Progress in primary focal segmental glomerular sclerosis treatment

Focal segmental glomerulosclerosis (FSGS) is a group of similar pathological changes of chronic progressive glomerular disease, the characteristic pathological changes were part of the glomerular (focal, <50%, nearly marrow The glomerular easily sclerosis-like changes (matrix increase, capillary loop collapse) involved), part of the vascular loops (segmental vessels and vascular loops Yi involvement). FSGS was first described in 1957 by Rich in 1970 as an independent type of renal pathology. In recent years, renal biopsy data show that FSGS showed a trend of increasing year by year, and minimal change disease (MCD), mesangial proliferative glomerulonephritis (MsPGN) and FSGS can be transformed into each other. FSGS treatment response to glucocorticoids and cytotoxic drugs vary, their prognosis is directly related to the response to treatment, poor response to treatment are prone to chronic progressive renal damage, until the end stage renal disease (ESRD). The impact of FSGS is an important prognostic factor is the degree of proteinuria of FSGS's treatment objectives are: to reduce or eliminate proteinuria, prevent complications, slow down FSGS progress to ESRD. Are mainly elaborated primary FSGS treatment progress. 1 of FSGS glucocorticoid treatment.
The primary FSGS clinical performance as nephrotic syndrome, the majority reported that FSGS is not sensitive to hormone treatment, the response rate of eight weeks of the regular enough amount of hormone treatment of FSGS urinary protein less than 50% (average 20%). In recent years that, to extend the time of hormone therapy, may have more than 50% of FSGS in remission, glucocorticoid is still the first choice of FSGS treatment.
1 1 conventional method prednisone 1 5 2 0 mg / (kg • d), once every 4 to 8 weeks and achieved complete remission or partial remission (hormone-sensitive or sensitive part), prednisone can be gradually reduced the amount of maintenance treatment to more than 1 a or 1 a; sufficient quantities of prednisone treatment for four to eight weeks without remission (steroid-resistant), the joint use of immunosuppressive agents. 2 long course of hormone therapy program (1) Mendoza, program [4]: ​​① methylprednisolone intravenous pulse dose of 30 mg / (kg) (single maximum dose of 000mg): 1 - 2 weeks, every other day 1, 3 times / week; 3 - 10 weeks, 1 time / week; 11 - 18 weeks, every two weeks; 19 - 52 weeks, 1 times / month; 53 - 78 weeks, every 2 months to 1 year. ② prednisone oral dose of 2 mg / (kg) (single maximum dose of 60 mg): 1 - 2 weeks not 3 - 8 weeks, every other day, Dayton clothing, after the discretion to gradually decrease. The total course of treatment of men's-doza program, 5 a, the response rate and prognosis of urinary protein significantly improved compared with conventional hormone therapy program. (2) other long course of hormone therapy programs: the International Pediatric Nephrology Study Group (ISKDC) conventional treatment options recommended by the nephrotic syndrome did not distinguish between types of renal pathology, either MCD or of FSGS herein are prednisone 60 mg / (m * 2 d), in divided doses four weeks, followed by prednisone 40 mg / m 2, the next day orally for 4 weeks, tapering; the first 8 weeks of treatment of urinary protein-free remission are considered for steroid-resistant. Domestic pediatric prednisone 1 5 2 0 mg / (kg • d) After 8 weeks of treatment, remission, steroid-resistant criteria. However, the above criteria to judge the FSGS hormone resistance is not appropriate, and often lead to physicians reluctant to use hormone therapy, rather than FSGS real steroid-resistant, because the simple extension of hormone treatment can significantly improve urinary protein ease and prognosis. Experience in the treatment of adult FSGS: 8 weeks courses of sufficient quantities of hormones, sufficient quantities of hormone-induced FSGS urine protein remission time of 3 to 4 months of oral prednisone over 6 invalid before considering FSGS steroid-resistant.
But the lack of a long course of sufficient quantities of hormone treatment of FSGS samples and randomized controlled studies (RCT) data, its advantages and disadvantages to be subject to further evaluation, sufficient quantities of a long course of hormone therapy on children with adverse reactions (such as infection, growth developmental disorders, osteoporosis, high blood pressure and electrolyte imbalance, etc.), especially long-term effects can not be ignored.
2 combination therapy of FSGS
Of steroid resistance, dependence, frequency of recurrence of refractory primary of FSGS, in combination with other drugs to treat clinical inevitable choice.
2.1 cyclophosphamide (CTX) hormone the joint CTX treatment of FSGS common report, the CTX past as first-line drugs for the treatment of steroid-resistant FSGS. Rennert, etc. to the hormone oral and CTX intravenous pulse (at a dose of 500 mg / m * 2, the impact of 1 times / month) 6 months of treatment, results showed that 10 cases of steroid-resistant FSGS children, seven cases of complete remission, 1 cases partial remission (overall response rate 80%), two cases of no response. And CTX, Hari, etc. using the impact of hormone intravenous, oral treatment of 12 weeks, which, methylprednisolone 30 mg / kg or dexamethasone 5 mg / kg, every other day, six times every two weeks, four times, followed by a times / month, eight times, re-poured nylon oral tapering, were treated for 52 weeks. 59 cases of steroid-resistant FSGS patients with urinary protein / inosine values ​​from 10 0 to 0.75, serum albumin level rise by 19 g / L to 24 g / L; Among them, 17 cases of complete remission, eight cases of partial remission ; follow-up time of 3 of more than 34 cases, 22 cases (64.7%) with good prognosis, the majority of continuous complete remission. Gulati and so a prospective study: 1 / CTX shock, a dose of 500 to 750 mg / m * 2, while I poured nylon, four weeks before a dose of 60 mg / (m * 2 • d), then every other day taking splashed nylon (40 mg / m * 2) 4 weeks, decreasing the amount of 4 weeks is disabled. 20 cases of steroid-resistant FSGS patients, 13 cases of complete remission (65%), urine protein was negative CTX treatment time (12 ± 11.9) months follow-up time (21 2 ± 13 4) monthly urine protein continued negative. Bajpai and other every other day oral poured nylon and CTX intravenous pulse treatment of 24 cases of steroid-resistant FSGS patients, the CTX dose of 750 mg / m * 2, the impact of 1/6 months, only to find 7 cases of short-term (29. 2%) complete or partial remission, long-term follow-up only 5 cases (20.8%) remission, 17 cases of invalid (70.8%), and ease the untreated sensitive secondary steroid-resistant patients, suggesting that CTX on the original limited efficacy of drug resistance FSGS. Al Salloum et al reported 15 cases of steroid-resistant FSGS patients prednisone and CTX intravenous pulse therapy and were followed up for 4 years, prednisone 60 mg / (m * 2 • d) - 4 weeks, followed by every other day 40 mg / m * 2, 4 weeks, decreasing the amount of four weeks withdrawal; the CTX dose of 500 mg / m * 2, 1 / shock, 6 months. Were followed up for 4 years, 5 cases of primary resistant cases of treatment response (3 cases the development of chronic renal insufficiency), 10 cases of secondary resistance in patients with CTX pulse therapy is effective, but in the end are hormone-dependent, suggesting that hormone and CTX therapy for steroid-resistant FSGS, there is no significant effect, many studies also support the above conclusion.
Date, although some data show the efficacy of hormone and CTX treatment of drug-resistant FSGS, but still lack the RCT study, is generally believed that the subsequent secondary resistance in addition to the early governance hormone-sensitive FSGS patients have a certain effect, steroid and CTX treatment the efficacy of drug-resistant FSGS, there is no sufficient evidence. In addition, CTX adverse reactions (such as height, severe infections, hair loss, leukopenia, hemorrhagic cystitis, transient hypertension and drug injection, transient nausea, vomiting, etc.) must be given.
2.2 cyclosporine (CsA) of CsA is currently the treatment of FSGS have the exact effect of drugs, but usually require a longer course of treatment to maintain remission after renal toxic effects and withdrawal to recur is worthy of clinical attention. Mah-moud such as retrospective analysis of 106 cases to CsA treatment in patients with primary FSGS (45 cases of steroid-resistant, 61 cases of hormone dependent, of which 54 cases had received CTX treatment) of CsA starting dose of 6 mg / (kg • d), and gradually adjust the dose of CsA blood concentration maintained at 80 to 150 μg / L, treatment for 6 to 8 months after discontinuation of follow-up (6 ± 1 1 9) a. The rate of complete remission, partial remission rate and inefficiency were 71 7%, 7.5% and 20.8%. 31 cases but was discontinued in 91 cases of hormone relapse; 20 cases tried to stop the proteinuria disappeared CsA 16 cases immediately recurrence, and four cases, re-enable the CsA resistance. The results suggest that the significant effect of CsA on primary FSGS, but a higher relapse rate after stopping. Goumenos and other follow-up observation 5a CsA treatment, the efficacy of primary FSGS, with similar results. Recurrence of FSGS, Raafat large dose CsA treatment at a dose of 6 ~ 25 mg / (kg • d) of CsA by the low dose and gradually increase to remission or adverse renal effects until remission, CsA gradually reduction to the normal range, the results show a significant effect and can maintain for a long time in remission.
Long-term use of CsA adverse events (renal insufficiency, hypertension, gingival hyperplasia, hirsutism psychosis) is worthy of clinical concern. Chishti of a single small dose of CsA treatment of FSGS, the CsA dose (6 ± 0 8) mg / (kg • d), 1 / d, treatment time was 2 to 27 months without monitoring blood drug mass concentration. Results The total effective rate was 76% (16/21 cases), of which 52% (11/21 cases) in complete remission, partial remission 24% (5/21 cases), the onset time (2 ± 0 8 8 ) months; decreasing the amount of nine cases of complete remission of CsA withdrawal, including three cases of maintenance of remission (follow-up of 6 to 13 months), six cases of recurrence (follow-up 1.5 to 18. 7 months), recurrence of retreatment CsA or increased dose of CsA to sensitive. Treatment and follow-up period, CsA adverse reactions is small, suggesting that small-dose CsA treatment of FSGS is safe and effective. El - Husseini, 117 cases of children with primary FSGS to long-range small-dose CsA maintenance therapy of CsA starting dose is 5 mg / (kg • d), and gradually adjust the mass concentration of 1 to 2 months before the dose so that blood CsA Valley maintained at 100 ~ 150μg / L, after CsA plasma mass concentration maintained at 50 and with 100 μg / L, as long as proteinuria continue to ease of CsA blood concentration was maintained at 30 μg / L can also be low-dose CsA treatment time is 2 a (average 34 months), the results show a long time small dose CsA treatment of FSGS effective.
That CsA effectively reduce urinary protein and protection of renal function, used alone, especially with the hormone combination of CsA markedly hormone-sensitive FSGS, steroid-resistant and steroid-dependent children with primary FSGS have a certain effect. CsA as a steroid-dependent or steroid-resistant FSGS priority treatment options. CsA treatment should be emphasized that the individual differences of CsA dose can not be static, must adjust the dose according to blood concentration. It should be noted is easy to relapse after CsA withdrawal, and therefore adequate treatment, based on monitoring of adverse drug reactions (if necessary, repeat renal biopsy for renal tubulointerstitial injury), maintenance treatment is required more than 1 a.
2.3 other immunosuppressants new immunosuppressive agents try for the treatment of drug-resistant FSGS, including mycophenolate mofetil (MMF), he tacrolimus (FK506) and Manila neomycin, reported a lot, but Case, the efficacy of different, but its low toxicity and a more significant effect demonstrated its good prospects and look forward to the findings of the RCT. Joint and sequential use of immunosuppressive therapy for refractory of FSGS, is expected to achieve better results. Type of renal pathology, such as el - Reshaid, reported 21 cases of steroid-resistant MCD or FSGS patients with nephrotic syndrome treatment: the initial application of 12 weeks of CsA or of FK506, and then 3 months of MMF, and then 3 months MMF plus of CsA; if not complete remission in the MMF plus CsA on the basis of 1 / impact of CTX, three times in a row; complete remission plus complete remission after 3 times with 1 / CTX impact, every four months, decreasing the amount of MMF or CsA to the minimum dose to maintain urine protein negative; such as the above-mentioned program has not yet reached complete remission, repeated 1 time / month impact of CTX three times, plus methylprednisolone pulse therapy for 3 consecutive days. changed to oral prednisone and tapered. Immunosuppressants used in conjunction with the experience is not yet mature, but has a different mechanism of action combined with different immunosuppressive agents, and thus a synergistic therapeutic effect, will reduce the amount of immunosuppressants, and reducing the adverse effects of immunosuppressants advantage.
2.4 other ancillary drugs such as angiotensin-conversion enzyme inhibitors (ACEI) and (or) the use of angiotensin II receptor antagonist (ARB), as well as for high cholesterol lowering therapy, for a hypercoagulable state anti- coagulation therapy, have helped to reduce proteinuria and slow the deterioration of renal function and FSGS progress to ESRD can be used as adjuvant therapy for high blood pressure and antihypertensive treatment.
3 FSGS non-drug treatment Replacement of low-density lipoprotein (LDL), immunoadsorption and plasmapheresis can be used as adjuvant therapy for the treatment of refractory FSGS. In view of hyperlipidemia, especially high LDL effects on the kidneys, reported LDL replacement can make proteinuria reduced to improve the response rate and delaying the progress of renal pathology. Plasma replacement therapy can be used for the treatment of recurrent FSGS after kidney transplantation, plasma exchange before kidney transplantation, urine protein to reduce migration to maintain graft function have a certain effect; but the mechanism of humoral factors in FSGS is not yet clear. the efficacy of plasma exchange still need to be further determined.