The Clinical Efficacy of Low-Dose Tacrolimus Combined with Tripterygium to Treat the Steroid-Resistant Nephrotic Syndrome

Objective: To observe the clinical efficacy and safety of low dose tacrolimus (TAC) combined with tripterygium (TW) in treatment of steroid resistant nephritic syndrome (SRNS). Method: The patients, who were diagnosed with mesangial proliferative glomerulonephritis (MesPGN) and focal segmental glomerulosclerosis (FSGS) by biopsy and failed to respond to a 3-month treatment with prednisone (1 mg/kg·d), were randomly divided into 2 groups (TAC + TW Group and TW Group). Initially TAC + TW group took TAC 0.05mg/(kg·d) 2 h after meal at 12 h interval. The plasma TAC level was examined after 3 days and was kept at 1.5 - 4 ng·ml;meanwhile, TW was given at 60 mg/d before meal. TW group only took TW (60 mg/d). The efficacy, adverse reactions and plasma TAC levels were observed in each group. Results: 1) Totally 20 SRNS patients completed the trial, 11 of TAC + TW Group and 9 of TW Group. There is no statistical difference between the two groups in terms of age, gender, duration since onset of the disease, blood pressure, 24 h UPQ, serum albumin, creatinine, cholesterol, triglyceride, FBG, kidney pathological categories, time of taking prednisone etc.;2) Urine protein started to decrease after 1 month treatment in both of TAC + TW and TW groups. By the 12th month of treatment, TAC + TW group showed 8 cases of complete remission (72.7%), 2 cases of partial remission (18.2%) and 1 case of no improvement (9.1%), while those of TW groups were 2 (22.2%), 4 (44.5%) and 3 (33.3%), respectively;3) With treatment, the TAC + TW Group patients’ plasma protein was significantly higher than that of pretreatment stage and recovered to normal level after 6 month of treatment. However, there was no significant plasma protein increase in TW Group. No obvious changes were observed on serum creatinine level of patients of both the two groups;4) The incidence of adverse reactions was not significantly different between the two groups. Conclusion: TAC + TW reduced proteinuria of SRNS patients, increased clinical remission rate and was tolerant to SRNS patients. We conclude that TAC + TW treatment is an effective way to treat patients with SRNS.

Crumbs homolog 2 mutation in two siblings with steroid-resistant nephrotic syndrome:Two case reports

BACKGROUND Crumbs homolog 2(CRB2)is a recently discovered gene that is closely related to the maintenance of normal polarity in podocytes;mutations can directly lead to steroid-resistant nephrotic syndrome(SRNS).However,the characteristics of nephrotic syndrome(NS)caused by CRB2 mutations have not been described.CASE SUMMARY We report a novel compound heterozygous mutation of the CRB2 gene in two siblings with SRNS.The two siblings had edema,proteinuria,hypoproteinemia and hyperlipidemia.Both their father and mother had normal phenotypes(no history of NS).Whole exon sequencing(WES)of the family showed a novel compound heterozygous mutation,c.2290(exon 8)C>T and c.3613(exon 12)G>A.Glucocorticoid therapy(methylprednisolone pulse therapy or oral prednisone)and immunosuppressive agents(tacrolimus)had no effect.During a 3-year follow-up after genetic diagnosis by WES,proteinuria persisted,but the patient was healthy.CONCLUSION CRB2 mutations related to SRNS often occur in exons 7,10,and 12.Clinical manifestations of SRNS caused by CRB2 mutations are often less severe than in other forms of SRNS.

NPHS2 Gene Mutation and Polymorphisms in Indonesian Children with Steroid-Resistant Nephrotic Syndrome

Objective:?Although several NPHS2 gene mutations and polymorphisms were described and?associated with clinical manifestation of steroid-resistant nephrotic syndrome (SRNS),?the?occurrence of these genetic abnormalities or variants appeared?to be influenced by race and ethnic group. We have investigated?probable mutations and variants in NPHS2 gene involved in SRNS and their association with clinical manifestations. Methods: We examined 28 children?with primary SRNS?whovisited?the pediatric nephrology division of 10 teaching hospitals in Indonesia. Molecular genetic studies of the NPHS2 gene were?conducted through screenings?for the exon 1, exon 2, and exon 8. The mutational analysis of NPHS2 was performed by DNA sequencing.?Fisher’s Exact Test was used to determine?the?correlation?between?NPHS2 polymorphisms and clinical manifestations.Results:?Seven?females (25%) and 21 males (75%)?participated in the study.?The mean age of the subjects with 95% CI is: 7.6 (6.1 - 9.0) years while the mean age at onset of disease with 95% CI is: 5.4 (3.9 - 7.0) years. Sixteen patients (57.14%) were younger than 6 years at the onset of disease. Seventeen (60.7%) subjects had normal eGFR, while 11 (39.3%) had chronic renal insufficiency. The mean eGFR of the subjects with 95% CI is: 111.4 (87.7 - 135.1) ml/min/1.73 m2. The mean systolic blood pressure with 95% CI is: 117.0 (108.9 - 125.1) mmHg and the mean diastolic blood pressure with 95% CI is: 77.0 (70.3 - 83.7) mmHg.?We identified 6 NPHS2polymorphisms,?i.e.?g.-52G>T, c.101A>G, g.-117C>T, c.288C>T, c.954C>T, and c.1038A>G and no mutation?was found. There was?no correlation?between?NPHS2 polymorphisms and clinical manifestations (p > 0.05). Conclusion: The?results demonstrate no mutation of NPHS2 gene, and the 6 NPHS2 gene polymorphisms that were identified have no correlation with the clinical manifestation in Indonesian children with SRNS.

Efficacy and safety of tacrolimus and low-dose prednisone in Chinese children with steroid-resistant nephrotic syndrome

Background Tacrolimus,a calcineurin inhibitor,is recommended by the recent guidelines from the Kidney Disease Improving Global Outcomes Group as the first-line treatment for steroid-resistant nephrotic syndrome(SRNS),but its clinical application in China is still limited.We investigated the efficacy and safety of tacrolimus combined with low-dose corticosteroids in a population of Chinese children with SRNS.Methods In this prospective non-randomized,non-controlled study,Chinese children with SRNS who failed the previous full-dose prednisone treatment were given tacrolimus(0.1 mg/kg/day)and low-dose prednisone(0.25-0.50 mg/kg/day).We compared the overall remission rate(ORR)and adverse events in the follow-up period with this therapeutic regimen.Results A total of 76 children were enrolled into the study with an average follow-up period of 18±6 months(maximum 36 months).ORR achieved by the first,third,and sixth months was 94.7%,94.7%,and 96.0%,respectively.All patients who attained an initial tacrolimus trough concentration(FK506C0)>6 ng/mL(60.3%)achieved remission.The relative risk of relapse at FK506C0<3 ng/mL compared to 3-6 ng/mL,6-9 ng/mL,and 9-12 ng/mL was 2.3,3.2,and 16.9,respectively.During the follow-up period,adverse effects that had been previously reported were rare.Conclusions Combination of tacrolimus and low-dose prednisone was safe and effective for the treatment of children with SRNS,with high remission rates observed as early as the first month.Relapses were infrequent,but tended to increase significantly with decreases in FK506C0.

Low-intensity aerobic exercise training attenuates airway inflammation and remodeling in a rat model of steroid-resistant asthma

Background Aerobic exercise can improve symptoms,reduce airway inflammation,and even ameliorate airway remodeling in asthmatic animals and patients.However,previous studies have focused mainly on the effect of aerobic exercise on steroid-sensitive asthma （SSA）.The goals of this study were to determine the effect of low-intensity aerobic exercise training on airway hyperresponsiveness,inflammation,and remodeling in a rat model of steroid-resistant asthma （SRA） and to identify the potential mechanisms underlying these effects.Methods Endotoxin-free ovalbumin with or without lipopolysaccharide were applied to establish rat models of SRA and SSA,respectively.Airway hyperresponsiveness,inflammation,remodeling,expression of interleukin （IL）-25,IL-33,thymic stromal lymphopoietin （TSLP）,high mobility group box-1 （HMGB1）,and IL-17 in bronchoalveolar lavage fluid （BALF）,and the role of dexamethasone （DXM） were compared between these two asthmatic rat models.The effect of low-intensity aerobic exercise training and anti-HMGB1 treatment on airway hyperresponsiveness,inflammation,and remodeling in SRA rats also was evaluated.Results SRA rats developed neutrophil-dominated airway inflammation （（29.5±4.1）％ of the total cell numbers in BALF）,whereas SSA rats developed eosinophil-dominated airway inflammation （（24.0±6.1）％ of the total cell numbers in BALF）.Compared with SSA rats,SRA rats had more severe airway hyperresponsiveness,lower levels of IL-25 （（33.6±10.3） vs.（104.8±24.9） pg/ml）,IL-33 （（87.5±25.0） vs.（226.6±40.7） pg/ml）,and TSLP （（1 933.2±899.5） vs.（7 224.0±992.1） pg/ml）,and higher levels of HMGB1 （（21.2±4.5） vs.（5.4±1.6） ng/ml） and IL-17 （（780.5±261.7） vs.（291.4±76.4） pg/ml） in BALF （all P ＜0.05）.However,there was no significant difference in goblet cell hyperplasia,subepithelial collagen thickness,and airway smooth muscle remodeling between the two groups.Compared with control SSA rats,airway hyperresponsiveness,inflammation,and remodeling in SRA rats were less sensitive to DXM treatment.Anti-HMGB1 treatment attenuated airway hyperresponsiveness,inflammation,and remodeling in SRA rats to a certain extent and was accompanied by lower levels of IL-17 （（369.2±126.7） vs.（780.5±261.7） pg/ml in control SRA rats） in BALF （P ＜0.05）.Low-intensity aerobic exercise training decreased the expression of both HMGB1 （（14.1±2.9） vs.（21.2±4.5） ng/ml in control SRA rats） and IL-17 （（545.3±148.6） vs.（780.5±261.7） pg/ml in control SRA rats） in BALF （all P ＜0.05） and was accompanied by improved airway hyperresponsiveness,inflammation,and remodeling in SRA rats （all P ＜0.05）.Conclusions Low-intensity aerobic exercise training attenuated airway hyperresponsiveness,inflammation,and remodeling in a rat model of SPA.Decreased HMGB1 and IL-17 levels in BALF by aerobic exercise training at least partly contributed to the improvements of SPA.

Mesenchymal stem cells for treatment of steroid-resistant acute rejection after liver transplantation

A patient with steroid-resistant acute rejection 50 days after ABO-compatible orthotopic liver transplantation(LT)received regular infusion of allogeneic mesenchymal stem cells(MSCs)after three sessions of steroid pulse therapy which failed to control the pathogenetic condition as shown by biopsy.Liver function improved gradually after intravenous injection of MSCs once weekly for 10 weeks(as confirmed by biopsy)and remained stable under administration of conventional immunosuppressive agents.There was no evidence of neoplasms 5 years after treatment.MSCs infusion appears to successfully reverse resistance to immunosuppressive agents and may be a useful treatment for post-liver transplant steroid-resistant rejection.

Anti-thymocyte globulin for treatment of T-cell-mediated allograft rejection

Anti-thymocyte globulin(ATG)is a pivotal immunosuppressive therapy utilized in the management of T-cell-mediated rejection and steroid-resistant rejection among renal transplant recipients.Commercially available as Thymoglobulin(rabbit-derived,Sanofi,United States),ATG-Fresenius S(rabbit-derived),and ATGAM(equine-derived,Pfizer,United States),these formulations share a common mechanism of action centered on their interaction with cell surface markers of immune cells,imparting immunosuppressive effects.Although the prevailing mechanism predominantly involves T-cell depletion via the complement-mediated pathway,alternate mechanisms have been elucidated.Optimal dosing and treatment duration of ATG have exhibited variance across randomised trials and clinical reports,rendering the establishment of standardized guidelines a challenge.The spectrum of risks associated with ATG administration spans from transient adverse effects such as fever,chills,and skin rash in the acute phase to long-term concerns related to immunosuppression,including susceptibility to infections and malignancies.This comprehensive review aims to provide a thorough exploration of the current understanding of ATG,encompassing its mechanism of action,clinical utility in the treatment of acute renal graft rejections,specifically steroid-resistant cases,efficacy in rejection episode reversal,and a synthesis of findings from different eras of maintenance immunosuppression.Additionally,it delves into the adverse effects associated with ATG therapy and its impact on long-term graft function.Furthermore,the review underscores the existing gaps in evidence,particularly in the context of the Banff classification of rejections,and highlights the challenges faced by clinicians when navigating the available literature to strike the optimal balance between the risks and benefits of ATG utilization in renal transplantation.

Relationship between bronchial asthma and glucocorticoid receptor gene bcl-I single nucleotide polymorphism

Objective: To investigate the relationship between bronchial asthma in children and glucocorticoid receptor (GR) gene bcl-I single nucleotide polymorphism and to analyze the relationship between bronchial asthma and the plasma cortisol level. Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques were used to deter-mine the GR gene bcl-I single nucleotide polymorphism in 76 children patients with asthma and 50 healthy controls. The plasma cortisol levels were detected by radio immunoassay in two groups respectively. Results: There were three genotypes found in bcl-I gene locus of these two groups, which were genotype CC, GG and CG. The frequencies of CC, CG, GG genotypes were 48.7%, 27.6%, 23.7% in the asthma group and 76%, 20%, 4% in the control group. The difference was of statistical significance (p < .05). The frequency of G allele in the asthma group was 37.5%, which was significantly higher than 14% in the control group (p < .05), indicating that G allele was associated with asthma. Conclusions: GR gene bcl-I polymorphism is significantly associated with the occurrence of bronchial asthma. G allele may be a susceptibility gene for steroid-resistance in asthma. Steroid-resistance has no correlation to the plasma cortisol level.

Histopathology Review of Idiopathic Steroid Resistant Nephrotic Syndrome and Outcome in Children in North-West of Iran

Introduction: There is currently little information in the literature on the spectrum of histopathologic patterns in children presenting with idiopathic steroid-resistant nephrotic syndrome (iSRNS) in Iran. We conducted to compare the histopathologic distribution of different subtypes’ glomerular morphologic patterns in iSRNS and the clinical and biochemical parameters at the time of diagnosis and outcome of patients after immunosuppressive therapy. Material and Methods: This cross sectional study was done in two hundred children, aged 1 - 15 years, who were diagnosed for iSRNS and no response to 4 weeks of standard prednisone therapy (60 mg/m2/day) referred to nephropathology Department of Emam Reza hospital between 2005 and 2013. Demographic, clinical, laboratory, and histopathological data were retrieved from files and original renal biopsy reports. We discussed histopathologic diagnosis and outcome of iSRNS after initial therapy in patients separately. This study investigated prognostic effects of histopathologic pattern on outcome of iSRNS. Results: The study included 200 children with iSRNS: 141 (70.5%) were males and 59 (29.5%) females, with male-to-female ratio of 2.4:1. The mean age was 7.23 ± 4.37 years (range: 1 - 15 years). Upon pathologic investigation of iSRNS cases, focal segmental glomerulosclerosis (NOS subtype) was the first, with a highest prevalence at a rate of 102/200 (51%) and MGN was the last, at a rate of 7/200 (3.5%). Children with iSRNS secondary to MCD are more likely to achieve remission and have better long term prognostic value (P 0.00). Focal segmental glomerulosclerosis (FSGS) (Tip and Collapse subtypes) is more likely to have worse outcome in response to immunosuppressive therapy (P 0.04). Conclusions: This study defines the true spectrum of clinicohistopathology patterns underlying iSRNS in children in Northwest of Iran. Also this study shows that the response to cyclosporine can be correlated with the underlying histopathology patterns which have been earned by adequate renal biopsy.

Genetic Architecture of Childhood Kidney and Urological Diseases in China

Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration system is being imple-mented based on the Chinese Children Genetic Kidney Disease Database(CCGKDD).In this study,all the patients with kidney and urological diseases were recruited from 2014 to 2020.Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features.The genetic diagnosis was confirmed in 883 of 2256(39.1%)patients from 23 provinces in China.Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome(SRNS,23.5%),glomerulonephritis(GN,32.2%),congenital anomalies of the kidney and urinary tract(CAKUT,21.2%),cystic renal disease(3.9%),renal calcinosis/stone(3.6%),tubulopathy(9.7%),and chronic kidney disease of unknown etiology(CKDu,5.8%).The pathogenic variants of 105 monogenetic disorders were identified.Ten distinct genomic disorders were identified as pathogenic copy number variants(CNVs)in 11 patients.The diagnostic yield differed by subgroups,and was highest in those with cystic renal disease(66.3%),followed by tubulopathy(58.4%),GN(57.7%),CKDu(43.5%),SRNS(29.2%),renal calcinosis/stone(29.3%)and CAKUT(8.6%).Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions.We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed.Our data demonstrate the utility of family-based exome sequencing,and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.