Preface
1. Background of this guideline
2. The Intended Purpose, Anticipated Users, and Predicted Social Significance of the Guidelines
3. Patients within the scope of the guidelines
4. Preparation procedure
5. Contents of the guideline
6. Evidence levels and recommendation grades
-
[Evidence Levels]
-
Level 1: Systematic review/meta-analysis.
-
Level 2: At least 1 randomized controlled trial (RCT).
-
Level 3: A non-RCT.
-
Level 4: An analytical epidemiologic study (cohort study or case–control study) or a single-arm intervention study (no controls).
-
Level 5: A descriptive study (case report or case series).
-
Level 6: Opinion of an expert committee or an individual expert, which is not based on patient data.
-
[Recommendation Grades]
-
Grade A: Strongly recommended because the scientific basis is strong.
-
Grade B: Recommended because there is some scientific basis.
-
Grade C1: Recommended despite having only a weak scientific basis.
-
Grade C2: Not recommended because there is only a weak scientific basis.
-
Grade D: Not recommended because scientific evidence shows treatment to be ineffective or harmful.
7. Issues on the preparation of this guideline
1. Little evidence on Japanese patients
2. Compatibility with the CKD clinical guideline and past NS guidelines
3. Issues on medical resources
4. Guideline reflecting the opinions of patients
8. Financial sources and conflict of interest
9. Publication and future revisions
1. Public information on the guideline
2. Practice and adherence to this guideline
3. Setting of necessary research themes in the future
4. Plan for revision
I. Disease entity · definition (pathogenesis)
1. Proteinuria: ≥3.5 g/day and continuous (comparable to ≥3.5 g/gCr at spot urine) |
2. Hypoalbuminemia: Serum albumin ≤ 3.0 g/dL |
Serum total protein ≤ 6.0 g/dL is helpful |
3. Edema |
4. Dyslipidemia (Hyper LDL cholesterolemia) |
The therapeutic evaluation is done by the amount of urine protein at 1 and 6 months after the initiation of treatment |
Complete remission: urine protein <3.0 g/day |
Incomplete remission I: 0.3 g/day ≤ urine protein <1.0 g/day |
Incomplete remission II: 1.0 g/day ≤ urine protein <3.5 g/day |
Non-response: urine protein ≥3.5 g/day |
Steroid resistant nephrotic syndrome: The enough dose of steroid treatment fails to achieve complete remission or incomplete remission I at 1 month after the initiation of treatment |
Refractory nephrotic syndrome: The various treatments including steroid and immunosuppressive agents fail to achieve complete remission or incomplete remission I at 6 months after the initiation of treatment |
Steroid dependent nephrotic syndrome: Steroid treatment is impossible to discontinue, because repeated over 2 times relapses appear after the reduction or discontinuation of steroid |
Frequent relapse nephrotic syndrome: Over 2 times relapses appear in 6 months |
Nephrotic syndrome requiring chronic treatment: Nephrotic syndrome to be treated by steroid or immunosuppressive agents over 2 years |
1. Nephrotic syndrome: Massive proteinuria (40 ≥ mg/h/m2) + hypoalbuminemia (serum albumin ≤ 2.5 g/dL) |
2. Steroid sensitive nephrotic syndrome: Daily administrated prednisolone treatment attains the remission within 4 weeks |
3. Relapse: After the remission urine protein of 40 ≥ mg/h/m2 or morning urine 100 mg/dL or more by dip stick continues for 3 days |
II. Diagnosis
1. Symptomatology · clinical condition
2. Laboratory findings
Examination | Measurement items | Major findings |
---|---|---|
Urinalysis | Urine volume, urine protein increase: urine protein, albuminemia (24-h collection or spot urine) fatty cast, oval fat body Fraction of urine protein Occult blood, urinary sediments Granular cast, waxy cast Selectivity of urine protein (clearance ration of IgG and transferrin) | Increase: urine protein, albuminemia fatty cast, oval fat body |
Blood examination | Peripheral blood examination | Sometimes decrease: red blood cell, hemoglobin |
Biochemical examination | Decrease: total protein, albumin Sometimes decrease: Na, vitamin D, GFR Sometimes increase: BUN, Cr | |
Lipid examination | Increase: total cholesterol, LDL, VLDL, La(a) ApoB, ApoC II, HDL-3 Stable: HDL Decrease: HDL-2 | |
Coagulation test | Increase: fibrinogen, FDP, D-dimer Decrease: antithrombin III, plasminogen | |
Immunological test | Decrease: IgG and other immunoglobulins, complements | |
Chest X-ray | Cardiothoratic ratio, pulmonary vascular shadow cost-phrenic angle shadow of lung field | Sometimes: pulmonary congestion |
Ultrasonography | Deep vein thrombosis in lower extremities | Collapse of venous system due to decrease of circular blood volume |
Renal biopsy | Light microscopy Immunofluorescence microscopy | The definitive diagnosis is usually determined electron microscopy by renal biopsy |
Examination | Measurement items | Major findings |
---|---|---|
Urinalysis | Occult blood Urine Bence Jones protein | Positive in purpura nephritis or vasculitis positive in paraproteinemia |
Blood examination | Peripheral blood examination | Pancytopenia or hemolytic anemia in lupus nephritis Leukocytosis and thrombocytosis in the cases with infectious diseases ad vasculitis |
Biochemical examination | Blood sugar markers such as blood glucose, HbA1c, and glycoalbumin in diabetic nephropathy CRP and inflammatory reactions increase in vasculitis and purpura nephritis Paraprotein or cryoglobumin is confirmed in in the cases with paraproteinemia | |
Lipid examination | The abnormality of IDL or ApoE is confirmed in lipoprotein glomerulopathy | |
Immunological examination | Anti-nuclear antibody , anti-ds-DNA antibdy, anti-Sm antibody, anti-phosphlipid antibody increase and complements decrease in lupus nephritis The positive findings are confirmed in bacterial culture and antigen/antibody detection for pathogenic microbes | |
Renal biopsy | The specific findings are observed in each secondary disease, thus the renal biopsy is useful for the definitive diagnosis of secondary diseases | |
Imaging test | Neoplastic diseases are diagnosed by various imaging tests such as CT, MRI, ultrasonography and bone marrow aspiration | |
Genetic test | Genetic tests are useful in the genetic illnesses |
III. Epidemiology · prognosis
1. Incidence · prevalence · recurrence rate
2. Remission rate · nonresponsive rate · renal prognosis
3. Incidence of complications
IV. Treatment
1. Clinical Questions for Treatment
1. Minimal change nephrotic syndrome and focal segmental glomerulosclerosis
2. Membranous nephropathy
3. Membranoproliferative glomerulonephritis
4. How to use steroids
5. Immunosuppressive agents not allowed by medical insurance (at the time of description of this guideline in 2013)
6. Nephrotic syndrome in the elderly
7. Adjunctive and supportive treatments
2. Dietary Instruction
3. Treatment Interpretation and Treatment Algorithm
4. Minimal change nephrotic syndrome (MCNS)
1. Initial treatment
-
In the evaluation of efficacy, MCNS shows a high response rate to initial oral steroid treatment (CQ1).
-
We recommend that oral steroid alone be prescribed for preventing the acute decline of renal function at the initial treatment (CQ1).
-
Steroid pulse therapy may be considered when absorption of oral steroids seems difficult (CQ1).
-
Oral steroid administration should be considered on days when patients are not receiving steroid pulse treatment (CQ14).
-
In patients with severe intestinal edema associated with systemic edema, we suggest that increasing the dose of oral steroid or changing the administration routes be considered (CQ15).
-
The efficacy of alternate-day steroid administration is not clear because there are few relevant reports in adult nephrotic syndrome (CQ16).
-
There is no clear goal about the duration of continued steroid therapy after remission; however, at least 24 weeks may be necessary in MCNS (CQ18).
2. Relapse cases
-
As for steroid therapy for recurrent nephrotic syndrome, the opinions differ as to whether the dose of treatment should the same as that of the first treatment or lower than that of the first treatment (CQ17).
3. Frequently relapsing, steroid-dependent, and steroid-resistant cases
-
In MCNS, we recommend that cyclosporine with steroid be prescribed for reducing the urinary protein level in steroid-resistant and relapse cases (CQ2, CQ5).
-
In frequently relapsing nephrotic syndrome derived from MCNS and FSGS in adult patients, we recommend cyclosporine or cyclophosphamide be additionally prescribed to steroid for reducing the urinary protein level (CQ5).
-
The addition of mizoribine to steroid decreases the relapse rate in children with frequently relapsing nephrotic syndrome, whereas it is not known whether the same is true in adults. Mizoribine may be considered depending on the cases (CQ5).
-
In steroid-dependent or steroid-resistant nephrotic syndrome derived from MCNS and FSGS, we recommend cyclosporine or cyclophosphamide be additionally administered with steroid for reducing the urinary protein level (CQ5).
-
Recently, MCNS is found even in elderly patients. Few clinical studies have evaluated the efficacy of immunosuppressive agents in elderly patients with nephrotic syndrome; however, the efficacy of these agents for reducing the urine protein level was reported to be similar to that in younger patients. The incidence rate of adverse effects in elderly patients is higher than that in younger patients. Careful observation is necessary in the treatment of elderly patients with nephrotic syndrome (CQ22).
4. Immunosuppressive agents not covered by medical insurance (at the time of description of this guideline in 2013)
5. Focal segmental glomerulosclerosis (FSGS)
1. Initial treatment
-
Oral steroid therapy as an initial treatment is effective for FSGS, showing a remission induction rate from 20 to 50 %. We recommend steroid therapy as the initial treatment (CQ3).
-
Steroid pulse therapy may be considered for patients with severe intestinal edema (CQ3).
-
Oral steroid should be administered on days when patients are not receiving steroid pulse treatment (CQ14).
-
In patients with severe intestinal edema associated with systemic edema, we suggest increasing the oral steroid or changing the prescription routes (CQ15).
-
The efficacy of alternate-day steroid administration is not clear in preventing the adverse effects of steroid (CQ16).
-
There is no clear goal about the duration of continued steroid use after remission; however, steroid was continually used for at least 6 months in observational studies in patients with FSGS (CQ18).
-
The efficacy of immunosuppressive agents for reducing the urine protein level in elderly patients was reported to be similar to that in younger patients. The incidence rate of adverse effects in elderly patients is higher than that in younger patients. Careful observation is necessary in the treatment of elderly patients with nephrotic syndrome. The selection of steroid treatment or combination treatment with steroid and immunosuppressive agents should be determined on the basis of the age or complications of patients (CQ22).
2. Relapsing and frequently relapsing cases
-
The combination of oral steroid and cyclosporine is selected for patients with relapsing and frequently relapsing FSGS instead of steroid-alone treatment (CQ5, CQ17, CQ22).
3. Steroid-dependent and steroid-resistant cases
-
Compared with steroid-alone treatment, the combination treatment of cyclosporine and steroid may be more effective for reducing the urinary protein level in steroid-resistant FSGS. The nephrotoxicity of cyclosporine due to long-term use is unclear (CQ4).
-
It is not clear whether cyclosporine is more effective than mizoribine or cyclophosphamide for reducing the urinary protein level (CQ6).
-
The efficacy of immunosuppressive agents for reducing the urine protein level in elderly patients was reported to be similar to that in younger patients. The incidence rate of adverse effects in elderly patients is higher than that in younger patients. Careful observation is necessary in the treatment of elderly patients with nephrotic syndrome. The selection of steroid treatment or combination treatment with steroid and immunosuppressive agents should be determined on the basis of the age or complications of patients (CQ22).
4. Immunosuppressive agents not covered by medical insurance (at the time of description of this guideline in 2013)
6. Membranous nephropathy (MN)
1. Initial treatment
-
In some patients with MN with nephrotic syndrome, we suggest that no treatment or supportive treatment alone without immunosuppressive agents may reduce the urinary protein level. However, we cannot expect that no treatment or supportive treatment alone is effective for preventing the decline of renal function (CQ7).
-
Steroid-alone treatment is not more effective than no treatment for reducing the urinary protein level. We recommend steroid-alone treatment for preventing the decline of renal function (CQ8).
-
In a retrospective study on Japanese patients with MN, the remission rates did not show any significant differences between three treatment groups (steroid alone, steroid and cyclophosphamide, and supportive treatment); however, treatment with steroid alone and the combination of steroid and cyclophosphamide showed significant effectiveness in preventing the decline of renal function when compared with supportive treatment (CQ8).
-
In steroid-resistant MN, we recommend the combination of steroid and cyclosporine for reducing the urinary protein level and preventing the decline of renal function (CQ9).
-
Between steroid with cyclosporine and steroid with alkylating agents, the superiority of the treatment with steroid with cyclosporine has not been recognized (CQ9).
-
In patients with severe intestinal edema associated with systemic edema, we suggest increasing the dose of oral steroid or changing the prescription (CQ15).
-
The efficacy of alternate-day administration is not clear in preventing the adverse effects of steroid (CQ16).
-
There is no clear goal about the period of continued steroid administration after remission; however, steroid was continued for at least 6 months in observational studies on patients with MN (CQ18).
-
The efficacy of immunosuppressive agents for reducing the urine protein level in elderly patients was reported to be similar to that in younger patients. The incidence rate of adverse effects in elderly patients is higher than that in younger patients. Careful observation is necessary in the treatment of elderly patients with nephrotic syndrome. The selection of steroid treatment or combination treatment with steroid and immunosuppressive agents should be determined on the basis of the age or complications of patients (CQ22).
2. Steroid-resistant cases
-
In steroid-resistant MN, we recommend the combination of steroid and cyclosporine for reducing the urinary protein level and preventing the decline of renal function (CQ9).
-
In steroid-resistant or refractory MN, we suggest that the addition of mizoribine to steroid is effective for reducing the urinary protein level (CQ10).
-
In MN, we recommend the addition of cyclophosphamide to steroid for reducing the urinary protein level and preventing the decline of renal function (CQ11). Because of the frequent adverse effects of alkylating agents and the limited evidence of the efficacy of these agents in Japanese patients, we suggest that the use of alkylating agents be considered carefully.
3. Non-nephrotic cases
-
In patients with MN showing non-nephrotic proteinuria, we suggest that conservative treatment with RAS inhibitors, lipid-lowering agents, or antiplatelet agents is effective for reducing the urinary protein level in some cases. (CQ12).
-
However, it is not clear whether those conservative treatments are effective for preventing the decline of renal function (CQ12).
7. Membranoproliferative glomerulonephritis (MPGN)
-
In children with MPGN, steroid is recommended for reducing the urinary protein level and preventing the decline of renal function. In adult cases, the efficacy of steroid is unclear, although steroid may be considered in some patients with MPGN (CQ13).
8. Adjunctive and supportive treatments
1. Renin-angiotensin system (RAS) inhibitors
-
In patients with hypertension and nephrotic syndrome, we recommend RAS inhibitors be prescribed for reducing the urinary protein level. It is not known whether RAS inhibitors are effective for patients with nephrotic syndrome without hypertension (CQ23).
2. Diuretics
-
In edematous patients with nephrotic syndrome, we recommend oral diuretics, particularly loop diuretics, be prescribed for reducing edema. The use of intravenous diuretics should be considered if the effect of oral diuretics is insufficient, because they effectively reduce body fluid volumes (CQ24).
3. Albumin agents
-
Albumin administration does not improve hypoalbuminemia or edema in patients with nephrotic syndrome and may exacerbate hypertension; therefore, it is not recommended for this condition. However, in cases of severe shock or pulmonary edema, albumin administration may have a temporary but useful effect (CQ25).
4. Antiplatelet and anticoagulant agents
-
For patients with nephrotic syndrome, we do not recommend prescribing antiplatelets and anticoagulants as monotherapies because their effectiveness in reducing the urinary protein level is not clear. We suggest that administration of anticoagulants may be prescribed for preventing thrombosis (preventative administration is not covered by insurance). The efficacy of antiplatelet agents for preventing thrombosis is not clear (CQ26).
5. Statins
-
In nephrotic syndrome, we recommend statins be prescribed for lipid metabolism abnormalities because they have been proven effective for improving such conditions. However, it is not clear whether statins reduce the incidence of cardiovascular disease and improve prognosis (CQ27).
6. Ezetimibe
-
In nephrotic syndrome, it is not clear whether this treatment improves the lipid metabolism abnormalities or prognosis of patients (CQ28).
7. Low-density lipoprotein (LDL) apheresis
-
In patients with refractory nephrotic syndrome and high LDL cholesterol levels, we recommend LDL apheresis for reducing the urinary protein level (CQ29).
8. Extracorporeal ultrafiltration method (ECUM)
-
In patients with nephrotic syndrome, we recommend the ECUM for the removal of body fluids in refractory edema and ascites that are difficult to control using drug-based therapy (CQ30).
9. Trimethoprim-sulfamethoxazole combination
-
In patients with nephrotic syndrome, we recommend treatment with the trimethoprim-sulfamethoxazole combination for preventing pneumocystis pneumonia during immunosuppressive therapy (CQ31).
10. Immunoglobulin supply
-
In nephrotic syndrome, we suggest supplying immunoglobulin to patients with hypogammaglobulinemia for the prevention of infectious diseases. (Prevention treatment with immunoglobulin supply is not covered by medical insurance.) (CQ32).
11. Antituberculous drugs
-
We recommend antitubercular agents be given for patients with nephrotic syndrome who are suspected to have latent tuberculosis. (Prevention treatment with antitubercular agents is not covered by medical insurance.) (CQ33)
12. Hepatitis B virus treatment
-
In patients with nephrotic syndrome, we recommend that immunosuppressive therapy be started after the initiation of hepatitis B treatment (CQ34).
9. Lifestyle and dietary instruction
1. Screening for cancer
-
The incidence of cancer in patients with membranous nephropathy is not higher in Japan than in Europe and the United States. However, it is unclear whether the incidence of cancer in patients with membranous nephropathy is higher than that in the general population in Japan (CQ35).
2. Bed rest and/or exercise restriction
-
We do not recommend bed rest and/or exercise restriction for patients with nephrotic syndrome because it is not clear whether these measures have beneficial effects (CQ36).
3. Vaccination
-
During the treatment with corticosteroids and immunosuppressive agents, we recommend administering inactivated vaccines against influenza virus and Streptococcus pneumoniae according to the risk of infection to patients with nephrotic syndrome (CQ37).
4. Steroid-induced femoral head necrosis (FHN)
-
No study has investigated the preventive measures against FHN in patients with nephrotic syndrome. The use of only the essential dose of steroid may prevent the development of steroid-induced FHN (CQ38).
5. Avoidance of mental stress
-
In steroid-dependent and/or frequently relapsing nephrotic syndrome in children, avoidance of mental stress is effective to prevent relapse; thus, we recommend the avoidance of mental stress in these patients. However, it is not clear whether avoidance of mental stress is effective for preventing the relapse of nephrotic syndrome in adults (CQ39).
6. Fat-restricted diet
-
We recommend providing fat-restricted diet for the treatment of dyslipidemia in patients with nephrotic syndrome. It is not clear whether a fat-restricted diet improves the prognosis of nephrotic patients (CQ40).