激素抵抗性哮喘的研究进展

支气管哮喘的本质是气道慢性非特异性炎症,肾上腺糖皮质激素抗炎治疗已成为哮喘现代治疗的主要方法。但约5%-10%的患者对激素治疗不敏感而成为难治性哮喘,这种对激素治疗效果较差的哮喘被称为“激素抵抗性哮喘”（steroid-resistant asthma,SRA）。其发生机制不明,可能与糖皮质激素受体β、基因表达和热休克蛋白异常等有关,免疫和非免疫治疗可以改善哮喘症状。     

Insertion/Deletion (I/D) Polymorphism of Angiotensin-Converting Enzyme Gene in Steroid-Resistant Nephrotic Syndrome for Children: A Genetic Association Study and Meta-analysis

Abstract

An assessment of the association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with steroid-resistant nephrotic syndrome (SRNS) risk in children is still controversial. A meta-analysis was performed to evaluate the relation between ACE gene polymorphisms and SRNS susceptibility. The relevant studies were screened from electronic database and eligible investigations were synthesized using meta-analysis methods. Seven investigations were identified for the analysis of association between ACE I/D gene polymorphism and SRNS risk in children, including five in Asians, one in Caucasians, and one in Africans. There was not a markedly positive association between D allele or DD genotype and SRNS susceptibility in Asians (OR = 1.60, p = 0.26; OR = 1.90, p = 0.38) and for Caucasian population (OR = 0.92, p = 0.86; OR = 0.27, p = 0.22). However, an association of D allele with SRNS susceptibility was observed (OR = 4.67, p = 0.003) in Africans, but not for DD genotype (OR = 6.00, p = 0.05). Interestingly, II genotype seemed to play a positive role against SRNS onset for Asians and African children (OR = 0.51, p = 0.02; OR = 0.07, p = 0.02), but not for Caucasians (OR = 0.33, p = 0.30). In conclusion, our results indicate that D allele or DD homozygous might not be a significant genetic molecular marker for the development of SRNS in Asians and Caucasian children. However, D allele seemed be associated with SRNS risk for Africans but DD genotype did not.     

多靶点治疗激素抵抗型肾病综合征的临床研究

目的研究多种免疫抑制剂联合治疗激素抵抗型肾病综合征的临床疗效。方法14例患者均接受小剂量环孢素A（CsA）和来氟米特联合中等剂量的强的松治疗，在治疗后第2、4．6、8、12周动态监测各项临床指标。结果24h尿蛋白定量较治疗前明显下降，血浆白蛋白在治疗后明显升高，完全缓解率为64．3％，总有效率为86．7％。结论多靶点治疗激素抵抗型肾病综合征有显著疗效，并且不良反映少，安全性较高。     

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 SUMMARYWe 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.     

Vincristine in steroid-resistant nephrotic syndrome

The therapeutic response to vincristine was examined in seven children (aged 2–15 years) with corticosteroid-resistant (CR) nephrotic syndrome (NS) with focal and segmental glomerulosclerosis (FGS). Five were also resistant to cyclophosphamide. Vincristine was given weekly (1.5 mg/m² intravenously) for 8 weeks. Simultaneously, prednisone (60 mg/m² per day, orally) was given for 4 weeks and then gradually tapered. Two of these patients had a complete and stable remission; in five no benefit was observed. It was not possible to identify any characteristics to predict the response to vincristine. Although there is a case for trying vincristine therapy in CR NS with FGS, the results of this study are not encouraging and a better understanding of its action and indications is necessary.     

Incidence,risk factors,and outcome of antithymocyte globulin treatment of steroid-resistant rejection after liver transplantation

We retrospectively analyzed the incidence and outcome of steroid-resistant rejection (SRR) during the first 6 months after OLT in 126 patients receiving triple immunosuppression. A total of 95 patients either did not experience acute rejection at all or had acute rejection that subsided without additional treatment. A total of 31 patients had biopsy-proven acute rejection that required therapy: 18 patients had acute rejection that responded to steroid therapy (steroidsensitive rejection, SSR); the remaining 13 patients had SRR and received ATG. At the onset of acute rejection, no differences in clinical, biochemical, or immunological parameters were present between patients with SSR and SRR. However, the histological grade of acute rejection in the initial biopsy was higher in patients with SRR (P=0.05). ATG treatment was effective in 10 of the 13 patients and was not associated with an increased incidence of opportunistic infections. Patient and graft survival rates at 2 years were comparable in the three groups. These data show that the incidence of SRR during the first 6 months after OLT is low, and that its treatment with ATG is both effective and well tolerated.     

Steroid-resistant,cyclosporine-responsive,relapsing nephrotic syndrome

Eighteen children with steroid-resistant nephrotic syndrome received cyclosporine A (CsA), including 7 patients with minimal change disease, 4 with focal segmental glomerulosclerosis and 7 with mesangial hypercellurarity. Doses were adjusted to maintain whole blood trough levels at 80–200 ng/ml and ranged from 5 to 10 mg/kg (mean 7 mg/kg). Fourteen patients responded after 2 months of therapy with either a complete or partial remission, and received a total of 12 months of CsA with low-dose corticosteroids. Remission rates were similar among the three histological types, although complete remissions occurred more commonly in minimal change disease, while the other two histological types tended to have partial responses. Serum creatinine values ranged from 0.3 to 1.2 mg/dl at the start of treatment and were stable in 17 of 18 patients during CsA therapy. CsA was discontinued after 12 months in 11 responders. Relapses were a significant problem. Nine patients had 16 relapses, all occurring within 6 months after discontinuing CsA; 13 of 16 relapses responded to CsA and corticosteroids. Five children had multiple relapses. Three patients who initially responded to treatment had CsA-resistant relapses. There were no differences among the histological types with respect to the occurrence of relapses or response to CsA after relapsing. Four patients developed chronic renal failure, including 2 of 4 who failed initial therapy and 2 of 3 who developed CsA-resistant relapses. In conclusion, initial therapy with CsA was effective in resolving nephrotic syndrome in steroid-resistant patients. However, CsA dependency, frequent relapses and the development of chronic renal failure presented significant problems.     

Steroid-resistant rejection in kidney-transplanted patients: is ATG treatment for three or ten days preferable?

Abstract  We carried out a randomized prospective trial to compare a 3-day with a 10-day course of anti-thymocyte globulin (ATG)- (Frese-nius) for treatment of steroid-resistant rejection after renal transplantation. The aim was to study whether a short 3-day course was as safe and effective as the longer 10-day treatment. Thirty patients over a 3-year period were included. Patients that did not respond to treatment after 3 days received additional ATG from day 5 to day 10. The graft survival and the proportion of rejections reversed with the treatment were compared. Fifty percent responded promptly in the 3-day group and a further 29 % after additional treatment. In the 10-day group, 62 % reponded to the treatment. There was no significant difference between the groups. We, therefore, suggest that the standard antirejection treatment with ATG could be shortened without an increased risk of graft failure.     

Fifteen-year remission of a steroid-resistant nephrotic syndrome sustained by cyclosporine A

Many children with a late steroid-resistant nephrotic syndrome (SRNS) and focal glomerulosclerosis have a poor prognosis and enter end-stage renal failure (ESRF) within five years. Reports are scarce on the long-term follow-up of patients entering remission while receiving immunosuppressive therapy after steroids have failed. A two-year-old boy with focal and segmental glomerulosclerosis having both late steroid and cyclophosphamide resistance entered complete remission of the SRNS almost two years after starting induction therapy with cyclosporine A (CSA). During the 15-year follow-up, the patient experienced five relapses during CSA maintenance therapy. All relapses were successfully treated within 10 days by intravenous methylprednisolone pulses in addition to CSA. The relapses were accompanied by a drop in the glomerular filtration rate (GFR). At the age of 18 years, the patient had grade II chronic kidney disease (GFR=61 ml/min/1.73 m²). At the age of 14 years, mycophenolate mofetil (MMF) was added to the maintenance therapy and the CSA dosage was reduced. Two renal biopsies at the ages of 10 and 18 years failed to detect CSA nephrotoxicity. We conclude that children with SRNS may have long-term benefit from a combination therapy using intravenous methylprednisolone pulses and CSA.