Nephrotic syndrome is a clinical syndrome caused by various glomerular diseases. It is defined as: massive proteinuria 33.5 g/d; hypoalbuminemia, plasma albumin <30 g/L; often with varying degrees of edema and hyperlipidemia, with massive proteinuria and hypoalbuminemia as diagnostic requirements.
The main pathological types of primary nephrotic syndrome in adults are, in order, membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and microdegenerative nephrotic syndrome (MCD), the exact etiology of which is unknown. The diagnosis of primary nephrotic syndrome can be made only after secondary factors (including genetic factors) are carefully excluded.
I. Microdegenerative nephrotic syndrome
The typical clinical manifestation of MCD is nephrotic syndrome, only about 15% of which is accompanied by microscopic hematuria, usually without persistent hypertension and hyperalgesia, and the development to end-stage renal disease (ESRD) is uncommon. Adrenocorticosteroid therapy is the treatment of choice because it significantly increases the proportion of patients who achieve complete remission early. Prednisone 1 mg/kg・d (maximum 80 mg/d) achieves complete remission in approximately 76% of patients at 8 weeks of treatment, with up to 16 weeks of observation. Adrenocorticotropic hormone dose adjustment should be observed during treatment, followed by a 10% reduction of the original dose every 2-4 weeks, and a more gradual reduction at 15 mg/d or less to reduce relapses.
For patients with adrenocorticotropic hormone dependence or recurrent relapses, the combination of prednisone 1 mg/kg/d and cyclophosphamide 2 mg/kg/d can be used for 12 to 16 weeks. If this treatment does not maintain long-term remission, or in patients with contraindications to glucocorticoid use or glucocorticoid resistance, treatment with cyclosporine is indicated. The starting dose is 3.5~4 mg/kg・d with a titrated trough concentration of 100~200 ng/ml. After 4~6 months, if partial or complete remission occurs, the dose is slowly reduced by 0.5 mg/kg・d every 1~2 months for at least 1 year, and can be maintained in small doses (1~1.5 mg/kg・d) for a long time.
The combination of low-dose glucocorticoids (prednisone 0.5 mg/kg・d or less) may improve the remission rate. If ineffective, cyclosporine should be discontinued and tacrolimus (FK506), morte-macrolimus (MMF) and azathioprine should be considered in that order after repeat renal biopsy to verify the diagnosis.
To reduce the degree of dependence on adrenocorticotropic hormone in hormone-dependent patients and in patients with cyclosporine resistance, FK506 can be tried at a starting dose of 0.05-0.1 mg/kg・d and a titrated trough concentration of 5-10 ng/ml, with a slow dose reduction initiated after 4-6 months if partial or complete remission occurs. Experience in its clinical use still needs to be accumulated.
MMF or azathioprine may be tried in patients who fail to respond to the above treatment.
II. Focal segmental glomerulosclerosis
FSGS is a group of glomerular diseases with focal segmental distribution of glomerulosclerosis as the basic pathological change. The etiology includes primary, secondary and hereditary three categories, and the pathological subtypes are: collapsed, tip, cellular, hilar and non-specific.
Among FSGS patients, 100% have varying degrees of proteinuria, more than 60% have nephrotic syndrome, about 50% have varying degrees of hematuria, and 1/3 have hypertension and renal insufficiency at the onset, often with manifestations of impaired tubular function. In persistent nephrotic syndrome, if left untreated, more than 50% of patients will enter ESRD within 5 to 10 years.
Due to the low rate of complete remission in patients treated with adrenocorticosteroids alone and the significant side effects of glucocorticoids associated with long-term high-dose (prednisone 1 mg/kg・d) use, the preferred treatment options are high-dose glucocorticoids (prednisone 1 mg/kg・d) combined with cyclophosphamide or low-dose glucocorticoids (prednisone <0.5 mg/kg・d) combined with cyclosporine A therapy.
Tacrolimus (0.05-0.1 mg/kg/d, trough concentration 5-10 ng/ml) may be effective in patients who have failed cyclosporine A therapy.
For glucocorticoid-dependent patients with recurrent relapses, cyclophosphamide, cyclosporine, azathioprine, and morte-macrolide (1-2 g/d for 3-6 months) may be beneficial for prolonging the maintenance of remission.
Patients who fail to respond to the above treatments may be tried with rituximab or plasma exchange.
III. Membranous nephropathy
Most patients with membranous nephropathy present with nephrotic syndrome and the rest with proteinuria in the non-nephrotic range. 50% of patients may have microscopic hematuria and, rarely, erythrocyte tubular or sarcoid hematuria. Most patients have normal blood pressure. Most patients have normal renal function at the beginning of the disease, and renal insufficiency usually progresses more slowly.
The natural course of membranous nephropathy varies widely, with some patients in spontaneous remission and some progressing to ESRD. low-risk patients have normal blood creatinine and persistent proteinuria of less than 4 g/d; intermediate-risk patients have normal or almost normal blood creatinine and urinary protein of 4-8 g/d; high-risk patients have abnormal creatinine or persistent deterioration and urinary protein >8 g/d. For intermediate- and low-risk patients, only non-immunosuppressive therapy can be considered.
For high-risk patients, aggressive immunosuppressive therapy is required. Treatment with glucocorticoids alone is not effective in improving the rate of complete remission or in improving long-term renal survival. The combination of glucocorticoids and alkylating agents is preferred for immunosuppressive therapy; when there are concerns about adequate glucocorticoids or contraindications to glucocorticoids, cyclosporine or cyclosporine combined with low-dose glucocorticoids can be used with comparable efficacy; long-term maintenance at low doses (1-1.5 mg/kg・d) after slow taper of cyclosporine can avoid relapse.
FK506 is also effective in relieving proteinuria and protecting renal function, and its treatment regimen is still to be determined after experience has been gained. Mycophenolate may have some effect on short-term reduction of urinary protein, but due to the lack of additional evidence of effectiveness, it should only be considered when the above treatments are ineffective. Azathioprine does not improve overall remission of proteinuria or long-term renal survival in patients with IMN and is not recommended as a routine immunosuppressive therapeutic agent for membranous nephropathy.