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Study on immunosuppressive therapy for nephrotic syndrome

Dec 29, 2016
1 the history of immunosuppressive agents used in kidney disease
Since 1827 Rrichard Bright and other reports of kidney disease, many scholars have done a lot of research on the treatment of this disease. In 1917, Esherich and Schick first proposed an immune response in the pathogenesis of kidney disease. In 1949, New York's Farnsworth and Barnett pioneered the use of adrenocorticotropic hormone (ACTH) treatment of lipid nephropathy; Chasis the use of nitrogen mustard in treatment of chronic glomerulonephritis and preliminary efficacy, which pioneered the use of ISA to treat kidney disease first. New York is thus known to the world as the cradle of glomerular disease therapeutics. The Luetscher and Denning will be used for cortisone nephropathy. The number of ISA entering 1960s for nephropathy has increased. Children with nephrotic syndrome (NS) were treated with cyclophosphamide (CTX) in 1963. In 1966, West expanded the use of CTX in kidney disease. Then chlorambucil and azathioprine (Aza) have been used for the treatment of kidney disease. Acute rejection in 1971 Bell intravenous methylprednisolone treatment of renal transplantation, laid the foundation for rescuing acute severe renal diseases. Cyclosporine (CSA) was also used in the treatment of various glomerular diseases in 1985. In recent years, some new ISA such as mycophenolate mofetil (MMF) and leflunomide should also and used to obtain certain curative effect in clinical. Other ISA drugs such as 6-, such as purine, methotrexate, due to side effects, the effect is not ideal and less use.
2 clinical application of immunosuppressive agents
2.1 cyclophosphamide (CTX)
Cyclophosphamide (CTX) for nitrogen mustard and phosphorus amide binding compounds and is a commonly used alkylating agent immunosuppressants. Can be used to treat a variety of autoimmune diseases, which can inhibit the proliferation of cells, non-specific killing antigen sensitive small lymphocytes, limiting its transformation into immune cells. Commonly used in nephrotic syndrome, allergic purpura, systemic lupus erythematosus (SLE) and other autoimmune diseases.
In view of the western ethnic and genetic and environmental factors are different, Ali and so on. The maximum tolerated dose for the treatment of CTX Pakistani primary nephrotic syndrome, the results show that the maximum tolerated dose of female CTX 1.34 mg/ kg, suggested CTX beginning in dose should be less than 1 mg/ K G. Fujimoto and other studies have shown that CTX (2mg#kg-1#d- 1) + prednisone (1 mg# kg- 1#48 h) in treatment of membranous nephropathy (MN) induced by NS, complete and partial remission rate increased along with the prolongation of time, 6 months after treatment were 32%, 21%, 12 months to 54%, 29%, 1 when was 79% and 11%, suggesting that MN nephrotic syndrome therapy with methylprednisolone combined with strong reaction in early stage of CTX, elevated serum IgG levels and decreased the selectivity index is a sign of early response to treatment.
Hormone dependence is the main problem existing in treatment of children with idiopathic nephrotic syndrome, CTX effect in the treatment of frequent relapses have reached a consensus, but the CTX oral or intravenous administration of the effect is the same? Bircan were studied in 19 cases, the results of two groups of the cumulative dose of CTX had no significant difference under the condition of vein the drug group without infection, hemorrhagic cystitis, hair loss and other complications and side effects, and reduce the recurrence rate, remission duration and hormone consumption, that CTX is effective and safe for intravenous administration. Ka wa SA ki will methylprednisolone and urokinase impact combined with CTX in the treatment of severe Henoch Schonlein purpura nephritis (>? Degrees), after 6 months, the average urinary protein, and chronic disease activity index combined with CTX treatment group than before treatment and methylprednisolone and urokinase impact group decreased significantly. The effective rate of massive proteinuria and / or moderate to severe IgA was 61.6%. The advanced IgA nephropathy, CTX parallel impact with a small dose of prednisolone can protect renal function.
2.2 azathioprine (Azathioprine, Aza)
Ali in the study of Pakistani people showed that the maximum tolerated dose of Aza treatment of female primary nephrotic syndrome was 1.03 mg/kg, while its induced neutropenia and thrombocytopenia incidence was higher than CTX, the initial dose of Aza is 0.75 ~ 1.0mg/kg, then according to the clinical response and auxiliary examinations in the dose adjustment. On IgA nephropathy proteinuria or renal insufficiency, Aza combined with prednisone can induce remission; and the damage to the renal function of severe chronic kidney disease with obvious unfavorable use of the program, because it not only can improve the clinical characteristics of patients and lesions, and increase the incidence of side effects of drugs. Mok + Aza in the hormone treatment of idiopathic membranous nephropathy, 12 months later, 67% patients with complete remission, 22% partial remission, complete and partial remission continue with low-dose corticosteroids + Aza, follow-up of 90.4. 59 months after the recurrence of 19%, confirmed that hormone combined with Aza can be used for the treatment of early membranous LN. Aza is an effective drug for the treatment of lupus nephritis. A multicenter randomized controlled trial of 32 patients with proliferative lupus nephritis were randomly pided into two groups: Aza+ group and CTX group. The results showed that there was no significant difference in the efficacy and side effects between the two treatment regimens in the treatment of CTX. Contreras is also compared with LN maintenance treatment, 46 cases of LN patients with different pathological grading by CTX and hormone induced remission were pided into 3 groups: intravenous injection of CTX group and Aza group (1~ 3mg# kg-1#d-1), MMF group (500~ 3000 mg/ d), the treatment group MMF, chronic renal failure the incidence rate of Aza was higher than that in group CTX, the recurrence rate in group MMF was higher than group CTX, but the hospital, amenorrhea, infection, the incidence of nausea and vomiting in MMF group and Aza group were significantly lower in CTX group, LN CTX think hyperplastic short-term intravenous induction of remission after Aza or MMF treatment than CTX to maintain long-term intravenous maintenance therapy more safe and effective. Other studies have shown that the increase of LN Aza+ hormone can reduce the mortality rate, but it has no obvious protective effect on renal function.
Mycophenolate mofetil (mycophenate Ma 2.3 ftil, MMF)
Mycophenolate mofetil first as antibacterial and antifungal drugs used in clinical surgery, 60s began as antitumor drugs in clinical application, until the late 80s people will treat it as immunosuppressive agents used in autoimmune disease and organ transplantation rejection inhibition reaction, in operation for the first time MMF Academician Li Leishi for the treatment of glomerular diseases.
The beginning of 1998 South medical researchers began to concern and clinical practice of application development of mycophenolate mofetil in glomerular diseases, the treatment of children refractory mycophenolate mofetil results of the clinical observation of nephropathy and Briggs reported similar, achieved good therapeutic effect. They reported the treatment of 20 cases of MMF treated in children with nephrotic syndrome within 1 months after the 19 cases of urinary protein negative l cases, reduce urinary protein, plasma albumin, cholesterol significantly improved, plasma albumin, cholesterol were returned to normal after 2 months; patients were followed up for 1 to 24 months, including 3 cases of recurrence, but with the extension of time for observation, we believe that the long-term efficacy of MMF in treating primary nephrotic syndrome especially the recurrence of nephrotic syndrome should be re evaluated.
Mycophenolic acid by specifically inhibit the de novo synthesis of guanine via enzyme to inosine 5-monophosphate dehydrogenase and T, inhibit B lymphocyte proliferation and activation, reduce the secretion of IgG and the expression of autoantibodies, have a better therapeutic effect on autoimmune diseases. At the same time can reduce the expression of adhesion molecules and inhibit the adhesion and inhibition of formation of hyperplasia and vascular endothelial cells, vascular smooth muscle cells and fibroblasts, has therapeutic effects on inflammatory lesions. Mycophenolate mofetil also has antiviral effect and slight increase of antiviral drugs (such as ganciclovir) antiviral properties and inhibition of atherosclerosis induced by high fat diet and the effect of hepatic and renal toxicity, and other immunosuppressive agents can increase the viral replication and exacerbation of atherosclerosis, and has certain toxicity of kidney and liver. Therefore, the liver, renal insufficiency or CsA, CTX, Tripterygium Wilfordii and other immunosuppressive agents can not be tolerated, severe Cushing's syndrome in children with nephrotic syndrome, can choose MMF. At present, the study of controversial mycophenolate mofetil treatment of hepatitis B virus associated glomerulonephritis is large, were needed to choose a variety of indicators carefully and closely observe the virus replication.
2.4 cyclosporine A (Cyclosp or in A, CSA) randomized controlled study showed that short-term use of CSA can reduce proteinuria in patients with idiopathic membranous nephropathy (2/3) and preserve residual renal function. Other studies have shown that extending the duration of CSA to 6 months to 1 years can reduce the recurrence rate of idiopathic membranous nephropathy in adults. Recently, Ahmed reported that Sprague- Dawley in left renal warm ischemia for 30 minutes and lasted for 30 days by intraperitoneal injection of CSA15 mg#kg- 1#d-1, COL, TGF, simultaneous detection of -B1, MMP-2, TIMP-1mRNA, found that renal warm ischemia or CSA may cause mild renal injury and renal fibrosis, and when both synergistic effect, CSA can promote warm ischemia caused by renal tubular interstitial fibrosis, showed COL, TGF-B expression increased, TIMP-1 activity decreased, inflammatory cell infiltration and accumulation of extracellular matrix.
2.5 FK506 (Tacrolimus, tacrolimus, tacrolimus)
At present, there are few reports on the treatment of FK506 in clinic. In recent years, 25 cases of Segarra patients with CSA resistant or dependent idiopathic FSGS were treated with FK506 combined with hormone for a period of 6 months, and the urinary protein was significantly reduced in all of the 68% patients. The complete remission rate and partial remission rate were respectively 40% and 80%. 76% of the patients with recurrence after withdrawal, again to FK506 for 1 years, of which 38.4% patients with complete remission, 30.7% partial remission, suggesting that FK506 combined hormone therapy can make quite the standard hormone and CSA therapy in idiopathic FSGS patients in remission. Szeto Tacrolimus (mg#kg- 0.2 1#d- 1) in the treatment of 3 cases of hormone low resistant or intolerant of cytotoxic drugs in primary MN, Tacrolimus maintain the blood concentration of 5~ 10ng/ml, the results of 1 cases of urinary protein in patients with completely disappeared, the other 2 cases of urinary protein is down to 50% of the original. Tac two patients after stopping drug rolimus urine protein increased again, but the amount of urine protein is less than before treatment, Tacrolimus is considered to have a certain effect on hormone low resistance of membranous nephropathy. Animal experiments show that FK506 can significantly reduce the expression of IFN-rmRNA, IL-2 and A- in glomerular mesangial cells by inhibiting the production of Th1 cytokines, and reduce the expansion of urinary protein and extracellular matrix. Sugiyama FK506 (10mg#kg-1#d-1, 2.5mg#kg-1#d-1) for the treatment of LN after 8 weeks, the survival rate of mice were 7/8, 5/8, and 10mg# kg-1# D-1 treatment group IL-2, the expression of IFN-rmRNA and IgG anti DNA antibody level was significantly inhibited by IgG2a, why. At the same time, the deposition of IgG2a and IgG2b in glomeruli decreased, suggesting that the treatment of LN by FK506 was mainly through the inhibition of Th1 cytokines.
2.6 leflunomide (leflunomide, LEF) leflunomide is a propylene nitrile amide (MNAs) immunosuppressant, the name of the product, if the love of China. At present, it is mainly used for kidney transplantation, and the treatment of kidney disease is still in the stage of clinical exploration. Previous reports show that LEF can be used for acute rejection in animal model of renal transplantation and inhibition slowed the progression of CAN. In 2002 Har dinger will replace Aza or MMF was applied in 12 cases of renal transplant patients, renal function deterioration, slow down in order to reduce the renal toxicity of CSA or delay the occurrence of CAN, the results of 6 months after renal transplantation and the survival rate of the patients were 100% and 91%, the average serum creatinine decreased, all patients were not because of liver damage, infection or acute rejection and readmission, confirmed that LEF can progress to reverse CAN and low toxicity.
3 other related research
A small dose of heparin synthase hormone or immunosuppressant can significantly reduce blood lipid, NS, prevention of thromboembolic disease, has the advantages of simple operation, low cost, small side effect and no laboratory monitoring etc., can be used as a routine medication. Heparin calcium seems to be more suitable for sodium and water retention in patients with NS. It is well known that ISA plays a very important role in the treatment of kidney disease. It is the key to choose a reasonable drug regimen and closely monitor the side effects of drugs. At the same time, the development and application of new immunosuppressive agents will lead to a new step in the treatment of nephropathy.

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