m2 at presentation. Of the 110 patients, 63 (57.3%) achieved remission [complete remission 30 (27.3%), partial remission 33 (30%)], and 47 (42.7%) had no remission. Kidney function survival was 87.3% and 14 cases (12.7%) had progression to CKD (G3-8, G4-3, G5-1, and G5D-2). Median duration of follow up was 36 months (IQR 24, 60). Age of onset, cyclosporine/tacrolimus, eGFRcr, and histopathology (MCD/FSGS) did not affect remission. Similarly, remission status in addition to age of onset, drug protocol, and histopathology did not significantly affect kidney function during a period of 5 years. Hypertension, cushingoid facies, short stature, cataract, and obesity were observed in 37.7, 29.8, 25.5, 17.5, and 0.7% of cases, respectively. Conclusion: About half of the cases achieved remission. Age of onset of disease, cyclosporine/tacrolimus use, and histopathological lesion neither affected remission status nor short-term kidney function survival in SRNS.

RESUMO Introdução: A síndrome nefrótica idiopática córtico-resistente (SNICR) apresenta desfechos variáveis em crianças. O objetivo principal deste estudo foi avaliar a taxa de remissão cumulativa. Os objetivos secundários foram avaliar fatores que afetam status de remissão, sobrevida da função renal e efeitos adversos de medicamentos. Métodos: Foram incluídos 114 pacientes com SNCR. Utilizou-se protocolo de tratamento baseado em inibidores de calcineurina juntamente com prednisolona e inibidor da enzima conversora de angiotensina. Os pacientes foram acompanhados durante 5 anos. Resultados: A idade mediana foi 4,5 anos; 53,5% dos casos tinham entre 1 e 5 anos. 62 pacientes (54,4%) estavam em estágio inicial; 52 (45,6%) em estágio tardio da SNCR. A TFGecr mediana foi 83,5 mL/min/1,73 m2 na apresentação. Dos 110 pacientes, 63 (57,3%) alcançaram remissão [remissão completa 30 (27,3%), remissão parcial 33 (30%)], e 47 (42,7%) não apresentaram remissão. A sobrevida da função renal foi 87,3%; 14 casos (12,7%) progrediram para DRC (G3-8, G4-3, G5-1, G5D-2). A duração mediana do acompanhamento foi 36 meses (IIQ 24, 60). Idade no início, ciclosporina/tacrolimus, TFGecr e histopatologia (DLM/GESF) não afetaram a remissão. Igualmente, status de remissão, além da idade no início, protocolo de medicamentos e histopatologia não afetaram significativamente a função renal por 5 anos. Observou-se hipertensão, fácies cushingoide, baixa estatura, catarata e obesidade em 37,7; 29,8; 25,5; 17,5; e 0,7% dos casos, respectivamente. Conclusão: Aproximadamente metade dos casos alcançou remissão. Idade no início, uso de ciclosporina/tacrolimus e lesão histopatológica não afetaram o status de remissão nem a sobrevida da função renal a curto prazo na SNICR.

Role of podocyte injury signaling pathway in steroid-resistant nephrotic syndrome and research progress in traditional Chinese medicine intervention / 中国中药杂志

As one of the main diseases leading to end-stage renal disease, steroid-resistant nephrotic syndrome(SRNS) can cause serious complications such as infection. Without effective control, this disease can further lead to the malignant development of the renal function, bringing serious social and economic burdens. As previously reported, the formation of SRNS is mostly related to the podocyte injury in the body, i.e., the injury of glomerular visceral epithelial cells. Phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway, nuclear transcription factor-κB(NF-κB) signaling pathway, mammalian target of rapamycin(mTOR)/adenosine monophosphate(AMP)-activated protein kinase(AMPK), transforming growth factor(TGF)-β1/Smads, and other signaling pathways are classical signaling pathways related to podocyte injury. By regulating the expression of signaling pathways, podocyte injury can be intervened to improve the adhesion between podocyte foot processes and glomerular basement membrane and promote the function of podocytes, thereby alleviating the clinical symptoms of SRNS. Through the literature review, traditional Chinese medicine(TCM) has unique advantages and an important role in intervening in podocyte injury. In the intervention in podocyte injury, TCM, by virtue of multi-target and multi-pathway role, can regulate and intervene in podocyte injury in many ways, alleviate the clinical symptoms of SRNS, and interfere with the progress of SRNS, reflecting the unique advantages of TCM. On the other hand, TCM can directly or indirectly inhibit podocyte injury by regulating the above signaling pathways, which can not only promote the effect of hormones and immunosuppressants and shorten the course of treatment, but also reduce the toxic and side effects caused by various hormones and immunosuppressants to exert the advantages of small side effects and low price of TCM. This article reviewed TCM in the treatment of SRNS by interfering with podocyte injury-related signaling pathways and is expected to provide a reference for the in-depth study of TCM in the treatment of SRNS, as well as a theoretical basis and a new direction for the clinical application of TCM to shorten the course of treatment of SRNS and delay the progression to end-stage renal disease.

Gene mutation and clinical analysis in children with steroid resistant nephrotic syndrome in a single center / 中国医师杂志

Objective:To analyze the gene mutation, clinical manifestations and prognosis of children with steroid resistant nephrotic syndrome (SRNS), and to provide reference for the treatment of hereditary SRNS in children.Methods:The clinical data of 29 patients with SRNS and whole exon sequencing (WES) diagnosed in Xi′an Children′s Hospital from January 1, 2018 to December 31, 2020 were retrospectively analyzed.Results:In 29 cases of SRNS with genetic testing, 10 cases (34.5%) were gene mutations, including 2 cases of congenital nephrotic syndrome. The onset age of the patients with gene mutation ranged from 0.1 to 10.7(4.06±3.73)years, and the median age of onset was 3.3 years. The clinical type was mainly nephritis (8/10), and the pathological type was mainly focal segmental glomerulosclerosis (FSGS) (5/7). The main mutant genes were NPHS1 (2 cases), NPHS2 (2 cases), WT1 (2 cases), SMARCAL1 (1 case), COQ8B (1 case), TRPC6 (1 case) and COL4A3 gene (1 case). The main types of genetic variation were missense mutations, and 6 (60%) cases were new mutations that had never been reported in the database containing human pathogenic mutations before. Compared with the non-gene mutation group, 24 hour urinary protein was higher [(177.92±164.59)mg/(kg·24 h) vs (84.99±40.79)mg/(kg·24 h)] in gene mutation group, with statistically significant difference ( P<0.05). In the gene mutation group, there were 2 cases of complete remission, including 1 case of complete remission treated with coenzyme Q10, 1 case of partial remission, and 8 cases of immunosuppression treatment, with an effective rate of 2/8, while in the non-gene mutation group, the effective rate of immunosuppression treatment was 17/19, with statistically significant difference in prognosis between the two groups ( P<0.05). Conclusions:The pathological type of children with hereditary SRNS is mainly FSGS, which are often ineffective to immunosuppressive therapy, poor prognosis and easy to progress to end-stage renal disease. Gene detection is of great significance for etiological diagnosis, treatment and prognosis evaluation in children with SRNS.

Case report of sphingosine phosphate lyase insufficiency syndrome / 中华实用儿科临床杂志

The data of a child with sphingosine phosphate lyase insufficiency syndrome (SPLIS) admitted to Children′s Hospital of Hebei Province on February 4, 2020 were retrospectively analyzed.The child had edema, complicated with ichthyosis, adrenal calcification, and hearing loss from the early infancy.Laboratory examination results suggested a low albumin level, hypercholesterolemia, a high proteinuria level, abnormal liver and renal functions, and hyponatremia.The child gave up treatment and died at home.Whole Exome Sequencing (WES) results showed two hete-rozygous mutations of SGPL1 gene (chr10: 72604336, c.134G>A, p.W45X; chr10: 72629563, c.719G>T, p.S240I). SPLIS is inherited in an autosomal recessive manner.It starts in infancy, and affects the kidney, skin, endocrine, nervous and immune systems.It is suggested that SPLIS patients should take genetic examination.Early diagnosis, appropriate intervention, and vitamin B 6 treatment may relieve some symptoms of SPLIS patients.Adeno-associated virus mediated SGPL1 gene replacement therapy can be a novel cure of SPLIS and is worthy of investigation.

Clinical features and pathological analysis of steroid resistant nephrotic syndrome in children in a single center / 中国综合临床

0bjective To analyze the clinical characteristics, pathological types, treatment and prognosis in children with steroid resistant nephrotic syndrome (SRNS) in Northwest China, in order to provide reference for the treatment of SRNS. Methods:The clinical data, renal pathological results, treatment plan and efficacy of 102 children diagnosed with SRNS in the Department of Nephrology, Xi'an Children's Hospital of Shaanxi Province from January 1st, 2018 to December thirty-first, 2020 were analyzed retrospectively. All children were divided into groups according to age, clinical classification, pathological type, treatment scheme and treatment outcome, and the risk factors affecting the prognosis of children with SRNS were discussed. The measurement datas conforming to normal distribution were expressed as xˉ± s, and t test was used for comparison between groups. Measurement datas that did not conform to normal distribution were represented by M ( Q1, Q3), and Kruskall-Wallis test was used for comparison between groups.Enumeration datas were compared by χ 2 test. Risk factors were analyzed by multiple factor Logistic regression analysis. Results:The median age of onset of 102 children with SRNS was 3.0 years. Focal segmental glomerulosclerosis (FSGS) accounted for 36.3% (37/102), minimal lesions accounted for 33.3% (34/102), and mesangial proliferative glomerulonephritis accounted for 23.5% (24/102). The prevalence rates of hypertension (35.1% (13/37)), 24-h urine protein quantification (130.5 (91.5, 159.6) mg/(kg·24 h) and renal insufficiency (21.6% (8/37)) in FSGS group were higher than those in non-FSGS group (13.8% (9/65), 65.8 (51.2,85.5) mg/(kg·24 h), 4.6% (3/65)). The differences between the two groups were statistically significant (statistical values were χ 2=6.32, Z=5.90, χ 2=7.09; P values were 0.012, <0.001, 0.008). Logistic multivariate regression analysis showed that the hypertension ( OR=4.055, 95% CI 1.178-3.962) and 24 hour urinary protein ( OR=1.036, 95% CI 1.020-1.053) were associated with the increased risk of FSGS ( P values were 0.026 and <0.001). ROC curve ananlysis showed that the optimal critical value of 24 hour urinary protein was 85.65 mg/(kg·24 h) in FSGS. After treatment, complete remission was 61.8%(63/102), partial remission was 14.7%(15/102), and no remission was 23.5%(24/102). By the end of follow-up the treatment effective rate in the small lesion group (94.1%(32/34)) was higher than that in the FSGS Group (51.3%(19/37)), and the difference between the two groups was statistically significant (χ 2=16.02, P<0.001). In the initial immunosuppressive treatment, the complete remission rate of hormone combined with calcineurin inhibitor group (77.1%(37/48)) was higher than that of hormone combined with cyclophosphamide Group (11.1%(3/27)). There was significant difference between the two groups ( Z=32.28, P<0.001). Conclusion:The most common pathological type in children with SRNS was FSGS, and the age of onset was generally small. The prognosis of patients with pathological type FSGS was the worst, and the prognosis of small lesions was better. Hypertension and 24-hour urinary protein quantification were the risk factors of FSGS. Calcineurin inhibitors were the first choice for the second-line immunosuppressants of SRNS in children.

Treatment progress of pediatric steroid-resistant nephrotic syndrome / 中华实用儿科临床杂志

Primary nephrotic syndrome (PNS) is one of the most common glomerular diseases in children.Steroid-resistant nephrotic syndrome (SRNS) is defined as no remission of nephrotic syndrome after daily Prednisone treatment at an adequate oral dose for 4 weeks, which is classified as idiopathic SRNS and inherited SRNS according to the presence or absence of monogenic disorder.At present, steroid combined with calcineurin inhibitor (CNI) is preferred to idiopathic SRNS, and 50%-70% of children can achieve complete or partial remission.A small proportion of children with idiopathic SRNS and the majority of inherited SRNS may be resistant to different immunosuppressive agents with two different mechanisms, including CNI.They, unfortunately, gradually progress to end-stage renal disease within 5-10 years.In this paper, the therapeutic advances and future prospects in pediatric SRNS are reviewed.

Schimke immune osseous dysplasia: a rare case report

Schimke immune-osseous dysplasia (SIOD) is primarily characterized by the combination of spondyloepiphyseal dysplasia (SED), unique clinical phenotype, immune complex nephropathy (focal segmental glomerulosclerosis) and progressive immune defects with T-cell immunodeficiency. SIOD is caused by mutations in SMARCAL1 gene. Here we report a case of a 6-year-old girl who presented to us with disproportionate short stature, short neck kyphoscoliosis, hyper pigmented macules and severe herpes zoster. On further evaluation, she had evidence of T cell deficiency and nephrotic range of proteinuria. Renal histopathology documented focal segmental glomerular sclerosis. Genetic analysis confirmed homozygous missense mutation of SMARCAL gene on exon 8 variant c1358G>c. On extensive literature survey, this is noted to be the first case of SIOD reported from India. These children need close surveillance to watch for infections and progressive renal failure and require special care during administration of certain drugs and live vaccines.

Relative safety of steroid sparing agents in frequently relapsing, steroid dependent and steroid resistant nephrotic syndrome in pediatric patients

Background: In patients with frequently relapsing nephrotic syndrome (FRNS), steroid-dependent nephrotic syndrome (SDNS) and steroid resistant nephrotic syndrome (SRNS) steroids are either used for prolonged period of time or ineffective. To reduce the degree of steroid dependency and avoid steroid toxicity, several immunosuppressive steroid sparing agents (SPAs) have been proposed to treat these children. The present study tried to study the relative safety of most commonly steroid sparing agent in such children.Methods: A multi-centred, prospective observational study was conducted in paediatric nephrology OPD of two tertiary care hospitals in Kolkata over a period of 24 months. All consecutive children with diagnosed FRNS, SDNS and SRNS who were started on steroid sparing agents were enrolled and followed up for at least 6 months. Records of clinical examination, laboratory tests were collected and measured at the baseline and regular intervals. Safety parameters were noted and statistically analysed.Results: A total 110 patients were screened, examined and enrolled. Levamisole, cyclophosphamide and MMF were commonly used SPAs. Of the two tertiary care hospitals, all the patients of FRNS and SDNS were started with levamisole and SRNS with cyclophosphamide in one set-up, while in the other hospital some SDNS patients were started with cyclophosphamide and SRNS with MMF but without clinically significant outcomes. In comparison with few minor adverse events in MMF group, some serious adverse events were documented in the both cyclophosphamide and levamisole groups.Conclusions: Levamisole being a very efficacious, safe and easily affordable drug, should be used as an initial first line SPA in treating FRNS and SDNS children. The side effect profiles of levamisole and MMF are much more patient friendly.

Comparison of clinical and lab profile between steroid sensitive and steroid resistant nephrotic syndrome at onset of disease and evaluating predictors for developing steroid resistance in nephrotic syndrome

Background: Nephrotic syndrome is a notable chronic disease in children. The objective of this study was to compare the clinical and lab profile between steroid sensitive nephrotic syndrome and steroid resistant nephrotic syndrome at the onset of disease. Certain parameters were tested if they could be significate predictors of developing steroid resistance at the onset of first episode of nephrotic syndrome.Methods: Retrospective observation study done children 1-12 years diagnosed with nephrotic syndrome in Sri Ramachandra Medical College and Hospital, Department of Paediatrics, Chennai. Sample size 150. Period of study Jan 2013- Dec 2015. Variables considered were age at onset, sex, parental consanguinity with essential lab parameters done at the onset of nephrotic syndrome proteinuria, pyuria, microscopic hematuria, urine protein creatinine ratio, serum creatinine, serum triglycerides and serum albumin. Children less than 1 year of age, cases with secondary causes of nephrotic syndrome and steroid dependant nephrotic syndrome, children with incomplete records were not included in this study. 150 cases who fulfilled the study criteria were included in this study.Results: 75 cases of steroid sensitive nephrotic syndrome (SSNS) were compared with an equal number of steroid resistant nephrotic syndrome (SRNS). 85 children had onset of disease before 3 years of age and majority had 3+ proteinuria and males predominated in both the groups. The overall consanguinity rates were higher among SRNS group. Triglyceride level >300 mg/dl predominated in SRNS group along with a higher severity of hypoalbuminemia when compared to SSNS group. None of the parameters tested were significant predictors of developing SRNS subsequently.Conclusions: Comparing steroid sensitive with steroid resistance nephrotic syndrome, no lab parameter could identify the risk of a child developing steroid resistance subsequently. This could be a field of interest in future studies that could predict the development of steroid resistance at the onset of first episode of nephrotic syndrome itself.

Role of urinary nitrites in predicting steroid responsiveness of nephrotic syndrome: a study conducted in tertiary care center

Background: Nephrotic Syndrome (NS) is a common chronic disorder, characterized by alterations of selective permeability at the glomerular capillary wall, resulting in its inability to restrict the urinary loss of protein. Urinary nitrite excretion serves as a useful investigation in differentiating between steroid responsive and steroid resistant nephrotic syndrome. The aim of the study was to assess the relation between urinary nitrite levels and steroid responsiveness in nephrotic syndrome in children.Methods: 76 children were enrolled in the study suffering with nephrotic syndrome of which 58 children were Steroid Sensitive (SSNS) and 18 were Steroid Resistant (SRNS). 25 children were enrolled as controls. The urinary nitrites were estimated in these subjects and the results were analyzed.Results: All the control subjects were tested negative for urinary nitrites. After achieving remission with steroids, out of 58 SSNS subjects' 27 subjects tested positive for urinary nitrites, remaining 31 tested negatives for the same. Of the 18 SRNS subjects 1 subject tested positive for urinary nitrites remaining 17 subjects were tested negative for the same.Conclusions: The findings of present study suggest that urinary nitrite excretion is increased in patients with steroid responsive nephrotic syndrome. The urinary nitrite estimation has low NPV and high PPV in predicting steroid responsiveness.

Application of rituximab in children with primary nephrotic syndrome / 医学研究生学报

Childhood primary nephrotic syndrome (PNS) is a challenging and persistent renal disorder. Corticosteroids is the first-line drug for the treatment of PNS. To reduce the side effects caused by the accumulation of corticosteroids dose and to maintain the remission state of the disease, immunosuppressants are applied to the treatment of PNS. However, many children with PNS still cannot get remission. Rituximab (RTX) is a novel immunosuppressive agent. In recent years, many studies have reported the treatment of PNS in children with RTX. This review analyzes the mechanism, course of treatment, dose, efficacy, and safety of RTX in the treatment of children with PNS.

A study to assess the prevalence of hypertension in children with nephrotic syndrome

Background: Hypertension is been one of the most common co morbidity of this disease. It was mostly attributed to sodium retention, which is a major clinical feature of nephrotic syndrome. These mechanisms likely have a role in the development of hypertension in nephrotic syndrome, where hypertension may be difficult to control, and provide new therapeutic options for the management of blood pressure in the setting of nephrotic syndrome. Objective of study the prevalence of hypertension in children with NS and also the number of antihypertensive required to control it.Method: A Retrospective study of the hospital records of 100 children diagnosed with nephrotic syndrome admitted to Pediatric and Nephrology Ward at YMCH was accessed.Results: In our study 35 (35%) of them were Infrequent relapse nephrotic syndrome (IFNS) and 35(35%) were' Frequent relapse nephrotic syndrome (FRNS) ,while 30 cases (30%) were First episode nephrotic syndrome (FENS). 65 cases were steroid sensitive, while 28 and 7 of them were steroid dependent and resistant respectively. Of the 100 study population 54 of them had hypertension while 46 of them did not develop it .Of the 54 hypertensive nephrotic syndrome children, 15 of them (28.%) required three anti hypertensives to control the pressure, while 19 (35%) and 20 (37%) required single and dual anti hypertensives respectively.Conclusion: Prevalence of hypertension is increasing among the children with nephrotic syndrome. Its more prevalent among the male then female FRNS, SRNS and SDNS are more prone to develop hypertension and also they needed two or more antihypertensives to control the hypertension, whereas hypertension in SSNS could be managed with single drug.

Clinical study for treating steroid-resistant nephrotic syndrome by the methods of Shugan-Yiqi-Yangyin / 国际中医中药杂志

Objective To observe the clinical effect of the method of Shugan-Yiqi-Yangyin treatment for the steroid-resistant nephrotic syndrome (SRNS). Methods A total of 80 patients with SRNS were divided into 2 groups by random number table method, 40 in each group. The control group received glucocorticoids combined with Tripterygium Glycosides;and the treatment group received Shugan-Yiqi-Yangyin on the basis of the control group, 3 month as a course. The 24 h urine protein quantitative (propagated), plasma albumin, blood lipid (total cholesterol, triglycerides), hemorrheology, blood urea nitrogen (BUN), creatinine (Cr), urinary inhibition C (Cys C) were detected before and after the treatment of two groups, and the clinical effect was compared. Results The total effective rate of the treatment group was 92.50% (37/40) and 82.50% (33/40) in the control group, and the difference was statistically significant (Z=-1.966, P<0.05). After the treatment, the 24 hPRO (1.03 ± 0.64 mg vs.2.81 ± 1.43 mg,t=3.025),Cys C(0.35 ± 0.41 mg/L vs.0.76 ± 0.51 mg/L, t=3.058) of the treatment group was significantly lower than those of the control group(P<0.05).The Alb(34.88 ± 2.17 mg vs. 31.69 ± 2.05 mg, t=2.986) of the treatment group was significantly higher than this of the control group (P<0.05), After treatment,the whole blood high shear viscosity(7.84 ± 1.42 mPa?s vs.8.94 ± 1.38 mPa?s,t=3.160),the whole blood low shear viscosity(4.55 ± 0.37 mPa?s vs.5.02 ± 0.44 mPa?s,t=3.825),plasma viscosity(1.33 ± 0.10 mPa?s vs.1.95 ± 0.26 mPa?s,t=2.981),hematocrit(0.28 ± 0.03 vs.0.34 ± 0.03,t=2.993),fibrinogen(3.96 ± 0.57 g/L vs.4.52 ± 0.47 g/L,t=4.863)of the treatment group were significantly lower than those of the control group(P<0.05).The TC(5.04 ± 1.72 mmol/L vs.6.99 ± 1.06 mmol/L,t=3.67),TG(1.4 ± 0.64 mmol/L vs.2.02 ± 0.31 mmol/L, t=3.040) of the treatment group were significantly lower than those of the control group (P<0.05). Conclusions The Shugan-Yiqi-Yangyin treatment for SRNS can obviously improve the symptoms,reduce the side effects of hormone of antagonism. The possible mechanisms are to restore kidney function, improve blood viscosity and lower blood lipid levels.

Hepatitis autoinmune refractaria: ¿cómo escoger el tratamiento de segunda línea o de rescate? / Refractory autoimmune hepatitis: how to choose second-line or rescue therapy?

Autoimmune hepatitis (AIH) is a liver disease of unknown etiology, with a breakdown in peripheral selftolerance against hepatocytes with both genetic and environmental factors involved. It is characterized by an immune mediated liver injury, with detectable autoantibodies, elevated levels of immunoglobulin G and histological criteria including, necroinflammation, lymphoplasmacytic infiltrates and hepatitis interface. It can be asymptomatic or can present as acute hepatitis or liver cirrhosis. Most patients (70-80%) respond to first line therapy (based on steroids ± azathioprine). In those patients not tolerating azatioprine, in steroid resistant, and those with repeated relapses (20-40%), a long-term second line therapy must be considered to avoid progression of liver disease. This last medications include other immunosuppressants like mycophenolate mophetil, calcineurin inhibitors (cyclosporine or tacrolimus), biologic agents (infliximab and rituximab), and other immunosuppressive agents (sirolimus, everolimus), all with good overall clinical results, but not exempt of side effects. Other difficult scenarios include fulminant AIH, end-stage AIH cirrhosis and the management of post-transplant AIH. In this article we will review the literature related to second- line therapy especially of steroid resistant AIH. Future directions in the treatment of HAI should be guided to the individual patient (personalized) and may include cell therapies, such as infusion of autologous, antigen-specific, and liver-homing regulatory T cells to restore hepatic immune tolerance

La hepatitis autoinmune (HAI) es una hepatopatía de etiología desconocida, con pérdida de la tolerancia inmune contra los hepatocitos con factores genéticos y ambientales asociados. Se caracteriza por fenómenos de daño inmunológicos, con autoanticuerpos circulantes, una concentración elevada de gammaglobulina sérica y en la biopsia de hígado actividad necroinflamatoria, infiltrados linfoplasmocitarios y daño de interfase. La HAI es una entidad que se puede presentar en forma asintomática, como hepatitis aguda o como cirrosis hepática. El 70-80% de los pacientes responden adecuadamente al tratamiento inmunosupresor de primera línea (corticoides ± azatioprina). En los pacientes que no toleran azatioprina, en los corticorresistentes o en aquellos con recaídas repetidas a pesar de terapia (20-40%), es necesario recurrir a terapias de segunda línea de largo plazo, para evitar la progresión de la hepatopatía. Estas últimas incluyen micofenolato mofetil, inhibidores calcineurínicos (ciclosporina o tacrolimus), agentes biológicos (infliximab y rituximab), y otros fármacos inmunosupresores (sirolimus, everolimus), con resultados alentadores, pero no exentos de efectos colaterales. Otros escenarios complejos incluyen: la HAI de presentación aguda grave y fulminante, la cirrosis terminal autoinmune y la HAI post-trasplante. En este trabajo se revisa la literatura en relación a terapias de segunda línea especialmente en HAI corticoide resistente. El futuro del tratamiento de la HAI va encaminado a una terapia personalizada y que podría incluir terapias celulares como la infusión de células T regulatorias, antígeno específicas y autólogas, para reestablecer los mecanismos de tolerancia inmune hepática.

Application value of methacetin enteric-coated tablets in patients with steroid resistant severe ulcerative colitis / 中国生化药物杂志

Objective To study the application value of methadazine enteric-coated tablets in the treatment of steroid resistant severe ulcerative colitis.Methods 110 cases of patients with steroid resistance severe ulcerative colitis in our hospital from June 2015 to December 2016 were randomly divided into experimental group and control group (n=55).The control group was given bacillus subtilis duplex living bacterium enteric capsules,the experimental group was given methadazine enteric-coated tablets.The total effective rate, Mayo score, cytokine levels change, C-reactive protein and erythrocyte sedimentation rate were Compared between two groups.Results The total effective rate of the experimental group was 96.36% higher than that of the control group 85.45%(P< 0.05).The Mayo score of the experimental group was (3.17±2.03)and the control group was (3.69±1.97), the difference was not statistically significant.The levels of IL-8、TNF-α in the experimental group were(17.33±2.18) pg/mL ,(18.33±2.23) ng/mL,which were significantly lower than the those of the control group (25.33±2.18) pg/mL, (25.93±1.54) ng/mL (P<0.05).The C-reactive protein in the experimental group was (10.33±2.11) mg/L the ESR (22.39±5.33) mm/h,which was significantly lower than that of the control group (27.27±3.97) mg/L, (33.17±4.93)mm/h (P<0.05).Conclusion Mesalazine is effective in the treatment of steroid resistant severe ulcerative colitis,which can effectively control the inflammation,,reduce the level of IL-8 and TNF-α, worthy of clinical promotion.

Study progress of Tacrolimus treatment on steroid-resistant nephrotic syndrome in children / 中华实用儿科临床杂志

Steroid-resistant nephrotic syndrome (SRNS) is a relatively difficult clinical type of treatment.The major therapy measures in present include steroid and immunosuppressant.Commonly used immunosuppressant include tacrolimus,cyclosporin,cyclophosphamide,mycophenolate mofetil,ect.Tacrolimus-induced clinical remission rate is superior to other immunosuppressive agents,has been the first-line agent of SRNS.Because of the individual difference in metabolism,the drug concentration of tacrolimus should be determined periodically.In order to obtain optimal efficacy of tacrolimus and reduce renal toxicity,the treatment protocols of small doses with long courses for children with SRNS were recommended.

Clinical application of Tacrolimus to infant steroid-resistant nephrotic syndrome / 中华实用儿科临床杂志

Objective To analyze the peculiarity of infants steroid-resistant nephrotic syndrome (SRNS) and to assess the efficacy,side-effect and relapse of various of Tacrolimus prescribed in infants SRNS.Methods A total of 76 case of infant SRNS from August 2012 to August 2015 in Guangzhou Weman and Children's Medical Center grouped into oral Tacrolimus (TAC group),Methyprenisolone pulse therapy (MP group) and Methyprenisolong combined Cyclophosphamide(CTX) pulse therapy(MP + CTX group),were observed for 1 year,and the urine protein excretion,renal function (CCr),blood glucose (B G),urine retinal-binding-protein (URBP),lymphocyte count etc.were recorded and the situation of infection and relapse regularly were monitored regularly.The data were retrospectively analyzed by the statistical method.Results All SRNS children underwent kidney biopsy,and 36 cases of minimal change disease,32 cases of mesangial proliferative glomerulonephritis and 8 cases of focal segmental glome-rulosclerosis were contained in the patients.The pathological constituent ratios were not obviously different among these 3 groups.By 6-month follow-up,the complete remission ratio of TAC group was 63.64％,the total remission ratio was 95.45％,which were remarkably higher than those of MP group (26.09％,60.87％) and MP + CTX group (41.94％,74.19％);the urine protein excretion of TAC group [(7.8 ± 8.6) mg/(kg · d)] was distinctly lower than that of pretreatment and lower than that of MP group [(144.2 ± 118.3) mg/(kg · d)],and lower than that of MP + CTX group [(91.3 ± 87.4) mg/(kg · d)],and the difference was significant (F =22.69,P ＜ 0.05).The remission time of TAC group was about 2 months,that of other two groups was about 3 months.By 1-year follow-up,the lymphocyte counts including total T-cell (CD3 +),the helper T-cell (CD4 +) and the inhibited T-cell (CD8 +) of TAC group decreased obviously(all P ＜ 0.01),which were extremely lower than those of the M P group and MP + CTX group,and there were significant differences (all P ＜ 0.05).By 1-year follow-up,the person-time of infection existed superior to the other 2 groups,TAC group was compared with MP plus group,the rank sum was 348.5 (U =-3.69,P ＜ 0.01);compared with MP + CTX plus group,the rank sum was 369.5 (U =-4.18,P ＜ 0.01).During the observation the URBP of TAC group was distinctly higher than that of the MP group and the MP + CTX group [(13.77 ± 19.19) mg/L vs.(2.50 ± 1.77) mg/L,(2.06 ±3.63) mg/L],and the differences were significant(t =3.16,2.99,all P ＜0.05);the TAC group with BG and CCr maintained stably.Conclusions Tacrolimus shows its own advantages of more reliable effect and less side-effect in the infants with SRNS over MP therapy and MP combined CTX therapy,but it could not lessen the recurrence of the disease,and its long-term prognosis is still not very clear.

Identificación de variantes del gen NPHS2 en niños con síndrome nefrótico corticorresistente / NPHS2 Mutation analysis study in children with steroid-resistant nephrotic syndrome

Resumen: La podocina es una proteína localizada en el diafragma de filtración glomerular donde participa en la regulación de la filtración glomerular. Las mutaciones del gen NPHS2, que codifica a la podocina, son la principal causa de síndrome nefrótico corticorresistente (SNCR) autosómico recesivo en niños. Objetivos: Identificar mutaciones de NPHS2 en niños chilenos con SNCR, y establecer la prevalencia de las variantes más frecuentes en un grupo de adultos sanos. Pacientes y método: Análisis mutacional de NPHS2 en 34 niños chilenos con SNCR. Una vez identificadas las dos variantes de NPHS2 de mayor frecuencia, se realizó un screening de estas mutaciones en 223 adultos sanos. El análisis mutacional se realizó por secuenciación directa de los ocho exones codificantes amplificados por reacción de polimerasa en cadena. La secuenciación del DNA se realizó mediante método fluorométrico y las secuencias fueron evaluadas con el software SeqPilot. La asociación entre la presencia de variantes de NPHS2 y SNCR se calculó comparando las frecuencias alélicas entre los pacientes con SNCR y los voluntarios sanos utilizando prueba exacta de Fisher. Se consideró significativo p < 0,05. Resultados: Se detectaron mutaciones patogénicas de NPHS2 en siete de los 34 pacientes (21%) estudiados, de los cuales seis resultaron heterocigotos para p.R229Q y p.A284 V. En voluntarios sanos la prevalencia de p.R229Q fue de 2,46%. Conclusiones: Este estudio muestra que p.R229Q y p.A284 V son las variantes de NPHS2 más frecuentes en niños chilenos con SNCR. Por primera vez se describe esta asociación en niños chilenos, en base a la cual es posible proponer una estrategia de screening para estudio genético en pacientes con SNCR y sus familias. Se propone una estrategia de búsqueda de p.R229Q y p.A284 V en forma paralela o secuencial en estos pacientes.

Abstract: Podocin is a protein located in the glomerular slit diaphragm where it takes part in the regulation of glomerular filtration. Mutations of the NPHS2 gene that codes podocin are the main cause of autosomal recessive steroid resistant nephrotic syndrome (SRNS). Objectives: To identify the NPHS2 mutations in Chilean children with SRNS, and to determine the prevalence of the most common variants in a group of healthy adults. Patients and methods: Mutation analysis of NPHS2 in 34 Chilean children with SRNS. Once the two most common variants of NPHS2 were identified, screening for these mutations was performed on 233 healthy adults. The mutation analysis was performed by the direct sequencing of the eight coding exons by polymerase chain reaction amplification. The DNA sequencing was performed using a fluorometric method, and then evaluated with SeqPilot™ software. The relationship between the presence of NPHS2 variants and SRNS was calculated by comparing the allele frequency between patients with SRNS and those of the healthy volunteers using the exact Fisher test. A P < .05 was considered significant. Results: Pathogenic NPHS2 mutations were detected in 7 (21%) of the 34 patients studied, of which 6 were heterozygotes for p.R229Q and p.A284 V. The presence of p.R229Q was 2.46% in the healthy volunteers. Conclusions: This study shows that p.R229Q and p.A284 V are the most frequent variants in Chilean children with SRNS. It is the first time that this relationship has been reported in Chilean children. Based on this, a screening strategy is proposed for the genetic study in patients with SRNS and their families. A parallel or sequential search strategy for p.R229Q and p.A284 V in these patients is proposed.

Effect of tacrolimus on steroid-resistant nephrotic syndrome in infants / 实用医学杂志

Objective To assess efficacy, infection rate and recurrence rate of tacrolimus prescribed in infants with steroid-resistant nephrotic syndrome (SRNS). Method From August 2011 to August 2014, 22 cases of SRNS infants (treatment group) received oral tacrolinms treatment, 0.1 to 0.15 mg/ kg per day and once every 12 hours were enrolled in this retrospective longitudinal study and were compared with 23 cases infant SRNS (control group) treated with high-dose methylprednisolone pulse therapy. Followed up for 1 year we analysed the data of proteinuria, lymphocyte count, proteinuria relapse and complication (infection, hyperglycemia) of the two groups’ patients at every point time. Results The pathology of the patients maintains of MCD, MsPGN, FSGS and IgM nephropathy so on. Follow-up to 6 months, the total remission rate 95.45% of treatment group was significantly higher than that in control group (60.87%). Follow-up to 6 months , 24 h urinary protein of the treatment group were respectively 67.88 mg/(kg·d) which were remarkably lower than base line [657.5 mg/(kg·d)], meanwhile which were obviously lower than the 6th month point of control group [305.55 mg/(kg·d)]. Lymphocyte counts had been done during the initial and the destination in the treatment group. Follow-up to 12 months, the CD4+ 795.16/uL, CD8+ 496.85/uL, CD19+ 358.23/uL had decreased observably than when at origin what was 2697.45/uL, 2265.63/uL, 1579.34/uL. Followed-up 1 year, the person-time of infection of treatment group existed superior to the control groups; The recurrence rate was 71.43% in treatment group, which compared with control groups (60.87%) without no significant difference. The treatment group with BG and CCr maintained stably. Conclusion Tacrolimus show its own advantages of reliable effect and less side-effect on the infant with steroid-resistant nephrotic symdrome associated with genes , but it could not lessen the relapse of the disease, and it′s long-term prognosis is still not very clear.