Glucocorticoids (GCs) have been used clinically for more than half a century as the most important and preferred treatment for primary nephrotic syndrome (INS). Based on the response to GC, INS is clinically classified into hormone-sensitive nephrotic syndrome (SSNS) and hormone-resistant nephrotic syndrome (SRNS). Although most children with INS are sensitive to GC have a good prognosis; however, about 20% still present with SRNS and have a poor prognosis, and SRNS is one of the main causes of ESRD in children (accounting for 15% of ESRD in children). Therefore, how to treat SRNS properly, choose immunosuppressants rationally, reduce proteinuria and complications of nephrotic syndrome has been a thorny issue for nephrologists’ clinical treatment. The mechanism of hormone resistance in nephrotic syndrome is complex. In clinical work, we must first distinguish between primary hormone resistance and secondary hormone resistance. The former is mainly related to the resistance of the disease itself to hormone therapy, such as abnormalities in the structure, function, and distribution of glucocorticoid receptors, single gene mutations causing SRNS (at least nine single gene mutations in podocyte protein molecules are known to be associated with human SRNS: NPHS1, NPHS2, LAMB2, WT1, ACTN4 , CD2AP, TRPC6 , PLCE1, and (LMX1B). The latter may be associated with secondary hormone resistance such as irregular hormone therapy, infection, complications, renal tubular interstitial injury, and factors affecting hormone pharmacokinetics. Therefore, the clinical management of hormone-resistant nephropathy must pay attention to the following aspects: (1) First of all, the concept is clear and the importance of regular treatment is realized, in which the review of medical history and active search for the cause are especially crucial. (2) Active search for the causes of hormone resistance: including pathological type, treatment standardization, infection and complications, presence of renal tubular interstitial injury, factors affecting hormone pharmacokinetics, and molecular genetic level. (3) Treatment of SRNS: Try to individualize the medication according to the type of pathology, degree, or molecular level. In 1980, Ponticelli et al. used PMT (15-20 mg/kg/d for 3 d) to treat refractory MCD and obtained certain efficacy. 65% of patients were treated effectively. PMT has been reported in 32 children treated with PMT+CTX and followed for more than 6 years, resulting in 21 complete remissions and a 5-year incidence of ESRD of 5% (compared to 40% in the control group). (2) As FSGS treatment (Mendoza protocol): i.e., PMT 3 times a week for 2 weeks; weekly for weeks 3-10; every 2 weeks for weeks 11-18; every 4 weeks for weeks 19-50; every 8 weeks for weeks 5l-82; oral prednisone at 2 mg/kg every other day for weeks 3-8 and tapered thereafter. Add cytotoxic drugs if the above treatment is unsatisfactory. 2. CTX: A number of data from ISKDC and others have shown that oral CTX is ineffective in children with FSGS who exhibit SRNS, but effective in MCNS, and Bergstand et al. reported that CTX can convert hormone-resistant children into hormone-effective patients. (Elhence et al. reported 100% efficacy in 13 patients compared to 25% in the control group; another group reported that it was found to be effective in about 65% of 20 patients with FSGS). In a retrospective analysis of 81 SRNS cases from 1997-2004, we found that the complete remission rate and total effective rate of high-dose CTX intravenous therapy in this group of children were 28.6% and 61.9%. 3.Phenylbutyrate: The efficacy of CsA on SRNS varies from report to report. Baluarte et al. reported remission in l0 cases out of l7 cases, but Niaudet et al. reported that 74 cases applied 0.2 mg/kg for 2-6 months, only l4 cases entered complete or partial remission. 4. CsA: Singh et al. showed that 30% of treatment with CsA alone was effective, while the efficiency of combined treatment with hormones rose to 40%-50%. It was also found that for patients with pathological type MCD and FSGS the efficiency was 46% and 30% respectively. In a multicenter randomized treatment of 45 SRNS in Italy, 59% of the CsA-treated group achieved complete or partial remission, compared to 15% of the control group. The French Society of Pediatric Nephrology prospectively observed the efficacy of CsA in 65 children with SRNS, resulting in 42% complete remission and 6% partial remission. Our data showed that the overall complete remission rate and total effective rate of CsA for SRNS were 66.7% and 83.3%, respectively; and the efficacy was better than that of high-dose CTX shock therapy. 5. Other immunosuppressive drugs: MMF, tacmlimus, and rehmannia polysaccharide have been reported to be effective in the treatment of SRNS, but further evidence-based data from a large sample of multicenter data are needed to confirm. In conclusion, individualized treatment for children with SRNS should be performed by clarifying the pathological type after fully understanding the possible causes of hormone resistance. It is emphasized that: (1) individualized treatment based on evidence-based medicine is needed (2) the relationship between efficacy and side effects, as well as health economics values are also taken into account (3) parents and physicians work together. On the basis of the above, CsA therapy is used as appropriate, followed by consideration of high-dose CTX shock therapy; or MMF, tacrolimus, and rehmannia multi-glucoside. At the same time, drug toxicities and the patient’s immune status must be monitored during the treatment process and the treatment plan adjusted accordingly.