In March 2009, the China Primary Nephrotic Syndrome (INS) Treatment Expert Consensus Collaborative Group was established under the initiative of Professor Li Xuewang of Peking Union Medical College (PUMC), a famous Chinese nephrologist and president of the Nephrology Branch of Chinese Physicians Association. A total of 14 nephrologists from large tertiary hospitals across China participated in the consensus. The leaders of the three groups on membranous nephropathy and microscopic nephrotic syndrome finally completed the Expert Consensus on the Treatment of Primary Nephrotic Syndrome in China after 1 year, 5 large symposiums and review meetings, reviewing a large amount of the latest literature both at home and abroad, and bringing together a wide range of expert opinions. This is the first Chinese expert consensus that systematically introduces the clinical treatment of primary nephrotic syndrome in China, which provides very practical guidance for nephrologists in China in the clinical treatment of primary nephrotic syndrome.
Overview of nephrotic syndrome
Nephrotic syndrome is a clinical syndrome caused by various glomerular diseases. It is defined as: massive proteinuria 33.5g/d; hypoalbuminemia, plasma albumin <30g/L; often with varying degrees of edema and hyperlipidemia, with massive proteinuria and hypoalbuminemia as diagnostic necessities.
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.
Expert consensus on the treatment of primary nephrotic syndrome
Microscopic lesion nephrotic syndrome
The typical clinical manifestation of MCD is nephrotic syndrome, only about 15% are associated with microscopic hematuria, usually without persistent hypertension and renal hypofunction, and the development to end-stage renal disease (ESRD) is uncommon. Because adrenocorticotropic hormone therapy can significantly increase the proportion of patients who achieve complete remission early, it is the treatment of choice. 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 noted during treatment, after which the dose should be reduced by 10% of the original use every 2-4 weeks, and more slowly at 15 mg/d or less to reduce relapse.
For patients with adrenocorticotropic hormone dependence or recurrent relapses, the combination of prednisone 1mg/kg・d and cyclophosphamide 2mg/kg・d can be used for 12~16 weeks. If this treatment does not maintain long-term remission, or for patients with contraindications to glucocorticoid use or glucocorticoid resistance, treatment with cyclosporine is indicated. The starting dose is 3.5~4mg/kg・d with a titrated trough concentration of 100~200ng/ml. After 4~6 months, if partial or complete remission occurs, the dose is slowly reduced by 0.5mg/kg・d every 1~2 months for at least 1 year, and can be maintained in small doses (1~1.5mg/kg・d) for a long time. The combination of low-dose glucocorticoids (prednisone 0.5mg/kg・d or less) can 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 with a titrated trough concentration of 5-10 ng/ml, and a slow dose reduction will be 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 treatments.
Focal segmental glomerulosclerosis
FSGS is a group of glomerular diseases with focal segmental distribution of glomerulosclerosis as the basic pathological change. The etiology includes three major categories: primary, secondary and hereditary, 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 (1~2g/d for 3~6 months) may be beneficial in prolonging the maintenance of remission.
Rituximab or plasma exchange may be tried in patients who fail to respond to the above treatments.
Membranous nephropathy
Most patients with membranous nephropathy present with nephrotic syndrome, the remainder 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 with normal blood creatinine and persistent proteinuria less than 4 g/d; intermediate-risk patients with normal or almost normal blood creatinine and urinary protein of 4-8 g/d; and high-risk patients with 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; after slow reduction of cyclosporine, long-term maintenance at low doses (1~1.5 mg/kg・d) can avoid relapse. FK506 is also effective in relieving proteinuria and protecting renal function, and its treatment protocol can only be determined after experience has been gained. Mycophenolate may have some effect on short-term reduction of urinary protein, but in the absence of additional evidence of effectiveness, it should be considered only when the above treatments are ineffective. Azathioprine does not improve the overall rate of remission of proteinuria in patients with IMN, nor does it improve long-term renal survival, and is not recommended as a routine immunosuppressive treatment agent for membranous nephropathy.