Refractory nephrotic syndrome (RNS) is difficult to treat clinically. If long-term proteinuria is not effectively controlled or the disease is recurrent, it is likely to cause glomerulosclerosis and interstitial fibrosis, leading to chronic renal failure (CRF), which is a serious type of chronic kidney disease (CKD). Therefore, it is important to explore its more reasonable and effective treatment to achieve complete remission as much as possible to delay the deterioration of renal function.
I. Definition of RNS
The definition of RNS is not uniform in China, but is generally considered as “hormone resistance” and “partial effect” in primary nephrotic syndrome (NS) treated with standard dose of prednisone for 8 to 12 weeks and “hormone dependence” and “hormone remission” in the process of dose reduction. “Hormone dependence”, “recurrent attacks” and intolerance of hormone therapy. ①Hormone resistance: It refers to those who do not have significant reduction or decrease in proteinuria without leaving NS after sufficient dose of prednisone (1mg/Kg/d for adults, 1.5 to 2.0mg/Kg/d for children), and focal stage sclerosis (FSGS) is judged as hormone resistance only when hormone treatment is ineffective for 3 to 4 months or even 6 months. (ii) Partial effect: Those who are treated with standard dose of prednisone for 8 to 12 weeks but are not yet in complete remission despite being out of NS. ③Hormone dependence: After treatment with prednisone, urine protein is significantly reduced or even turned negative, but during the process of hormone reduction (maintenance dose has not yet been reached), NS relapses again, and then increasing the hormone dose is still effective. ④Recurring episodes: It refers to NS patients who relapsed 2 times within 6 months or 3 times within a year after being remitted by treatment with prednisone. ⑤ Hormone intolerance: NS with peptic ulcer, active tuberculosis, active hepatitis, glaucoma and diabetes mellitus cannot tolerate hormone therapy.
II. Analysis of common causes of RNS
The reasons why RNS is difficult to treat are complex and vary from patient to patient, and for the same patient, there may be different reasons at different times. It can be determined by the nature of the patient’s disease or due to irregular treatment. A comprehensive summary is as follows.
1. Irregular use of hormones
(1) Insufficient hormone dose: hormones can interfere with protein, fat, sugar metabolism (leading to centripetal obesity, young women are reluctant to accept) acne, hirsutism, gastrointestinal bleeding, immunosuppression prone to infection and other side effects. Some patients have insufficient starting amount and do not follow the standard dose.
(2) Hormone reduction too fast: clinical NS after effective hormone therapy, the maximum dose is less than 8-12 weeks, FSGS is less than 3-4 months, and the dose reduction starts less than 2 weeks after the urine protein turns negative early. Dose reduction is 10% every 2-3 weeks, that is, 1 tablet of prednisone every 2-3 weeks, and some reduce 1 tablet per week until discontinuation. Hormone reduction too quickly is one of the reasons for NS relapse, and some recurrent episodes become RNS.
(3) Those with insufficient hormone maintenance time: For NS patients with effective hormone therapy, when the hormone is reduced to maintenance dose, the maintenance dose is applied for 6-8 months, and the total duration of prednisone treatment is 1.5-2 years. Insufficient hormone maintenance time is one of the common causes of NS to become RNS in hormone-sensitive patients.
2, improper hormone use method
(1) The use of oral prednisone for those with severe swelling: NS is heavily swollen and the gastrointestinal tract is also highly swollen, at this time, after oral prednisone, the absorption and utilization of the gastrointestinal tract significantly decreases and does not reach the effective blood concentration, which affects the efficacy of the hormone.
(2) Patients with poor liver function use oral prednisone: prednisone itself has no therapeutic effect and needs to be converted into prednisolone by hepatic hydrogenation before it has biological effect. Therefore, oral prednisone is not effective in patients with poor liver function.
(3) The drug interaction makes the hormone drug concentration decrease, if the patient has chronic pain, is using drugs that can enhance microsomal cytochrome P450 plus monohydrogenase activity such as rifampin, carbamazepine, phenytoin sodium, imipenem, quinolone can make the hormone metabolism accelerate, blood concentration decrease, the drug effect decreases.
3.Co-infection
Various infections can cause NS patients to be insensitive to hormones, or NS patients who are sensitive to hormones can become insensitive due to infection during treatment. Glucocorticoid (GC) is formed by binding with glucocorticoid receptor (GR) in the cytoplasm to form GC-GR complex into the cell granules, and exerts its biological effect by binding with glucocorticoid response (GRF). And the infection produces a series of inflammatory factors, including interleukin 1β (IL-1β), tumor necrosis factor alpha (TNF-α), etc.
Activatable nuclear transcription factor activator protein and nuclear factor Kβ and NF-Kβ can inhibit the GC-GR complex from binding to GRF, thus reducing the biological effect of the hormone. NS common infections such as respiratory, gastrointestinal and urinary tract infections, as well as occult infections such as dental pulpitis, frontal sinusitis, osteomyelitis, etc.
4.Combined thrombosis
Deep vein thrombosis is a common complication of NS, especially membranous nephropathy (MN), when plasma albumin ≤20g/L, it is easy to form renal vein thrombosis, which will affect the blood circulation of kidney, even though the plasma concentration of hormones and other immunosuppressants is not low. In addition, some intrarenal micro thrombosis, is also one of the causes of RNS.
5, combined with acute renal failure
NS plasma volume decline, coupled with acute gastroenteritis and other causes of dehydration, resulting in a rapid drop in blood volume, can appear in renal antegrade acute renal failure (ARF) or a high degree of swelling, interstitial edema, reduced glomerular rate filtration, or a large amount of proteinuria, resulting in tubular blockage, or even NS original disease aggravated, combined with crescentic nephritis can develop to ARF.
6.Gene mutation
This year, it is reported that mutations in HPHS1 gene leading to abnormal Nephrin protein in glomerular plasma cells, mutations in Nphsz gene leading to abnormal Podocin protein in glomerular podocytes, mutations in CDαHP gene leading to abnormal CDα-related protein, and mutations in ACTIN4 gene leading to abnormal glomerular podocyte skeletal protein α-auxin 4 protein can all lead to RNS.
7. Severe pathological types
A large amount of clinical experience in evidence-based medicine proves that: severe thylakoid proliferative glomerulonephritis (MsPGN), FSGS, MN, and membranoproliferative nephritis (MPGN) tend to respond poorly to hormones and are prone to become RNS, although microscopic lesions (MCD) are sensitive to hormones, they are prone to relapse and also lead to RNS.
Third, RNS combined Chinese and Western medicine treatment
(I) General treatment: rest, high calorie, low salt (3g/d), moderate protein diet (0.8-1g/d), moderate water restriction.
(II) Symptomatic treatment
1. Diuresis: tab diuretics in combination with potassium-protective diuretics.
Intractable edema: (a) low molecular dextrose expansion after tachyphylaxis 20-40mg IV.
(ii) Plasma albumin expansion followed by tachykinuria 120mg IV.
Problems of albumin transfusion
(i) Severe hypoproteinemia, high edema and oliguria (<400ml/d).
②Highly edematous diuretics are ineffective.
③The appearance of blood volume deficiency such as dizziness and dizziness, drop in blood pressure and increase in heart rate after diuretic for high edema.
④Infusion of tachyphylaxis immediately after albumin infusion.
⑤Severe heart failure should be used with caution.
2.Reduce proteinuria
Large amount of proteinuria → glomerular hyperfiltration → tubular interstitial injury → glomerulosclerosis.
ACEI and ARB have renal protective effects other than antihypertensive.
ACEI: Lortinexin 10mg/d.
ARB: Dynavin or Ambrovir 1-4 capsules/d.
ARB should be high dose, but renal artery stenosis and hyperkalemia are prohibited.
3. Lipid lowering: hyperlipidemia ≥ 6 months to be treated with lipid lowering.
Increased cholesterol: statins (Lysergic, Sulforaphane)
Increased triglycerides: Betablocker (Libifed 0.25mg Qd)
(C) Standardize the use of hormones and the route of administration
For patients with RNS caused by irregular use of hormones, we should adjust the unreasonable hormone treatment plan and route of administration and follow the regular plan.
① Starting dose: (1mg/Kg/d for adults, 1.5 to 2.0mg/Kg/d for children) for 8-12 weeks
② Slow dose reduction: 10% of the original dose after 2-3 weeks of full dose treatment
③ Long-term maintenance: small dose (0.5mg/Kg/d) for 6-8 months, maintenance dose (0.2mg/Kg/d) for 10-12 months.
④ Intravenous administration for severe edema.
⑤ Use methylprednisolone orally for abnormal liver function.
⑥ Avoid cytochrome p450 agonist drugs such as carbamazepine and rifampicin as much as possible.
(iv) Cytotoxic agents and immunosuppressants
The following cytotoxic agents and immunosuppressants can be added according to the situation when hormones are not tolerated and hormone resistance, partial effect and recurrent attacks occur after 8-12 weeks of using sufficient amount of hormones.
1. Cyclophosphamide (CTX) is the most commonly used cytotoxic drug at home and abroad. In vivo hydroxylation by liver microscopic cells, producing alkylated metabolites, with strong immunosuppressive effects. It is mostly used for hormone resistance and frequently recurrent RNS. usage ①2 mg/Kg/d, divided into 2 doses. ②200mg every other day intravenously. ③8-12 mg/Kg/d twice a month. Total 150 mg/Kg/d. Side effects: bone marrow suppression, toxic liver damage, gonadal suppression (especially in men), alopecia, gastrointestinal reactions and hemorrhagic cystitis.
Caution: ①Refer to use with peripheral blood leukocytes below 4000 and abnormal liver function. ②Can not exceed the total amount and use once a year. ③ Intravenous use can only be used in the morning, not at night.
2.Cyclosporine A (CsA) selectively inhibits helper T cells and T cytotoxic cells, and is used as a second-line drug for RNS where hormone and cytotoxicity are ineffective. 2-5mg/Kg/d, divided into 2 oral doses on an empty stomach. Side effects: hepatic and renal toxicity, hypertension, hyperuricemia, hirsutism and gingival hyperplasia.
Note: ①The starting amount should not be too large, 2-3 mg/Kg/d to start, the effect is not obvious can increase the amount, but not more than 5 mg/Kg/d. ②6-9 months to judge whether there is an effect. ③Valley value MCD80-120ng/ML, FSGS125-175 ng/ml. peak value: 400-600ng/ml.
3. FK506
Neurocalcine inhibitor, and CsA is the same kind of drug, the difference is also can inhibit the expression of IL-10, FK506 is 100 times stronger than CsA, mostly used in renal transplantation, no evidence-based medical evidence for RNS. Recommended dosage: 0.08-0.12 mg/Kg/d in 2 divided doses on an empty stomach.
Side effects: Facial roughness, skin roughness, hirsutism, hyperlipidemia, impaired glucose tolerance, neurotoxicity, infection, malignancy, thrombosis, hyperuricemia, etc.
Note: ① There are still no indications in the instructions. ②Dosage is still being explored. 2-3mg/d by Leleishi Academician.
Novartis recommends 0.08-0.12mg/Kg/d. ③Valley value 3-5ng/ml.
4. primaquine (MMF).
In vivo metabolite is mycophenolic acid the latter is hypoxanthine mononucleotide dehydrogenase inhibitor, inhibiting the classical synthetic pathway of guanine nucleotide metabolism. Therefore, it inhibits the proliferation of Tβ cells and antibody formation for therapeutic purposes. It is used as a second-line drug in patients with RNS with abnormal liver function, diabetes mellitus, aseptic necrosis of the femoral head that cannot be treated with durable hormones and in patients in whom hormone + CTX is ineffective.
It has been reported to cause severe anemia and severe infections in patients with renal impairment and herpes zoster.
Dosage: 1.5-2.0g/d, divided into 2 oral doses.
Note: ① 3-6 months to judge if there is any effect, maintain 1.5-1 year.
②Valley 1-3g/L, renal transplant MPA-AUC(30-60mg.h)/L.