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Refractory nephrotic syndrome (RNS)

Dec 31, 2016
Clinical treatment of intractable, if long-term proteinuria is not effectively controlled or recurrent disease, caused by glomerular sclerosis and renal interstitial fibrosis, leading to chronic renal failure (CRF), is a chronic kidney disease (CKD) in severe type. Therefore, it is of great significance to explore the more reasonable and effective treatment, as far as possible to achieve complete remission for delaying the deterioration of renal function.
First, the definition of the RNS definition of RNS currently no unified opinion, generally considered to be the primary nephrotic syndrome (NS) with standard dose of prednisone for 8 to 12 weeks "hormone resistance" and "effect" and the reduction process in a "hormone dependent", "repeated attacks" and can not tolerate hormone treatment. Hormone resistance: refers to the amount of prednisone (1mg/Kg/d adults, children 1.5 to 2.0mg/Kg/d) proteinuria without significantly reduced or reduced from NS, focal hardening stage (FSGS) the use of hormone therapy for 3 to 4 months or even 6 months before the judgement for invalid hormone resistance. Part II effect: the standard dose of prednisone in the treatment of 8 to 12 weeks, although from the NS, but still can not be completely remission. The hormone dependent: prednisone treatment, urinary protein significantly reduced or even negative, but in the tapering process (has not yet reached the maintenance dose, NS) and then increase the recurrence, hormone dosage is still valid. The recurrent NS patients after remission: after treatment with prednisone, half year relapse 2 times, recurrence within a year 3 times. The hormone intolerance: NS accompanied by peptic ulcer, active tuberculosis, hepatitis, glaucoma, diabetes can not tolerate hormone treatment.
Two, RNS common cause analysis RNS lead to refractory reasons, different patients have different reasons, for the same patient, in different time may have different reasons. Not only because of the nature of the disease itself, but also because the treatment is not standardized. Comprehensive summarized as follows:
1 hormone use is not standardized
(1): lack of hormone dose hormone can interfere with glucose metabolism, fat and protein (lead to central obesity, young women are not willing to accept) acne, hirsutism, gastrointestinal bleeding, immunosuppression prone to infection and other side reactions. Some patients lack of starting, no standard dose.
(2) excessive hormone reduction: clinical NS after hormone treatment, the maximum dose less than 8-12 weeks, FSGS to 3-4 months, urine protein negative after less than 2 weeks ahead of start reduction. The reduction of every 2-3 weeks is minus 10%, minus 1 slice 2-3 weeks of prednisone, some 1 tablets per week, until the withdrawal of hormone reduction too quickly is one of the reasons of recurrence of NS, some repeated attacks, as RNS.
(3): hormone maintain enough time effective in NS patients with hormone therapy, when hormone reduction to maintenance dose, application maintenance dose of 6-8 months, the total course of prednisone 1.5-2. Lack of maintenance time is one of the most common causes of NS in patients with hormone sensitive RNS.
2 inappropriate use of hormone
(1) severe edema using oral prednisone NS: severe edema, gastrointestinal tract is also highly swollen, the oral prednisone decreased significantly after absorbed by the gastrointestinal tract, did not reach the effective blood concentration, the curative effect of hormone.
(2) poor liver function in patients with oral prednisone prednisone itself: therapeutic effect in liver hydrogenation into prednisolone, have biological effects. The liver function not good oral prednisone effect is not good.
(3) drug interactions that hormone drug concentration decreased, if the patient had chronic pain, being used can enhance the microsomal cytochrome P450 and single hydrogenase activity drugs such as phenytoin, rifampin, C Masi Bing, imipenem, quinolone can make the hormone metabolic rate, plasma concentration decreased, reduced efficacy.
3 complicated with infection
Infection can cause NS patients are not sensitive to hormones, or hormone sensitive NS patients, the treatment of infection and become insensitive. Glucocorticoid (GC) through the glucocorticoid receptor and within the cytoplasm (GR) combined with the complex formation of GC-GR cells into the grain, and the reaction of Glucocorticoid (GRF) binding to exert their biological effects. With a series of inflammatory cytokines, including interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF- alpha) etc..
Activation of nuclear transcription factor activator protein and nuclear factor beta K and NF-K beta can inhibit the GC-GR complex with GRF, thus reducing the biological effect of hormone, NS common infections such as respiratory tract, gastrointestinal tract, urinary tract infection, and occult infections such as acute pulpitis, frontal sinusitis, bone marrow inflammation etc..
4 combined thrombosis
Deep venous thrombosis is a common complication of NS, especially in membranous nephropathy (MN), when the plasma albumin is less than or equal to 20g/L, easy renal vein thrombosis can affect the renal blood circulation, even if the plasma concentrations of hormones and other immune inhibitors is not low. But the drugs that reach the kidney tissue are limited, resulting in RNS. In addition, some small renal thrombosis, is also one of the reasons leading to RNS.
5 complicated with acute renal failure
NS plasma volume decline, coupled with acute gastroenteritis and other reasons lead to dehydration, blood volume decline rapidly, can appear before renal acute renal failure (ARF) or high degree of edema, renal interstitial edema, glomerular filtration rate decreased, or proteinuria, leading to renal tubular congestion, even NS incidence increased, with crescentic glomerulonephritis when can develop to ARF.
6 mutations reported this year: HPHS1 gene mutations lead to glomerular Nephrin protein abnormal plasma cells, Nphsz gene mutation leads to abnormal glomerular podocyte Podocin protein, CD alpha CD alpha HP gene mutation leads to abnormal protein, mutations in the ACTIN4 gene cause podocyte cell skeleton protein alpha accessory protein 4 protein abnormalities can lead to RNS.
7 severe pathological types
A lot of clinical experience of evidence-based medicine proved that severe mesangial proliferative glomerulonephritis (MsPGN), FSGS, MN, mesangial proliferative glomerulonephritis (MPGN), often on the hormone response is poor, easy to become RNS, although small lesions (MCD) on hormone sensitive, but easy to relapse, but also easily lead to RNS.
Three.RNS integrated traditional Chinese and Western medicine treatment
General treatment: rest, high calorie, low salt (3g/d), moderate protein diet (0.8-1g/d), the right amount of water.
(two) symptomatic treatment
1: the combination of loop diuretics and diuretic potassium sparing diuretics. Refractory edema: (a) low molecular dextran expansion after giving furosemide intravenous infusion of 20-40mg. (two) plasma albumin expansion after furosemide intravenous infusion of 120mg. The problem of albumin transmission was severe hypoproteinemia, edema and oliguria (< 400ml/d). The height of edema after diuresis dizziness, decreased blood pressure and increased heart rate and insufficient blood volume. The albumin infusion of furosemide infusion immediately. The serious heart failure with caution.
2 reduce proteinuria, proteinuria, glomerular filtration and renal tubulointerstitial injury. ACEI and ARB have renal protective effects beyond bp. ACEI: Lotensin 10mg/d. ARB: or 1-4 /d particle Aprovel dioan. ARB is required for high doses, but renal artery stenosis and hyperkalemia are disabled.
3: more than half of lipid-lowering hyperlipemia to lipid-lowering therapy. Cholesterol: statins (Lescol, Shujiangzhi) triglyceride (0.25mg Libifei: Betley Qd)
(three) to regulate the use of hormones and the route of administration of hormone use in patients with RNS caused by non-standard, to adjust the treatment program and route of administration of irrational hormones, in accordance with the formal treatment program. The initial amount of foot: (adult 1mg/Kg/d, children 1.5 to 2.0mg/Kg/d). The reduction of 8-12 weeks: slow enough after 2-3 weeks treatment reduced dose 10% long-term maintenance: low dose (0.5mg/Kg/d) 6-8 months, maintenance dose (0.2mg/Kg/d) 10-12 months. The serious edema of intravenous administration. The abnormal liver function by oral methylprednisolone methylprednisolone. Try to avoid the drug use cytochrome P450 agonist enzymes, such as C Masi Bing, rifampin.
(four) cytotoxic agents and immunosuppressive agents on hormone intolerance and enough hormone 8-12 weeks of hormone resistance, effect, repeated attacks according to using the following cytotoxic and immunosuppressive condition.
1 cyclophosphamide (CTX) is the most commonly used cytotoxic drugs at home and abroad. Hepatic microsomal hydroxylation by cells in vivo, produce metabolites alkanisation, could inhibit the immune. Often used for steroid resistance and recurrent RNS. Usage: 2 mg/Kg/d, pided into 2 times. The next day intravenous injection of 200mg. 8-12mg/Kg/ times, 2 times a month. Total amount of 150 mg/Kg/d. Side effects: bone marrow suppression, toxic liver damage, gonadal suppression (especially men), hair loss, gastrointestinal reactions and hemorrhagic cystitis. Note: white blood cells in peripheral blood were lower than 4000 and liver function was slow. Can not exceed the total amount, the use of 1 years. Intravenous medication can only be used in the morning, can not be used at night.
2 cyclosporin A (CsA) selectively inhibited helper T cells and T cytotoxic response cells, acting as second-line drugs for hormonal and cytotoxic null RNS. 2-5mg/Kg/d, 2 oral fasting. Side effects: liver and kidney toxicity, hypertension, hyperuricemia, hirsutism and gingival hyperplasia.
Note: the starting amount should not be too large, 2-3 mg/Kg/d volume, the effect is not obvious, but not more than 5 mg/Kg/d. 6-9 months to determine whether the effect. Valley value MCD80-120ng/ML, FSGS125-175 ng/ml. Peak value: 400-600ng/ml.
3 FK506 calcineurin inhibitor, which is similar to CsA, can inhibit the expression of IL-10, and the effect of FK506 is more than 100 times stronger than that of CsA, which is used in kidney transplantation, and there is no evidence of RNS. Recommended dosage: 0.08-0.12 mg/Kg/d, 2 hours fasting. Side effects: rough face, rough skin, hirsutism, hyperlipidemia, impaired glucose tolerance, neurotoxicity, infection, cancer, thrombosis, high uric acid, etc.. Note: there is no indication on the instructions. The amount is still exploring, Academician Li Leishi 2-3mg/d. Novartis recommended 0.08-0.12mg/Kg/d. Valley value 3-5ng/ml.
4 Cellcept (MMF): the in vivo metabolites of mycophenolic acid in the inosine monophosphate dehydrogenase inhibitor, classic synthesis pathway inhibitory guanine nucleotide metabolism. Therefore, inhibition of T beta cell proliferation and antibody formation to achieve therapeutic purposes. As second-line drugs for patients with RNS with liver dysfunction, diabetes, aseptic necrosis of the femoral head can not be durable hormone and hormone +CTX ineffective patients. The side effect is small, which has led to severe anemia and renal function damage in patients with severe infection, herpes zoster. Usage: 1.5-2.0g/d, orally 2 times. Note: 3-6 months to determine whether the effect of maintaining 1.5-1 years. 1-3g/L, MPA-AUC (30-60mg.h) /L in renal transplantation.

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