The nephrotic syndrome with proteinuria, hypoproteinemia, hyperlipemia and edema of different degrees for clinical characteristics, can be pided into primary, secondary and 3 types of congenital nephrotic syndrome accounted for more than 90% children with nephrotic syndrome in children, is the most common glomerular disease. Foreign reports of children with primary nephrotic syndrome in the incidence rate of 1-3/10 million population, the prevalence rate was 16/10 million. Glucocorticoid (referred to as the "hormone") in treatment of primary nephrotic syndrome in 1950s, and has been the preferred drugs at home and abroad for the treatment of primary nephrotic syndrome on the basis of hormone therapy recognized. The reaction of primary nephrotic syndrome were pided into steroid sensitive nephrotic syndrome and steroid resistant nephrotic syndrome. 80% -90% children with primary nephrotic syndrome initial hormone therapy can get complete remission 10%-20%, which does not have a relapse, 10%-20% for non 40%-50% recurrence frequency, frequency of recurrence of nephrotic syndrome or steroid dependent nephrotic syndrome. Some frequently relapsing nephrotic syndrome or 1/3 syndrome in children with hormone dependent due to prolonged or repeated use of hormone and serious side effects such as kidney disease, hypertension, diabetes mellitus, growth inhibition, osteoporosis osteoporosis, glaucoma, cataract, and even blindness. Primary nephrotic syndrome 10%-20% children showed more than half of the drug resistance, hormone resistant nephrotic syndrome in children in 10 years will progress to end-stage renal disease (end-stage renal, disease, ESRD). Therefore, the frequency of recurrence nephrotic syndrome, hormone dependent nephrotic syndrome and steroid resistant nephrotic syndrome treatment has become the focus of clinical attention. In 2009 and 2010, pediatrics nephrology group established Frequent Relapse Nephrotic Chinese Medical Association The syndrome, hormone dependent syndrome and steroid resistant nephrotic syndrome guidelines for the treatment of nephrotic syndrome, for the clinical treatment of these diseases has played an important guiding role in.2012, kidney disease: improving global outcomes (KidneyDisease: Improving Global Outcomes, KDIGO) also released nephrotic syndrome recurrence frequency, guidelines for the treatment of hormone dependent and hormone resistance syndrome nephrotic syndrome nephrotic syndrome. The above guidelines based on a systematic review in recent years on the frequency of recurrence of nephrotic syndrome, hormone dependent nephrotic syndrome and steroid resistant nephrotic syndrome treated by Meta clinical research and literature analysis, treatment of these diseases are analyzed, in order to provide reference for clinical.
First, the diagnosis of primary nephrotic syndrome
1 diagnostic criteria
(1) a large amount of proteinuria: 3 times within 1 week of urine protein qualitative (3 + 4 +), or random or morning urine, urinary albumin/creatinine (u PCR) or 2000 mg/g, 24 h urine protein quantitative or 50 mg/kg;
(2) hypoalbuminemia, plasma albumin < 25 g/L;(3) hyperlipidemia: plasma cholesterol is higher than 5.7 tendency/L;(4) the different degree of edema;(5) ruled out secondary factors.The above (1) and (2) is necessary for diagnosis.
2 according to the classification of hormone response to treatment
(1) hormone sensitive nephrotic syndrome: prednisone adequate 1.5 2.0 mg/(kg? D) or 60 mg/m2 (maximum dose not more than 60 mg) treatment, 4-8 weeks or less urine protein.
(2) hormone resistant nephrotic syndrome: prednisone adequate treatment, 4 to 8 weeks after the urinary protein is still positive.Incipient resistance: incipient hormone adequate treatment, urine protein for more than 4 to 8 weeks;Delay resistance: one or more treatment recurrence after complete remission, hormone adequate treatment, urine protein for more than 4 weeks.
3 the primary nephrotic syndrome recurrence of recurrence, the recurrence of frequency, frequency and hormone dependent
Continuous 3 d: (1) the recurrence, the morning urine protein from negative to + 3 or 4 +, or random morning urine uPCR acuity or 2000 mg/g or 24 h urine protein quantitative or 50 mg/kg.
(2) the frequency recurrence within 6 months after the initial treatment of complete response 1 relapse, or in any 12 months with 1 or 2 or 3 times recurrence.
Recurrence frequency (3) : refers to the recurrence of nephrotic syndrome in the course of half a year or two, or a relapse within 1 year 3 or 4 times or more.
(4) hormone dependence refers to sensitive to hormone therapy, but 2 consecutive reduction or withdrawal recurrence in 2 weeks.Regional recurrence of judging the recurrence frequency and frequency standards vary, according to the number of domestic frequency of recurrence rate for 1 to 2 times / 12 months, recurrence 3 times / 12 months or more for recurrence frequency.
4 the curative effect of primary nephrotic syndrome
(1) complete remission: uPCR morning pee or 200 mg/g protein or less negative or trace for 3 days.
(2) the partial relief: uPCR between 200-2000 mg/g or 24 h urine protein decreased to the baseline of 50% or more.
(3) not relief: uPCR or 2000 mg/g or 24 h urine protein by less than 50% of the baseline.
5 the pathological types of primary nephrotic syndrome
Children with primary nephrotic syndrome Pathological types with small lesions, focal segmental glomerular sclerosis, mesangial proliferative glomerulonephritis, membrane proliferative glomerulonephritis, membranous nephropathy, etc.One small lesions are the main pathological type, only a small number of children appear when treated first hormone drug resistance.
Hormone resistant nephrotic syndrome pathogenesis mainly focal segmental glomerular sclerosis.Immune pathology is given priority to with IgM or Clq deposition of kidney disease patients often appear hormone drug resistance.
Second, the evaluation of evidence
(1) literature into and exclusion criteria included in the document type: Meta analysis, randomized controlled trial (RCT), non randomized controlled trials, observational studies and case reports;Diagnostic criteria in accordance with the literature of primary nephrotic syndrome;Literature research objects: the onset age children aged 18 or less;Treatment: the immunosuppressant and non immune inhibitors.Ruled out literature types: not in the same time comparative study of two groups of efficacy or safety observation object (history);No matching between groups in the literature description, or between groups matching conditions.
(2) the strength GRADE quality evaluation of evidence and recommendations According to the inclusion criteria of literature for GRADE evaluation standards (table 1).RCT preliminary rated as high quality research evidence, observational studies as low quality evidence, case reports and expert opinion as a very low quality evidence.
The recommended intensity of interventions is based on the relevant content of GRADE. The main determinant of the recommended strength is the relationship between treatment benefits (Table 2) and the quality of the literature evidence
Three, recurrent steroid sensitive nephrotic syndrome, hormone dependent nephrotic syndrome and steroid resistant nephrotic syndrome
(1) hormone therapy
1. non frequent relapse in steroid sensitive nephrotic syndrome: (1) to induce remission: prednisone 2mg/kg daily body weight or body surface area 60mg/m2 morning meal (maximum dose not more than 60 mg), at least to proteinuria after complete remission 3D (2D), and then the hormone changed every other day morning meal, dose 40mg/m2 surface area or 1.5mg/kg weight (less than 40 mg), at least 4 weeks, then stop hormone for 4 weeks or more time (2C). (2) using hormone infection: both in the re induction process in infection or maintenance dose in the treatment of hormone, upper respiratory tract infection when the hormone dosage should be increased, the next day will be changed to oral therapy with oral daily dose (2C).
2. Frequent Relapse Nephrotic Syndrome or steroid dependent nephrotic syndrome: (1) to induce remission: prednisone 2 mg/kg daily weight or 60 mg/m2 body surface area morning meal (maximum dose not more than 60 mg), at least to proteinuria after complete remission 3D (2D), and then changed to every morning hormone from the meal service, the same dose, time for at least 3 months (2C). (2): re maintenance therapy after induction of remission, every 4 weeks of hormone reduction of 0.25 mg/kg, to effectively maintain the minimum amount (0.25 - 0.5 mg/kg body weight) every morning meal service, the minimum effective maintenance dose should be to maintain remission but no obvious side effects (2D). If the dose of hormone dependent nephrotic syndrome in children with intermittent oral administration is invalid, the minimum amount to maintain the daily oral maintenance therapy, 9 - 18 months (2D). (3) the use of hormone of infection has been changed to day treatment The frequency of recurrence of nephrotic syndrome or steroid dependent nephrotic syndrome in children, such as upper respiratory tract infection or other infection, should be changed to a daily dose of hormones to reduce recurrence (2C). In the maintenance stage of infection, then changed to oral oral daily time is 5 - 7 d (2C).
3. steroid resistant nephrotic syndrome: methylprednisolone (methylprednisolone, MP) shock treatment: (1) after 4 weeks of oral prednisone enough urine protein was still positive, considering the impact of MP therapy, MP dose and method for 15 - 30 mg/ (kg? D), 1 times a day, for 3 D 1 course of treatment, the maximum dose was 1 g. shock after 1 courses of treatment, if the urine protein was negative, prednisone in steroid sensitive nephrotic syndrome reduction. If the urine protein is not negative, combined with immunosuppressive agents, hormones will also be changed every other day orally, then every 2 - 4 weeks - 5 reduction of 10 Mg, finally give a small dose of every meal served to maintain long-term, some children can deactivate the hormone (2D). (2) calcineurin inhibitors (calcineurin, inhibitors, CNI) did not obtain remission of the nephrotic syndrome in children with steroid resistance (see the following immunosuppressive therapy), can use MP Shock therapy, can be used repeatedly after an interval of 1 weeks, the general 6 courses are available, the impact can continue after oral prednisone therapy (2D).
(two) immunosuppressive therapy when Frequent Relapse Nephrotic Syndrome or steroid dependent nephrotic syndrome children with corticosteroid related side effects cannot tolerate treatment should be given immunosuppressive therapy, to reduce the amount of hormone or withdrawal of hormone (1B). If enough hormone oral treatment 4 weeks to achieve remission, should be combined with immunosuppressive agents (1B); if the children showed partial remission, may be appropriate to extend the time of adequate oral hormone, at least 8 weeks (2D). Hormones prolong after treatment, urine protein was negative, in accordance with the steroid sensitive nephrotic syndrome by reducing the amount of hormone; urine protein is still not a complete remission, can be combined with immunosuppressive agents (1B), non hormone recurrence frequency sensitive nephrotic syndrome, hormone induced treatment can alleviate, in accordance with the delayed treatment of steroid resistant nephrotic syndrome. CNI is the treatment of steroid resistant nephrotic syndrome preferred The drug, if CNI treatment failed to achieve remission, may consider the use of mycophenolate mofetil (Mycophenolate mofetil, MMF), high-dose corticosteroid (2D) or in combination with other immunosuppressive therapy (2D).
1. CNI: (1) CNI syndrome or syndrome in children with steroid dependent nephrotic hormone dosage to reduce the recurrence frequency (1C). The initial dose of cyclosporine 4 -- 5mg/ (kg/ d), 2 oral dose adjustment, make blood trough concentration was maintained at 80 - 120 ng/ml (2C), or initial tacrolimus 0.1 - 0.2 mg/ (kg/d), 2 oral dose adjustment, keep the plasma concentration in 5 - 10 g/L (2D).CNI at least 12 months, most patients relapse after drug withdrawal (2C). (2) CNI for children with steroid resistant nephrotic syndrome preferred immunosuppressive agent the use of CNI (1B), at least 6 months of treatment, if proteinuria is not mitigated, stop the drug; if partial remission, the treatment time for at least 12 months (2C).CNI can be used in combination with small dose of hormone (2D). The guidelines recommend the cyclophosphamide (cyclophosphamide, CTX) for steroid resistant nephrotic heald Sign the drug of choice, recent studies support the CNI as children with steroid resistant nephrotic syndrome. The drug of choice for cyclosporine and tacrolimus has no difference in the control of steroid resistant nephrotic syndrome, but the side effects of tacrolimus is relatively small, if children choose the initial rash and other side effects of CsA treatment can not be tolerated when also used tacrolimus instead of cyclosporine therapy (2D). WT1, NPHS2 and PLCE1 genes and the pathogenesis of nephrotic syndrome, known as hereditary nephrotic syndrome. Hereditary nephrotic syndrome are resistant to corticosteroids, most of the immunosuppressant is drug resistance, only a small part of the effective mechanism of genetic cyclosporine therapy cyclosporine therapy. Nephrotic syndrome is the effect of foot cytoskeletal function, stabilize podocytes, reduce urinary protein, inhibition and immune Little. Therefore, when necessary, consider the option of cyclosporine treatment of hereditary nephrotic syndrome (2D). The 2. alkylating agent: (1) syndrome or syndrome in children with steroid dependent nephrotic can reduce hormone dosage alkylating agent in treatment of nephrotic frequency recurrence, thus reducing the side effects of hormone (1B). The clinical used alkylating agent the main CTX and chlorambucil,.CTX 2 mg/ (kg / D) orally, the treatment time of 8 - 12 weeks, the maximum cumulative dose of less than 168 mg/kg (2C), to be achieved after the start of hormone use (2D). Chlorambucil 0.1 - 0.2 mg/ (kg? D) orally, 8 weeks of treatment, the maximum cumulative dose of less than 11.2 mg/kg (2C). Chlorambucil, CTX can be used as alternative medicines for treatment of frequently relapsing nephrotic syndrome / steroid dependent nephrotic syndrome (2D). The syndrome / steroid dependent nephrotic syndrome in children treated with alkylating agents without nephropathy frequency recurrence. Advocate the use of second courses (2D). (2) on steroid resistant nephrotic syndrome, two RCT study showed that CTX combined with prednisone group and prednisone group, treatment of hormone syndrome in children in remission of proteinuria and no difference nephrotic resistance, but also increase the CTX related side effects. Therefore, for CNI in the treatment of nephrotic syndrome in children with invalid hormone resistance, do not advocate the use of CTX treatment (2B). 3. MMF: (1) MMF in the treatment of nephrotic syndrome recurrence frequency or hormone dependent syndrome can reduce the dose of nephropathy, so as to reduce the side effects of hormone (1C) [13, 42], 20 - 30 mg/ initial dose (kg /d) or 800 - 1200 mg/ (m2 / D), 2 times a day (maximum dose 2 g), at least 12 months of treatment, most patients will relapse after drug withdrawal (2C). (2) for the treatment of CNI is invalid or due to various reasons can not use hormone therapy against the CNI Nephrotic syndrome can use MMF orally, maintain the valley concentration in 2.5 - 4 mg/L, at least 6 months, urine protein remission after 3 - 6 months reduced to 10 mg/ (kg /d) maintenance treatment, the total duration of 12 - 24 months; urine protein can not relieve, stop medicine (2D).
4. rituximab (rituximab): (1) the frequency of recurrence nephrotic syndrome or steroid dependent nephrotic syndrome, rituximab can be used prednisone and combined immunosuppression still frequent recurrence, or a serious dose and treatment of adverse effects associated with M2: 375 mg/ each time, 1 times a week, available 1 - 4 (2C). MMF in the rituximab maintenance therapy after treatment, the curative effect can be strengthened with rituximab, reduce recurrence (2D). (2) due to the lack of RCT in children with nephrotic syndrome of resistance to rituximab in the treatment of hormone, two observation study found that Li rituximab treatment of steroid resistant nephrotic syndrome as treatment of steroid sensitive nephrotic syndrome is as effective as currently being advocated for treatment of steroid resistant nephrotic syndrome (2D).
5.: mizoribine 1 Research RCT single center, mizoribine treatment group and the placebo group improved in steroid sensitive nephrotic syndrome between children with no recurrence, it is not recommended to mizoribine will reduce the amount of hormone treatment, Frequent Relapse Nephrotic Syndrome or hormone dependent renal disease syndrome (2C). 6. azathioprine: 2 a RCT study showed that azathioprine treatment group and the placebo group improved in steroid sensitive nephrotic syndrome between children with no recurrence, is not advocated to reduce the amount of hormone therapy with azathioprine, Frequent Relapse Nephrotic Syndrome or steroid dependent nephrotic syndrome (1B). (three) the other treatment measures
1. non recurrent frequency: frequency of recurrence of non actively looking for reasons, the main reason is caused by non frequent recurrent infection, infection sites and pathogens actively searched, infection control, a small number of children after controlling infection can be spontaneous remission (2D). 2. (1): levamisole 5 RCT study showed that Levamisole 2.5 mg/kg, every other day oral treatment for 12 - 24 months, the relative risk of hormone dependence syndrome or relapse of nephrotic syndrome recurrence to decrease 57%. nephropathy frequency so as to reduce drug levamisole should be the amount of hormone for nephrotic syndrome recurrence frequency or hormone dependent on nephrotic syndrome (1B), 2.5 mg/kg orally at least 12 day a month, can reduce the relapse rate, but most of the patients will relapse after drug withdrawal (2C). (2) actively looking for reasons of frequent relapses: evaluation of adrenal cortex function: long-term (> December) day of oral prednisolone Inhibition of adrenocortical function, impaired adrenal function is a risk factor for recurrence, long-term oral hormone children should be assessed in patients with adrenal function (2D). The assessment of immune function: long-term hormone or immunosuppressive therapy can reduce the immune function in patients with low immune function, prone to infection, infection is a major cause of recurrence the trace element zinc can enhance immunity, reduce the chances of infection, can reduce the steroid sensitive nephrotic syndrome recurrence. A cohort study showed that daily administration of zinc 10 mg orally for 12 months, compared with the placebo group, zinc treatment group can reduce the steroid sensitive nephrotic syndrome recurrence (2D 3.2.) on angiotensin converting enzyme inhibitors RCT and 1 angiotensin receptor antagonist cohort study showed that two can significantly reduce the risk of The amount of urine protein. It is recommended that children of children with steroid resistant nephrotic syndrome should be angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonist treatment (1B).
(four) note 1. master drug contraindications: nephrotic syndrome of various therapeutic drugs have their own contraindications, should avoid the use of the drug contraindications. 2. drug monitoring: each kind of nephrotic syndrome therapeutics have different side effects, should pay attention to all kinds of drugs to produce short-term and long-term side effects, and by monitoring. Such as the use of CNI children to regularly monitor renal function, treatment time of more than 2 years to renal biopsy monitoring renal toxicity. Immunosuppressive agents to achieve therapeutic effect, need blood concentration remained at a relatively constant range. Therefore, should be based on the generation of drugs