Evidence-Based Clinical Practice Guidelines for Nephrotic
Syndrome 2014

July 27th, 2015

Authors
Clinical Guidelines for IgA Nephropathy 2014 Advisory Committee
Committee chairman
Shinichi Nishi
Committee member
Yoshifumi Ubara
Yasunori Utsunomiya
Koichi Okada

Kobe University
Tranonom Hospital
Jikei University
Saitama Medical University

Yoko Obata
Hiroyasu Kai
Hideyasu Kiyomoto

Nagasaki University
Tsukuba University
Tohoku University

Shin Goto
Tsuneo Konta
Yoshie Sasatomi
Yoshinobu Sato
Tomoya Nishino
Kazuhiko Tsuruya

Niigata University
Yamagata University
Fukuoka University
Japan Community HealthOrganization Sendai Hospital
Nagasaki University
Kyushu University

Kengo Furuichi
Junichi Hoshino
Yasuhiro Watanabe

Kanazawa University
Toranomon Hospital
Saitama Medical Hospitalcare

Chief Chairman of the Clinical Practice Guidelines for Progressive Kidney
Diseases
Kenjiro Kimura
St. Marianna University
Leader of the Research for Progressive Kidney Diseases of the Ministry of
Health, Labour and Welfare
Seiichi Matsuo
Nagoya University

Cooperative Medical Society
The Japanese Association for Infectious Diseases
The Japanese Society for Pediatric Nephrology
The Japanese Society of Nephrology

Preface
1. Background of this guideline
In Japan, original researches on nephrotic syndrome (NS) were initiallyperformed by the Ministry of Health, Labour and Welfare (MHLW) NS
research group. The first definition of NS was reported by the MHLW NS
research group in 1973. Subsequently, the criteria for treatment effects were
documented in 1974. Based on the continued clinical researches and social
actions by the HLWM NS research group, the definition of refractory NS wasdetermined in 1999. NS already treated with various agents, including
steroids, that does not reach complete or incomplete remission within 6months after the initiation of treatment is known as refractory NS.
In 2002, the HLWM NS research group published the “Guideline for
Refractory Nephrotic Syndrome (Adult Cases).” This was the first NS
guideline in Japan. Consequently, this group and the Japanese Society ofNephrology (JSN) published the second guideline, “Guideline for Nephrotic
Syndrome,” in 2011. Currently, the collaborative working group of the MHLW
and JSN aimed to publish and establish the third NS guideline in 2014. The
new guideline aims to provide recommendations in clinical settings according
to evidence-based medicine and it uses a description of clinical questions(CQs) according to the policy of publication for the clinical practice guidelinesof the Medical Information Network Distribution Service (MINDS).
In 2012, an international guideline for glomerulonephritis, including NS, the“Guideline for Glomerulonephritis,” was published by the Kidney Disease
Improving Global Outcome (KDIGO). Thus, the working group of the third
NS guideline examined the contents of the KDIGO guideline as an importantreference and re-evaluated Japanese treatment strategy in the past and thecontents of previous guidelines already published in our country. We
attempted that the third clinical guideline was considered to be appropriate
for recent clinical practices for NS in Japan.
2. The Intended Purpose, Anticipated Users, and Predicted Social
Significance of the Guidelines
The third NS guideline is intended as a reference for physicians engaging in
the treatment of patients with NS. Practical clinical information on NS wasincluded in this guideline for both specialists and nonspecialists of nephrology.

We described essential knowledge concerning NS in the first part andproposed many CQs associated with treatment in the later part. The responseto each question was written as a statement with a recommendation grade.
In the last part, we proposed a summary of a treatment strategy. In thissummarized strategy, we proposed new treatment ideas based on previous
ideas. The new strategy with algorithm figures may be helpful for the decision
for treatment by physicians seeing nephrotic patients.
We found only limited articles on the treatments of adults with NS. The
number of subjective patients was small in these articles. Therefore, thestrategy addressed in this guideline did not absolutely force physicians tofollow the stereotyped protocol, but rather we expected that our strategy
would be helpful in decision making for the treatment of an individual patientwith NS. Because aging patients with NS having various complications are
increasing, the individual decision for the treatment of each patient is also
necessary. We want to strongly insist that this guideline is not a decision basis
for medical malpractice lawsuits or trials.
2. Patients within the scope of the guidelines
This guideline is intended as a reference for the treatment of patients withprimary NS. In the preparation process of the guideline, we used evidence
articles of pediatric patients if we could not find evidence articles of adultpatients. In a part of the guideline, we referred to non-nephrotic cases.
Recurrent NS occurring after kidney transplantation and NS associated withpregnancy were excluded from this guideline. For pregnant cases with NS,
we hope that you refer to the “Clinical Guideline for Pregnancy of Kidney
Disease Patients” that was edited by the JSN.
3. Preparation procedure
At first, we collected evidence articles available for guideline preparation. The
working group of the NS guideline was set up. Nephrologists with sufficientknowledge and experience voluntarily participated in this working group.
On September 9, 2011, a progressive kidney disease research group supportedby the MHLW research foundation, which acts to control refractory disease,
opened the first collaborative meeting concerning 4 major nephrology
diseases, including IgAN, NS, rapidly progressive glomerulonephritis, andpolycystic kidney disease. Dr. Tsuguya Fukui, the president of St. Luke’s

International Hospital, was invited as an adviser of this meeting. The
members of the 4 working groups of the guideline learned the significant
meaning of the guideline and the procedures for guideline preparation fromhis lecture. Thereafter, we began to write our guideline using common
concepts.
Consequently, our working group of the NS guideline determined CQs with
the Delphi method and free cross-talk communication. The survey ofreference articles was performed using the PubMed database. For a basic
survey, evidence articles were collected from already published papers until
July 2012, and important articles were selected on demand from papers
published after July 2012. Through several working group meetings and Email discussions, our working group summarized the contents of the NS
guideline. In addition, several collaborative meetings concerning the 4 major
kidney diseases, IgAN, NS, rapidly progressive glomerulonephritis, andpolycystic kidney disease, were opened. In these meetings, the first CQs were
properly revised. From August 2013 to October 2013, our working groupasked for a review of the guideline by designated reviewers belonging torelated academic societies. At the same time, we announced that we welcomed
public comments from the members of the JSN. According to the suggestions
from reviewers and public comments, we revised our guideline, establishedthe final version, and publically answered the comments on the home page of
the JSN.
4. Contents of the guideline
The contents of this guideline are related to those in Chapter 11 of the “2013CKD Clinical Guideline Based on Evidence” and the guidelines for the 4 major
kidney diseases, IgA nephropathy, NS, rapid progressive glomerulonephritis,and polycystic kidney, which were created based on research on progressive
kidney diseases that was funded by scientific research aid from the MHLW.
5. Evidence levels and recommendation grades
Evidence was classified into 6 levels based on study design, and it wasarranged roughly from the most reliable study type (Level 1) to the least
reliable (Level 6). These levels do not necessarily represent rigorous scientificstandards; they are intended for use as a convenient reference for quickly
assessing the significance of various clinical data during the physician’sdecision-making process.
[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 notbased on patient data.
However, for systematic review/meta-analysis, the evidence level was decided
based on the designs of underlying studies. If underlying study designs weremixed, the lowest level underlying the study was used to determine theoverall evidence level. For example, meta-analysis of cohort studies would be
Level 4, but the same Level 4 would also be assigned to meta-analysis
including both RCTs and cohort studies.
In addition, a decision based on committee consensus was that all
subanalyses and post hoc analyses of RCTs should be categorized at evidence
Level 4. Accordingly, it was decided that the evidence level of findings
representing the primary endpoints of a RCT would be Level 2, but that theevidence level of findings that were determined through subanalysis or post
hoc analysis of that RCT would be Level 4.
When a statement related to a certain treatment was presented,
consideration was given to the level of evidence serving as the basis of thatstatement, and a recommendation grade was assigned as follows:[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.

If we found only a weak scientific basis for a certain statement concerning
treatment, the members of the committee discussed the matter and decided
on C1 or C2 for the recommendation grade. Thus, discrimination between C1and C2 statements was based on expert consensus.
7.
Issues on the preparation of this guideline(1) Little evidence on Japanese patients
Compared with evidence articles regarding NS in foreign adult patients andJapanese children, evidence articles concerning Japanese adults with NS are
less. Therefore, our statements were strongly affected by evidence fromoverseas countries and children with NS. It is doubtful whether the evidence
from overseas country is suitable for Japanese nephrotic patients. Therefore,
we paid careful attention to differences in the clinical status of NS between
overseas countries and Japan. In Japan, observational and intervention
studies of adults with NS have gradually progressed, and further active
studies are expected in this field.
(2) Compatibility with the CKD clinical guideline and past NS guidelines
We paid careful attention to compatibility with the contents of Chapter 11 of
the “2013 CKD Clinical Guideline.” There were no major conflict points
between the current guideline and the past 2 guidelines, the “Guideline for
Refractory Nephrotic Syndrome (Adult Cases)” and the “Guideline for
Nephrotic Syndrome.” The current guideline was prepared according to thepolicy of the MINDS. The previous Japanese NS guidelines were notcompliant with that policy. Therefore, some statements of the current
guideline were distinct from the statements of previous guidelines. The
statements and algorithm of this guideline were determined by mutual
understanding of members belonging to the working group.
(3) Issues on medical resources
In general, the clinical guideline must consider medical resources associatedwith recommended statements. However, the current guideline did not
discuss issues on medical cost; thus medical financial problems did not affectthe contents of our guideline. In the next guideline, this point may be included.
(4) Guideline reflecting the opinions of patients
During the preparation processes of the clinical guideline, we needed to
introduce the opinions of patients. However, this time, we unfortunately could
not include the opinions of patients. We should refer to the opinions ofpatients in the next guideline, particularly in the case that the guideline isused for patients.
8. Financial sources and conflict of interest
All financial sources for this guideline were paid by the JSN and used for
traffic fees, conference fees, etc. No payments were made to the members of
the working group of this guideline.
All members of the working group of the guideline submitted documents fortheir conflicts of interest to the JSN. The submitted documents were kept
with the JSN. We were asked to revise the guideline according to thesuggestions from many reviewers from associated societies to avoid conflictsof interest. We asked for public comments from the members of the JSN.
Finally, we revised this guideline referring to the suggestions from reviewers.
9. Publication and Future Revisions(1) Public information on the guideline
This guideline was published in the Japanese version of the journal of the
JSN and was concurrently released as a book in Japanese (by Tokyo Igakusha,
Tokyo). This guideline was also uploaded to the homepage of the JSN. An
English-translated condensed version was published in Clinical andExperimental Nephrology, which is the English version of the journal of the
JSN. We hope this guideline will also be published on the MINDS website.
Finally, we are planning to inform general physicians and medical staff
regarding the contents of this guideline for the purpose of education them on
the clinical strategy for NS.
(2) Practice and adherence to this guideline
We are planning to evaluate the states of practice and adherence to thisguideline through a survey on the practical acts in the issue with grade B
recommendation.
(3) Setting of necessary research themes in the future
From the statements with a C1 recommendation, we will choose new researchquestions and determine the necessary research themes in the CKD field.
This point will be discussed in the Committee of CKD Action of the JSN.
Active clinical research on the treatment strategy that focuses on Japanese
adult patients with NS using approved immunosuppressive agents in ourcountry are absolutely necessary because our country has approved only

limited immunosuppressive agent use in the insurance system compared withoverseas countries.
(4) Plan for revision
Revision of this guideline should be done 3 or 5 years later because new
evidence is gradually increasing and new immunosuppressive agents are
expected to be approved in the insurance system. At that time, we must
document information from the perspective of patients and medical economy.

Content
I. Disease entity・Definition(Pathogenesis)]

II. Diagnosis
1. Symptomatology・Clinical manifestation
2. Laboratory findings
III. Epidemiology・Prognosis
1. Incidence・Prevalence・Recurrence rate
2. Remission rate・Nonresponsive rate・Renal prognosis
3. Incidence of complication
IV. Treatment
1. Clinical questions for treatment
1) Minimal change nephrotic

syndrome ・Focal

segmental

glomerulosclerosis
CQ 1. Is oral steroid recommended for reducing urinary protein level andpreventing the decline of renal function in minimal change nephrotic
syndrome?
CQ 2 . Is cyclosporine recommended for reducing urinary protein level andpreventing the decline of renal function in minimal change nephrotic
syndrome?
CQ 3 . Is steroid therapy recommended for reducing urinary protein andpreventing the decline of renal function in focal segmental
glomerulosclerosis?
CQ 4. Is cyclosporine recommended for reducing urinary protein level andpreventing the decline of renal function in focal segmental
glomerulosclerosis?
CQ 5. Is the addition of immunosuppressive agents recommended for
reducing urinary protein level or preventing the decline of renal function
in frequently relapsing nephrotic syndrome?
CQ 6. Are immunosuppressive agents administered in conjunction withsteroids recommended for reducing urinary protein and preventing thedecline of renal function in steroid-resistant focal segmental
glomerulosclerosis?

2) Membranous nephropathy
CQ 7. Is no treatment or supportive treatment alone without
immunosuppressive agents recommended for reducing urinary protein
level and preventing the decline of renal function in membranous
nephropathy with nephrotic syndrome?
CQ 8. Is steroid-alone treatment recommended for reducing urinary
protein level and preventing the decline of renal function in membranous
nephropathy?
CQ 9. Is cyclosporine recommended for reducing urinary protein level andpreventing the decline of renal function in membranous nephropathy?
CQ 10. Is mizoribine recommended for reducing urinary protein level andpreventing the decline of renal function in membranous nephropathy?
CQ 11. Are alkylating agents recommended for reducing urinary protein
level and preventing the decline of renal function in membranous
nephropathy?
CQ 12. Are conservative treatments recommended for reducing urinary
protein level and preventing the decline of renal function in membranous
nephropathy showing a non-nephrotic range of proteinuria?
3) Membranoproliferative glomerulonephritis
CQ 13. Is steroid treatment recommended for reducing urinary protein
level and preventing the decline of renal function in idiopathic
membranoproliferative glomerulonephritis showing nephrotic syndrome?
4) Steroid treatment
CQ 14. Is oral steroid treatment recommended during intervals between
steroid pulse treatments (i.e., at days when no steroid pulse treatment isgiven)?
CQ 15. Is the increase of oral steroid doses or the change of administrationroutes recommended for patients with systemic edema?
CQ 16. Is alternate-day administration as a means of steroid dose
reduction effective for inhibiting the incidence of adverse effects?
CQ 17. Is reducing the steroid dose compared with that of the firsttreatment recommended for the treatment of recurrent nephrotic
syndrome?
CQ 18. Is there a standard period for steroid maintenance therapy afternephrotic syndrome has remitted?
5) Immunosuppressive agents not allowed by medical insurance (at the timeof description of this guideline in 2013)
CQ 19. Is rituximab recommended for reducing urinary protein level andpreventing the decline of renal function in nephrotic syndrome?
CQ 20. Is mycophenolate mofetil recommended for reducing urinary
protein level and preventing the decline of renal function in nephrotic
syndrome?
CQ 21. Is azathioprine recommended for reducing urinary protein level andpreventing the decline of renal function in nephrotic syndrome?
6) Nephrotic syndrome in the elderly
CQ 22. Are immunosuppressive agents recommended for elderly patientswith nephrotic syndrome?
7) Adjunctive and supportive treatments
CQ 23. Are renin-angiotensin system (RAS) inhibitors recommended for
reducing urinary protein level in nephrotic syndrome?
CQ 24. Are diuretics recommended for reducing edema in nephrotic
syndrome?
CQ 25. Is albumin administration recommended to improvehypoalbuminemia in nephrotic syndrome?
CQ 26. Are antiplatelet and anticoagulant agents recommended for
reducing urinary protein level and preventing thrombosis in nephrotic
syndrome?
CQ 27. Are statins recommended to improve dyslipidemia and life
prognosis in nephrotic syndrome?
CQ 28. Is ezetimibe recommended to improve lipid metabolism
abnormalities and life prognosis in nephrotic syndrome?
CQ 29. Is low-density lipoprotein (LDL) apheresis recommended for
reducing urinary protein levels in refractory nephrotic syndrome?
CQ 30. Is the extracorporeal ultrafiltration method (ECUM) recommended
for refractory edema and ascites in nephrotic syndrome?
CQ 31. Is the trimethoprim-sulfamethoxazole combination recommended
for preventing infectious disease during immunosuppressive therapy innephrotic syndrome?

CQ 32. Is immunoglobulin supply recommended for preventing infectious
disease in nephrotic syndrome?
CQ 33. Is treatment with antitubercular agents recommended forpreventing tuberculous infection in nephrotic syndrome?
CQ 34. Is immunosuppressive therapy recommended for patients with
hepatitis B-positive nephrotic syndrome?
8) Lifestyle and dietary instruction
CQ 35. Is the prevalence rate of cancer in patients with membranous
nephropathy higher than that in the general population?
CQ 36. Is bed rest/exercise restriction recommended in nephrotic
syndrome?
CQ 37. Is vaccination recommended in patients with nephrotic syndromeduring treatment with corticosteroids and immunosuppressive drugs?
CQ 38. Are there any preventive measures against steroid-induced femoral
head necrosis in nephrotic syndrome?
CQ 39. Is the avoidance of mental stress recommended to prevent the onset
and relapse of nephrotic syndrome?
CQ 40. Is a fat-restricted diet recommended to improve dyslipidemia andlife prognosis in nephrotic syndrome?

I. [Disease entity・Definition(Pathogenesis)]

Nephrotic syndrome is a clinical syndrome showing specific features of heavy
proteinuria and hypoalbuminemia or hypoproteinemia as its consequence. It
is caused by increased permeability of serum protein through the damaged
basement membrane in the renal glomerulus. The definition of nephrotic
syndrome includes both massive proteinuria (>3.5 g/day) andhypoalbuminemia (serum albumin <3.0 g/dL) (Table 1,4). Primary nephrotic
syndrome has no background diseases, whereas secondary nephrotic
syndrome has any background diseases. As a result of massive proteinuria
and hypoalbuminemia, this syndrome is frequently accompanied by edema,
dyslipidemia, abnormalities in coagulation/fibrinolysis, reduced renal
function, and immunological disorders. The effect of treatment is determinedby the urinary protein level after treatment (Table 2,3).

II. [Diagnosis]
1. Symptomatology ・Clinical condition
The predominant symptom of nephrotic syndrome is edema. In the earlyphase, edema appears in local parts such as the eyelids; in the advanced
phase, generalized edema occurs with pleural effusion and ascites. Nephrotic
syndrome is sometimes induced by upper respiratory infection or allergic
reaction provoked by insect bites. It is important to evaluate the possibilities
of secondary glomerular diseases in elderly patients with nephrotic syndrome.
2. Laboratory findings
Patients with nephrotic syndrome show various urinary abnormalities andrenal dysfunction (Table 5,6). The degrees of proteinuria and hematuria differ
with each histological type of nephrotic syndrome. High urinary specificgravity and various kinds of cast formation, including hyaline, granular, waxy,
and fatty, are frequently noticed in nephrotic syndrome. Hematologicalabnormalities such as hypoalbuminemia, hypercholesterolemia, renal andliver dysfunction, electrolyte disorders, coagulation/fibrinolysis disorders,hormonal disorders, and anemia are usually found in patients with nephrotic
syndrome.

III. [Epidemiology・Prognosis]
1. Incidence・Prevalence・Recurrence rate
The researchers of the Committee for the Standardization of Renal
Pathological Diagnosis and the Working Group for the Renal Biopsy Databaseof the Japanese Society of Nephrology had set up the J-RBR/J-KDR (Japan
Renal Biopsy and Kidney Disease Registry) since 2007, and the epidemiologyof nephrotic syndrome in Japan was gradually revealed. In the analysis ofcases registered to the J-RBR until the end of 2010, primary glomerulardisease was the most frequently occurring glomerular disease and diabetic
nephropathy was the most frequent among the secondary glomerular diseases.
The total cases of membranous nephropathy (MN) and minimal change
nephrotic syndrome (MCNS) were close to 80% among the primary
glomerular diseases. In the analysis of nephrotic syndrome patients aged 65
years, the ratios of diabetic nephropathy and amyloid nephropathy werehighest, next to primary glomerular disease .
MCNS,
focal
segmental
glomerulosclerosis(FSGS),
MN,
andmembranoproliferative glomerulonephritis are known to relapse frequently.
However, a wide range of relapse rates was reported in previous articles; thus,
prospective follow-up surveys such as the Japanese Nephrotic Syndrome
Cohort Study (JNSCS) are expected to provide precise rates.
2. Remission rate・Nonresponsive rate・Renal prognosis
Remission rates, nonresponsive rates, and prognosis vary across thehistological types of nephrotic syndrome. MCNS shows a higher remission
rate of 90%, whereas the recurrence rate is also higher at 30–70%. Comparedwith MCNS, FSGS shows a lower remission rate and poorer renal prognosis
resulting in end-stage renal disease. About half of the cases of FSGS are
nonresponders to steroid treatment. The responsive rates and renal prognosis
vary across the variant types of FSGS. In the data in Japan, the renal survival
rate was 33.5% at the 20-year follow-up examination. MN showed a highremission rate in Japanese patients. Complete or incomplete remission by
single steroid treatment was achieved in 73.1%. Approximately 30% of cases
showed spontaneous remission. However, the renal survival rate was 59% at
the 20-year follow-up examination.
3. Incidence of complications

Various complications develop in patients with nephrotic syndrome. Althoughcohort studies performed abroad revealed a high incidence of cardiovascular
events, the actual state in Japan seems to be different. Treatment withglucocorticoids and/or immunosuppressants, and nephrotic syndrome itself,
often make patients susceptible to infection, the true rate of which remains
to be determined. Reports from abroad also highlighted a high incidence ofthromboembolic events. Furthermore, the westernized lifestyle makes theJapanese population more susceptible to thrombosis and therefore should
receive research attention. Malignant tumors have been considered a common
complication in patients with nephrotic syndrome. However, according torecent surveys, the co-occurrence rate of malignant tumors with nephrotic
syndrome seems relatively low in Asian countries such as Japan and China
compared with that in Western countries. Acute renal failure is anotherrepresentative complication in patients with nephrotic syndrome, especiallyin the elderly.

V. [Clinical Questions for Treatment]
1. Treatment of glomerular diseases[Minimalchangenephrotic
syndrome

and

focal

segmental

glomerulosclerosis]
CQ1. Is oral steroid recommended for reducing urinary protein level andpreventing the decline of renal function in minimal change nephrotic
syndrome?
Recommendation grade: B
In minimal change nephrotic syndrome, we recommend oral steroids beprescribed for reducing urinary protein level at the initial treatment.
Recommendation grade: C1
In minimal change nephrotic syndrome, we recommend oral steroid alone beprescribed for preventing the acute decline of renal function at the initial
treatment.
Recommendation grade: not graded
Steroid pulse therapy may be considered when absorption of oral steroids
seems difficult.
[Summary]
Oral steroid therapy is usually administered as the initial treatment forminimal change nephrotic syndrome. In the evaluation of efficacy, a highresponse rate of 90% was found. Steroid pulse therapy may be consideredwhen absorption of oral steroids seems difficult because of intestinal edema,
diarrhea, and other conditions.
CQ2. Is cyclosporine recommended for reducing urinary protein level andpreventing the decline of renal function in minimal change nephrotic
syndrome?
Recommendation grade: C1
In minimal change nephrotic syndrome, we recommend prescribing
cyclosporine with steroid for reducing urinary protein level in steroidresistant and relapsing cases.
Recommendation grade: not graded
However, it is not clear whether cyclosporine is effective for preventing thedecline of renal function.
[Summary]
Compared to steroid alone treatment, the combination treatment of
cyclosporine and steroid is effective for reducing urinary protein level andshortening the duration of achieving remission in relapsing cases of minimalchange nephrotic syndrome. However, it is not clear whether cyclosporine iseffective for preventing the decline of renal function.
CQ3. Is steroid therapy recommended for reducing urinary protein level andpreventing the decline of renal function in focal segmental
glomerulosclerosis?
Recommendation grade: C1
In focal segmental glomerulosclerosis, we recommend steroid therapy beprescribed for reducing urinary protein level and preventing the decline ofrenal function at the initial treatment.
Recommendation grade: not graded
Steroid pulse therapy may be considered when absorption of oral steroids
seems difficult.
[Summary]
Oral steroid therapy as an initial treatment is effective for focal segmental
glomerulosclerosis, showing a remission induction rate of 20–50%. However,
the efficacy of steroids varies depending on histological variants. The

concomitant use of immunosuppressants is necessary for steroid-resistantcases.
CQ4. Is cyclosporine recommended for reducing urinary protein level andpreventing the decline
glomerulosclerosis?

of

renal

function

in

focal

segmental

Recommendation grade: C1
In focal segmental glomerulosclerosis, we recommend the combination
treatment of cyclosporine and steroid be prescribed for reducing urinary
protein level.
Recommendation grade: not graded
The combination treatment of cyclosporine and steroid seems to be effective
for preventing the decline of renal function in focal segmental
glomerulosclerosis.
[Summary]
The combination treatment of cyclosporine and steroid is effective forinducing remission in focal segmental glomerulosclerosis. Evidence showingthat the combination treatment of cyclosporine and steroid is effective forpreventing the decline renal function is limited; however, some extent ofefficacy is expected. The possibilities of cyclosporine nephrotoxicity with thelong-term use of the drug are unclear.
CQ5. Is the addition of immunosuppressive agents to steroid recommended
for reducing urinary protein level or preventing the decline of renal function
in frequently relapsing nephrotic syndrome
Recommendation grade: C1
In frequently relapsing nephrotic syndrome in adults, we recommend
cyclosporine or cyclophosphamide be additionally prescribed with steroid for
reducing urinary protein level.
Recommendation grade: C1
The addition of mizoribine to steroid decreases the relapse rate of frequently
relapsing nephrotic syndrome in children; however, it is not known whether
the same is true in adults. Mizoribine may be considered depending on thecases.
Recommendation grade: not gradedIt is not clear whether the addition of cyclosporine, cyclophosphamide, or
mizoribine to steroid can inhibit the decline in renal function.
[Summary]
The addition of oral cyclosporine or cyclophosphamide to steroid is effective
for the reduction of urinary protein level in frequently relapsing nephrotic
syndrome in adults. However, the efficacy of mizoribine is unknown.
Although renal function might be preserved by maintaining complete
remission, there is no clear evidence indicating that these additional
immunosuppressive agents are effective for preventing the decline of renal
function.
CQ6. Are additional immunosuppressive agents to steroid recommended for
reducing the urinary protein level and preventing the decline of renal
function in steroid-resistant focal segmental glomerulosclerosis?
Recommendation grade: C1
In steroid-resistant focal segmental glomerulosclerosis in adults, werecommend additional cyclosporine (3.5 mgkg-1day-1) treatment with lowdose steroids for reducing urinary protein.
Recommendation grade: not graded
However, it is not known whether the addition of other immunosuppressive
agents is effective for reducing the urinary protein level and preventing thedecline of renal function in steroid-resistant focal segmental
glomerulosclerosis in adults.
[Summary]
The addition of cyclosporine is effective for reducing the urinary protein levelin steroid-resistant focal segmental glomerulosclerosis in adults. Maintaining
the remission of nephrotic syndrome is associated with preventing the declineof renal function. However, the addition of chlorambucil and mycophenolate
mofetil is not superior to that of cyclosporine for reducing urinary protein
level. There are no sufficient data indicating that these immunosuppressive
agents have direct renoprotective effects in adult cases of steroid-resistantfocal segmental glomerulosclerosis

[Membranous nephropathy]
CQ7.

Is

no

treatment

orsupportive

treatment

alone

without

immunosuppressive agents recommended for reducing the urinary protein
level and preventing the decline of renal function in membranous
nephropathy with nephrotic syndrome?
Recommendation grade: C1
In some patients with membranous nephropathy with nephrotic syndrome,
we suggest that no treatment or supportive treatment alone without
immunosuppressive agents may reduce the urinary protein level.
Recommendation grade: not graded
We do not recommend no treatment or supportive treatment alone without
immunosuppressive agents in the long term because it cannot prevent
declining renal function in patients with membranous nephropathy showing
nephrotic syndrome.
[Summary]
No treatment or supportive therapy alone without immunosuppressive
agents is effective for reducing the urinary protein level in some patients withmembranous nephropathy showing nephrotic syndrome; however, these are
not expected to prevent the decline of renal function. In particular, this type
treatment may worsen the renal prognosis of patients with severe urinary
protein excretion.
CQ8. Is steroid-alone treatment recommended for reducing the urinary
protein level and preventing the decline of renal function in membranous
nephropathy?
Recommendation grade: C1
In membranous nephropathy, we recommend steroid-alone treatment for
preventing the decline of renal function.
Recommendation grade: not graded
It is not clear whether treatment with steroid alone is effective for reducing
the urinary protein level.
[Summary]
Compared with no treatment, steroid-alone treatment is not effective for
reducing the urinary protein level in membranous nephropathy. In a
retrospective study in Japanese patients with membranous nephropathy, theremission rates did not show any significant differences between threetreatment groups (steroid alone, steroid and cyclophosphamide, andsupportive treatment); however, treatment with steroid alone and the
combination of steroid and cyclophosphamide showed significant
effectiveness in preventing the decline of renal function compared withsupportive treatment.
CQ9. Is cyclosporine recommended for reducing the urinary protein level andpreventing the decline of renal function in membranous nephropathy?
Recommendation grade: C1
In steroid-resistant membranous nephropathy, we recommend the
combination of steroid and cyclosporine be given for reducing the urinary
protein level and preventing the decline of renal function.
[Summary]
The combination treatment with steroid and cyclosporine is effective for
reducing the urinary protein level and preventing the decline of renal
function compared with treatment with steroid alone. Between steroid withcyclosporine and steroid with alkylating agents, the superiority of treatment
with steroid and cyclosporine has not been recognized.
CQ10. Is mizoribine recommended for reducing the urinary protein level andpreventing the decline in renal function in membranous nephropathy?
Recommendation grade: C1
In steroid-resistant or refractory membranous nephropathy, we suggest thatthe addition of mizoribine is effective for reducing the urinary protein level.
Recommendation grade: not graded
It is not clear whether the addition of mizoribine is effective for preventing
the decline in renal function.
[Summary]
It has been reported that the addition of mizoribine to steroid reduces theurinary protein level in patients with membranous nephropathy. However,this effect of mizoribine has not been confirmed in appropriately sized
randomized control trials. The dose of mizoribine should be carefully reducedin patients with chronic renal failure.

CQ11. Are alkylating agents recommended for reducing the urinary protein
level and preventing the decline of renal function in membranous
nephropathy?
Recommendation grade: C1
In membranous nephropathy, we recommend the addition of
cyclophosphamide to steroid for reducing the urinary protein level andpreventing the decline of renal function. Because of the frequent adverse
effects and the very few evidences showing the efficacy of alkylating agentsin Japanese patients, we suggest that the use of alkylating agents beconsidered carefully.
[Summary]
In overseas countries, it is generally accepted that the combination treatment
with steroid and alkylating agents is superior to steroid-alone treatment for
inducing the remission of nephrotic syndrome in membranous nephropathy.
Although the study is retrospective, the results suggest that the efficacy ofsteroid-alone treatment is similar to that of the combination treatment withsteroid and alkylating agents in Japanese patients. Attention should be given
to the high frequency of adverse effects of alkylating agents.
Cyclophosphamide has fewer adverse effects than chlorambucil.
CQ12. Are conservative treatments recommended for reducing the urinary
protein level and preventing the decline of renal function in non-nephrotic
membranous nephropathy?
Recommendation grade: C1
In some patients with non-nephrotic membranous nephropathy, we suggestthat conservative treatment with RAS inhibitors, lipid-lowering agents, or
antiplatelet agents may be effective for reducing the urinary protein level insome cases.
Recommendation grade: not graded
However, it is not clear whether those conservative treatments are effective
for preventing the decline of renal function.
[Summary]
Conservative therapies with RAS inhibitors, lipid-lowering agents, or
antiplatelet agents are effective for reducing the urinary protein level in somepatients with membranous nephropathy accompanied by a non-nephrotic

rage of proteinuria. However, these conservative treatments are not expected
to prevent the decline of renal function.
[Membranoproliferative glomerulonephritis]
CQ13. Is steroid recommended for reducing the urinary protein level andpreventing the decline of renal function
membranoproliferative glomerulonephritis?
Recommendation grade: C1
In
childrenwith
idiopathic

nephrotic

in

idiopathic

nephrotic

membranoproliferative

glomerulonephritis, we suggest that steroid be prescribed for reducing theurinary protein level and preventing the decline of renal function.
Althoughthebenefitofsteroidinadultswith
nephrotic
membranoproliferative glomerulonephritis is not known, we suggest thatsteroids may be effective for reducing the urinary protein level and preventing
the decline of renal function in some adult patients.
[Summary]
Observational studies suggest that steroid is beneficial for reducing theurinary protein level and preventing the decline of renal function in children
with idiopathic membranoproliferative glomerulonephritis. Althoughevidences concerning the treatment of adult patients with idiopathic
membranoproliferative glomerulonephritis are inconsistent, we suggest thatsteroid is the acceptable treatment agent in some adult patients with
idiopathic membranoproliferative glomerulonephritis.
2. How to use steroids
CQ14. Is oral steroid treatment recommended during intervals between
steroid pulse treatment (i.e., at days when steroid pulse treatment is not
given)?
Recommendation grade: not graded
Oral steroid treatment should be considered at least on days when steroid
pulse therapy is not given.
[Summary]
The half-life of methylprednisolone is short, i.e., 1–3 h, whereas that of oral
steroids is long, i.e., 12–36 h. Therefore, oral steroid treatment is considerednecessary on days when steroid pulse therapy is not given.

CQ15. Is the increase of oral steroid doses or the change in administrationroutes recommended for patients with systemic edema?
Recommendation grade: C1
In patients with severe intestinal edema associated with systemic edema, wesuggest that increasing the dose of oral steroid or changing the prescription
routes be considered.
[Summary]
The efficacy of oral steroid seems to be diminished in patients with systemic
edema. Therefore, it may be necessary to consider intravenous steroid
therapy or steroid pulse therapy in patients with systemic edema.
CQ16. Is alternate-day steroid administration as a means of steroid dose
reduction effective for inhibiting the incidence of adverse effects?
Recommendation grade: Not graded
The efficacy of alternate-day steroid administration is not clear because there
are few relevant reports in adult nephrotic syndrome.
[Summary]
Limited evidence exists on whether alternate-day steroid treatment fornephritis as a means of dose reduction is effective for inhibiting adverse
reactions. Further studies are warranted.
CQ17. In the treatment of recurrent nephrotic syndrome, is reducing the doseof steroid compared with that of the first treatment recommended?
Recommendation grade: C1
We recommend that the steroid dose be decided appropriately depending on
the relapse condition of individual patients.
Recommendation grade: not graded
Concerning steroid treatment of recurrent nephrotic syndrome, opinions
differ about whether the dose should be the same or reduced compared withthat in the first treatment.
[Summary]
In steroid treatment of recurrent nephrotic syndrome, opinions differ about
whether the treatment should be different from the initial treatment. There
are two conflicting opinions: (i) recurrent nephrotic syndrome should betreated in the same way as the initial treatment, and (ii) recurrent nephrotic

syndrome should be treated with prednisolone at a dose of 20–30 mg/day. No
consensus has been reached.
CQ18. Is there a standard period for steroid maintenance therapy after
nephrotic syndrome has remitted?
Recommendation grade: C1
We recommend that a period for steroid maintenance treatment be set after
nephrotic syndrome has remitted.
Recommendation grade: not graded
The duration of this period should be decided according to the disease types
and pathologies of individual patients.
[Summary]
There is no clear evidence suggesting a standard period for steroid
maintenance therapy after nephrotic syndrome has remitted.
3. Immunosuppressive agents not allowed by medical insurance (at the timeof description of this guideline in 2013)
CQ19. Is rituximab recommended for reducing the urinary protein level andpreventing the decline of renal function in nephrotic syndrome?
Recommendation grade: C1
It is not clear whether rituximab is effective for reducing the urinary protein
level and preventing the decline of renal function. In cases of frequently
relapsing or steroid-resistant nephrotic syndrome, we suggest that rituximab
may be effective for reducing the urinary protein level and preventing thedecline of renal function. (The use of rituximab for nephrotic syndrome is notallowed by medical insurance.)[Summary]
Rituximab may be effective for reducing the urinary protein level in nephrotic
syndrome; however, clinical studies are rare in adult cases. Rituximab could
be an option for the treatment of nephrotic syndrome, but we cannot conclude
that it is an effective agent.
CQ20. Is mycophenolate mofetil recommended for reducing the urinary
protein level and preventing the decline of renal function in nephrotic
syndrome?

Recommendation grade: C1
It is not clear whether mycophenolate mofetil is effective for reducing theurinary protein level and preventing the decline of renal function. In cases offrequently relapsing or steroid-resistant nephrotic syndrome, we suggest that
mycophenolate mofetil may be effective for reducing the urinary protein leveland preventing the decline of renal function. (The use of mycophenolate
mofetil for nephrotic syndrome is not allowed by medical insurance.)[Summary]
Mycophenolate mofetil may be effective for reducing the urinary protein levelin nephrotic syndrome; however, clinical studies are rare in adult patientswith nephrotic syndrome. Mycophenolate mofetil could be an option for thetreatment of nephrotic syndrome, but we cannot conclude that it is aneffective agent.
CQ21. Is azathioprine recommended for reducing the urinary protein leveland preventing the decline of renal function in nephrotic syndrome?
Recommendation grade: C2
In nephrotic syndrome, we do not recommend azathioprine as an initial
treatment because it is not clear whether this agent is effective for reducing
the urinary protein level and preventing the decline of renal function.
Recommendation grade: C1
We suggest that azathioprine may be prescribed as a second treatment agent
for the purpose of steroid dose reduction or in patients with steroid-resistantnephrotic syndrome.
[Summary]
Azathioprine may be effective for reducing the urinary protein level innephrotic syndrome; however, clinical studies of adult cases of nephrotic
syndrome are rare. Azathioprine could be an option for the treatment ofprimary nephrotic syndrome, but we cannot conclude that it is an effective
agent. We do not recommend this agent for initial treatment.

4. Nephrotic syndrome in the elderly
CQ22. Are immunosuppressive agents recommended for elderly patients withnephrotic syndrome?
Recommendation grade: C1
In elderly patients with nephrotic syndrome, we recommend the careful use
of immunosuppressive agents, with adequate attention to adverse effects. The
efficacy and safety of immunosuppressive agents is unclear in elderly patientswith nephrotic syndrome.
[Summary]
Few clinical studies have evaluated the efficacy of immunosuppressive agentsin elderly patients with nephrotic syndrome; however, the efficacy for
reducing the urine protein level was reported to be similar to that in younger
patients. In contrast, the incidence rate of adverse effects in elderly patients
is higher than that in younger patients. The incidence rate of adverse effects
of chlorambucil is higher than that of cyclophosphamide.
5. Adjunctive and supportive treatments
CQ23. Are renin-angiotensin system (RAS) inhibitors recommended for
reducing the urinary protein level in nephrotic syndrome?
Recommendation grade: B
In patients with hypertension and nephrotic syndrome, we recommend RAS
inhibitors for reducing the urinary protein level. It is not clear whether RAS
inhibitors are effective for patients with nephrotic syndrome without
hypertension.
[Summary]
A number of studies have shown that RAS inhibitors reduce the urinary
proteinlevel
inpatientswithmembranous
nephropathy,
membranoproliferative
glomerulonephritis,
and
focal
segmental
glomerulosclerosis with nephrotic syndrome; however, complete remission by
RAS inhibitors alone has been seldom reported. Furthermore, very little is
known about the effect of RAS inhibitors in patients with nephrotic syndrome
without hypertension.

CQ24. Are diuretics recommended for the reduction of edema in nephrotic
syndrome?
Recommendation grade: B
In edematous patients with nephrotic syndrome, we recommend oral
diuretics, particularly loop diuretics, for reducing edema.
Recommendation grade: B
The use of intravenous diuretics should be considered if the effect of oral
diuretics is insufficient, as they effectively reduce the volume of body fluids.
[Summary]
Oral loop diuretic monotherapy or oral loop diuretics combined with thiazide
diuretics are effective for edema reduction in patients with nephrotic
syndrome. Intravenous loop diuretics are considered appropriate for patientswith severe edema. No study has compared the effects of single injection,
multiple injection, and continuous injection.
CQ25. Is albumin administration recommended
hypoalbuminemia in nephrotic syndrome?

for

improving

Recommendation grade: DAlbumin administration does not improve hypoalbuminemia or edema inpatients with nephrotic syndrome and may exacerbate hypertension;
therefore, its use is not recommended in patients with nephrotic syndrome.
Recommendation grade: C1
However, in cases of severe shock or pulmonary edema, albumin
administration may have a temporary but useful effect.
[Summary]
It is not clear whether albumin administration improves edema or has adiuretic effect in patients with nephrotic syndrome. Rather, it may exacerbate
hypertension.
CQ26. Are antiplatelet and anticoagulant agents recommended for reducing
the urinary protein level and preventing thrombosis in nephrotic syndrome?
Recommendation grade: C2
In nephrotic syndrome, we do not recommend antiplatelets andanticoagulants because it is not clear whether these agents are effective for
reducing the urinary protein level when used as monotherapies.

Recommendation grade: C1
In nephrotic syndrome, we suggest that anticoagulants may be prescribed forpreventing thrombosis (preventative administration is not covered byinsurance). The efficacy of antiplatelet agents for preventing thrombosis is
not clear.
[Summary]
There is very little evidence to suggest that urinary protein levels are reducedin patients with nephrotic syndrome by antiplatelet and anticoagulant
monotherapies; thus, their effectiveness is unclear. However, warfarin has
been reported to reduce the incidence of fatal pulmonary embolism.
CQ27. Are statins recommended to improve lipid metabolism abnormalities
and life prognosis in nephrotic syndrome?
Recommendation grade: C1
In nephrotic syndrome, we recommend that statins be prescribed for lipid
metabolism abnormalities because they have been proven effective for
improving such conditions.
However, it is not clear whether statins inhibit the incidence of cardiovasculardisease and improve life prognosis.
[Summary]
Statins can lower triglyceride, total cholesterol, and LDL cholesterol levels
and increase HDL cholesterol levels in patients with nephrotic syndrome,
similar to its effect in healthy persons. However, there are no prospective
studies with primary endpoints such as the prevention of cardiovasculardisease or the improvement of life prognosis, and its effectiveness on
prognosis is unclear.
CQ28. Is ezetimibe recommended for improving lipid
abnormalities and life prognosis in nephrotic syndrome?

metabolism

Recommendation grade: C2
In nephrotic syndrome, we do not recommend ezetimibe monotherapy
because it is not clear whether ezetimibe alone improves the lipid metabolism
abnormalities or life prognosis of patients.
[Summary]
Studies verifying the clinical effect of ezetimibe monotherapy in patients with

nephrotic syndrome have not been conducted, and the effect of this treatment
on improving dyslipidemia or life prognosis is unclear.
CQ29. Is LDL apheresis recommended for reducing the urinary protein levels
in patients with refractory nephrotic syndrome?
Recommendation grade: C1
In patients with refractory nephrotic syndrome and high LDL cholesterollevels, we recommend LDL apheresis for reducing the urinary protein level.
[Summary]
LDL apheresis is reported to be effective in reducing the urinary protein
levels in approximately 50% of cases of refractory nephrotic syndrome.
CQ30. Is the extracorporeal ultrafiltration method (ECUM) recommended forrefractory edema and ascites in patients with nephrotic syndrome?
Recommendation grade: C1
In nephrotic syndrome, we recommend the extracorporeal ultrafiltration
method (ECUM) for removing body fluids in refractory edema and ascites thatare difficult to control using drug-based treatment.
[Summary]
ECUM has been reported be effective in improving edema and ascites inpatients with nephrotic syndrome.
CQ31. Is the trimethoprim-sulfamethoxazole combination recommended forpreventing infectious diseases during immunosuppressive therapy of thenephrotic syndrome?
Recommendation grade: C1
In nephrotic syndrome, we recommend treatment with the trimethoprimsulfamethoxazole combination for preventing pneumocystis pneumonia
during immunosuppressive therapy.
[Summary]
Although there are no direct evidences in nephrotic syndrome, guidelines forother similar immunosuppressive conditions recommend the prophylactic
administration of the trimethoprim-sulfamethoxazole combination forpneumocystis pneumonia. Therefore, this drug combination is recommended

for preventing pneumocystis pneumonia during immunosuppressive therapyof nephrotic syndrome.
CQ32. Is immunoglobulin supply recommended for preventing infectious
diseases in nephrotic syndrome?
Recommendation grade: C1
In nephrotic syndrome, we suggest supplying immunoglobulin to patientswith hypogammaglobulinemia for preventing infectious diseases. (Prevention
treatment with immunoglobulins is not covered by medical insurance.)[Summary]
Although there is limited evidence, immunoglobulin supply could prevent
infectious diseases in patients with nephrotic syndrome presenting withhypogammaglobulinemia. However, the risks and economic disadvantages ofthis treatment should be carefully considered.
CQ33. Is treatment with antituberculous drugs recommended for preventing
tuberculous infection in nephrotic syndrome?
Recommendation grade: C1
In nephrotic syndrome, we recommend antitubercular agents for patients
who are suspected to have latent tuberculosis. (Prevention treatment withantitubercular agents is not covered by medical insurance.)[Summary]
Immunosuppressive therapy for nephrotic syndrome increases the risk ofprogression of latent tuberculosis to active tuberculosis. There are few reports
about the treatment of latent tuberculosis in patients with nephrotic
syndrome; however, this treatment is necessary in patients with nephrotic
syndrome undergoing immunosuppressive therapy.
CQ34. Should immunosuppressive therapy be administered to patients with
hepatitis B-positive nephrotic syndrome?
Recommendation grade: C1
In nephrotic syndrome, we recommend that immunosuppressive therapy beadministered after the initiation of hepatitis B treatment.
[Summary]Before administering immunosuppressive therapy for nephrotic syndrome,
hepatitis B infection should be evaluated first. In case infection is present,
immunosuppressive therapy should be administered after the treatment of
hepatitis B infection.
6. Lifestyle and dietary instruction
CQ35. Is the incidence of cancer in patients with membranous nephropathy
higher than that in the general population?
Recommendation grade: not graded
The incidence of cancer among patients with membranous nephropathy is nothigher in Japan than in Europe and the United States. However, it is unclear
whether the incidence of cancer in patients with membranous nephropathy ishigher than that in the general population in Japan.
[Summary]
The incidence of cancer in patients with membranous nephropathy is lower nJapanese patients than in Europeans and Americans. However, it is unclear
whether the incidence of cancer in patients with membranous nephropathy ishigher than that in the general population in Japan.
CQ36. Is bed rest and/or exercise restriction recommended in nephrotic
syndrome?
Recommendation grade: C2
In nephrotic syndrome, we do not recommend bed rest and/or exercise
restriction because it is not clear whether these measures have beneficial
effects.
[Summary]
There have been no studies directly proving the beneficial effects of bed rest
or exercise restriction in patients with nephrotic syndrome. Excessive bed
rest is undesirable from the viewpoint of preventing pulmonary thrombosis
and embolism, as well as deep vein thrombosis due to the hypercoagulable
condition of nephrotic syndrome and the congestive condition associated withlong-term bed rest. Moderate exercise is considered acceptable.

CQ37. Is vaccination recommended in patients with nephrotic syndromeduring treatment with corticosteroids and immunosuppressive drugs?
Recommendation grade: B
During the treatment of patients with nephrotic syndrome withcorticosteroids and immunosuppressive agents, we recommend administering
inactivated vaccines against influenza virus and Streptococcus pneumoniae
according to the risk of infection.
[Summary]
Few studies have proved the direct blocking effect of vaccination against
influenza virus and Pneumococcus in patients with nephrotic syndrome
undergoing treatment with steroid or immunosuppressive agents. Nephrotic
patients have a high infection risk, and vaccination can provide safety
benefits for these patients. Therefore, we recommend vaccination in patientswith nephrotic syndrome, except in cases where vaccination is inappropriate.
However, the efficacy and safety of live vaccine in nephrotic syndrome arecontroversial.
CQ38. Are there any preventive measures against steroid-induced femoral
head necrosis in nephrotic syndrome?
Recommendation grade: not graded
There are no studies on the preventive measures against femoral headnecrosis (FHN) in patients with nephrotic syndrome. The use of only the
essential dose of steroid may prevent steroid-induced FHN.
[Summary]
No study has directly evaluated the preventive measures for steroid-induced
FHN. In nephrotic syndrome, avoiding the excess use of steroid may preventsteroid-induced FHN.
CQ39. Is the avoidance of mental stress recommended to prevent the onset
and relapse of nephrotic syndrome?
Recommendation grade: C1
In steroid-dependent or frequently relapsing nephrotic syndrome in children,
the avoidance of mental stress is effective for preventing relapse; thus, werecommend the avoidance of mental stress in these patients. However, it isnot clear whether the avoidance of mental stress is effective for preventing
relapse of nephrotic syndrome in adult patients.
[Summary]
There have been no reports that evaluated the relation between the new onsetof nephrotic syndrome and mental stress. In children with nephrotic
syndrome, the strong relation between the relapse of nephrotic syndrome andmental stress has already been suggested. However, the relation between theonset or relapse of nephrotic syndrome and mental stress in adulthood has
not been investigated thus far. Further studies are required in the future.
CQ40. Is a fat-restricted diet recommended for improving dyslipidemia andlife prognosis in patients with nephrotic syndrome?
Recommendation grade: C1
We recommend that patients with nephrotic syndrome be given a fatrestricted diet for the treatment of dyslipidemia. It is not clear whether a fatrestricted diet improves the prognosis of nephrotic patients.
[Summary]
In patients with nephrotic syndrome, a fat-restricted diet consisting of lowcholesterol-containing food and vegetables/beans ameliorates dyslipidemia.
No study has proved that a fat-restricted diet improves the life prognosis ofthese patients.
2. [Dietary Instruction]
Salt restriction is essential for the alleviation of edema in nephrotic syndrome.
Some patients with nephrotic syndrome show inhibited plasma renin activity(PRA) and elevated atrial natriuretic peptide (ANP) level that are comparable
to the condition of salt accumulation described in the overfilling hypothesis.
The efficacy of strict protein restriction is controversial; therefore, extreme
protein restriction is not recommended in patients with nephrotic syndrome.
The published guideline from the Japanese Society of Nephrology,“Guidelines of lifestyle and diet therapy for patients with chronic kidneydisease,” recommends a protein intake of 1.0–1.1 g/kg body weight (BW)/dayin minimal change nephrotic syndrome and 0.8 g/kg BW/day in othernephrotic syndromes. To keep the nitrogen balance, a calorie intake of 35
kcal/kg BW/day is recommended.

3. [Treatment Interpretation and Treatment Algorithm]
We summarized the treatments by histological types. The treatment
strategies and the statements or answers of related clinical questions arecomprehensively described for each strategy. Concerning adjunctive andsupportive treatments or lifestyle and dietary instructions, some of thestatements or answers of related clinical questions are listed.
The treatments mentioned here referred to the previous Japanese guideline“Clinical guideline for refractory nephrotic syndrome 2002” and the second
revised version, “Clinical guideline for nephrotic syndrome 2011,” publishedby the Research Group on Progressive Renal Disease of the Ministry of Health,
Labor and Welfare. Additionally a novel idea is introduced in the treatment
strategies based on published papers.
Unfortunately, we could not endorse all of mentioned treatment strategies
and treatment algorithms through our clinical questions. We provided theclinical questions to a maximum extent for decision making.
Patients with nephrotic syndrome are aging; thus, they have many medical
complications. Treatment for these patients must be decided on a case-by-casebasis rather than strictly adFigurehering to the guidelines. For the selectionof agents, we provide the opinions of members of the guideline committee,
with reference to the previous two guidelines in Japan. We consider that wecannot use the same types or doses of agents as those recommended byarticles published overseas.
Use of treatment agents not allowed by medical insurance depends on thedecision established in 2013, when the present guideline is published. In the
future, this decision may change.
1) Minimal change nephrotic syndrome (MCNS)
1. Initial treatment
Oral prednisolone is administered at a single daily dose starting at 0.8–1
mgkg-1day-1 (maximum 60 mg/day), and continued for 1–2 weeks after
remission. Thus, the initial dose is maintained for 2–4 weeks. Tapering ofprednisolone is performed through the following program: a 5–10 mg dose
reduction every 2–4 weeks. After the prednisolone dose is reduced to 5–10
mg/day, the minimum dose must be continued for preventing relapse forapproximately 2 years, and then gradually tapered and discontinued.
Steroid pulse therapy should not be performed readily; however, it may beconsidered for cases in which absorption of steroid from the gastrointestinal
tract is doubted (Fig. 1)









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 theacute 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 patientsare 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 theadministration 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
Steroids are administered at equal or lower doses than the initial dose at therelapse of nephrotic syndrome.
As for steroid therapy for recurrent nephrotic syndrome, the opinions
differ as to whether the dose of treatment should the same as that of thefirst treatment or lower than that of the first treatment (CQ17).

3. Frequently relapsing, steroid-dependent, and steroid-resistant cases
Immunosuppressive agents such as cyclosporine (1.5–3.0 mgkg-1day-1),
cyclophosphamide (50–100 mg/day), or mizoribine (150 mg/day) areadministered in addition to steroid.
The efficacy of mizoribine has been confirmed in children but not in adults.
Therefore, the choice of mizoribine for adult patients is suggested here.
During treatment with immunosuppressive agents, the patient’s age andcomplications should be considered. Elderly patients easily develop
complications.










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 considereddepending 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 agentsfor reducing the urine protein level was reported to be similar to that inyounger 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 timeof description of this guideline in 2013)
The use of agents not covered by medical insurance in Japan, such as
rituximab, mycophenolate mofetil, and azathioprine, may be considered forpatients resistant to agents allowed by medical insurance. However, it is notclear whether these agents are effective for reducing the urinary protein leveland preventing the decline of renal function in nephrotic syndrome. For
patients with frequently relapsing or steroid-resistant nephrotic syndrome,
we suggest that these agents may be effective for reducing the urinary protein
level and preventing the decline of renal function (CQ19, CQ20, CQ21).

2) Focal segmental glomerulosclerosis (FSGS)
1. Initial treatment
Oral prednisolone is administered at a single daily dose starting at 0.8–1
mgkg-1day-1 (maximum 60 mg/day) for 2–4 weeks as the initial treatment.
Steroid pulse therapy is considered for cases with massive urine protein
excretion or severe systemic edema. After remission, tapering of steroid doseis performed following the program of MCNS (Fig.2).
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 notreceiving 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 inpreventing 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 inobservational 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 thetreatment of elderly patients with nephrotic syndrome. The selection ofsteroid treatment or combination treatment with steroid andimmunosuppressive 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, 2.0–3.0 mgkg-1day-1, isselected for relapsing and frequently relapsing cases.

The combination of oral steroid and cyclosporine is selected for patientswith relapsing and frequently relapsing FSGS instead of steroid-alone
treatment (CQ5, CQ17, CQ22).

3. Steroid-dependent and steroid-resistant cases
If steroid-alone treatment for >4 weeks fails to attain complete or incomplete
remission, cyclosporine, 2.0–3.0 mgkg-1day-1, is added to steroid therapy.
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 thetreatment of elderly patients with nephrotic syndrome. The selection ofsteroid treatment or combination treatment with steroid andimmunosuppressive 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 timeof description of this guideline in 2013)
The use of agents not covered by medical insurance in Japan, such as
rituximab, mycophenolate mofetil, and azathioprine, may be considered forpatients resistant to agents covered by medical insurance. However, it is notclear whether these agents are effective for reducing the urinary protein leveland preventing the decline of renal function in nephrotic syndrome. In casesof frequently relapsing or steroid-resistant nephrotic syndrome, we suggestthat these agents may be effective for reducing the urinary protein level andpreventing the decline of renal function (CQ19, CQ20, CQ21).
3) Membranous nephropathy (MN)

1. Initial treatment
Oral prednisolone is administered at a single daily dose starting at 0.6–0.8
mgkg-1day-1 and continued for 4 weeks. Instead of oral steroid alone,
prednisolone and cyclophosphamide are administered as a starting dose of
50–100 mg/day. Lower-dose oral steroid and cyclosporine as the initial
treatment is considered for patients who are concerned about the adverse
effects of steroids, such as diabetic patients (Fig.3).
In some patients with MN with nephrotic syndrome, we suggest that notreatment or supportive treatment alone without immunosuppressive
agents may reduce the urinary protein level. However, we cannot expectthat no treatment or supportive treatment alone is effective forpreventing 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 treatmentgroups (steroid alone, steroid and cyclophosphamide, and supportive
treatment); however, treatment with steroid alone and the combination ofsteroid and cyclophosphamide showed significant effectiveness inpreventing the decline of renal function when compared with supportive
treatment (CQ8).
In steroid-resistant MN, we recommend the combination of steroid andcyclosporine for reducing the urinary protein level and preventing thedecline of renal function (CQ9).
Between steroid with cyclosporine and steroid with alkylating agents, thesuperiority of the treatment with steroid with cyclosporine has not beenrecognized (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 theadverse 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 inobservational 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 thetreatment of elderly patients with nephrotic syndrome. The selection ofsteroid treatment or combination treatment with steroid andimmunosuppressive agents should be determined on the basis of the age
or complications of patients (CQ22).

2. Steroid-resistant cases
If steroid-alone treatment for >4 weeks fails to attain complete or incomplete
remission, cyclosporine (2.0 – 3.0 mg/kg/day), mizoribine (150 mg/day), or
cyclophosphamide (50–100 mg/day) is added to steroid therapy.
In steroid-resistant MN, we recommend the combination of steroid andcyclosporine for reducing the urinary protein level and preventing thedecline of renal function (CQ9).

In steroid-resistant or refractory MN, we suggest that the addition ofmizoribine 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 Japanesepatients, 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 thatconservative treatment with RAS inhibitors, lipid-lowering agents, or
antiplatelet agents is effective for reducing the urinary protein level insome cases. (CQ12).



However, it is not clear whether those conservative treatments are
effective for preventing the decline of renal function (CQ12).

4) 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 insome patients with MPGN (CQ13).

5) 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 withnephrotic 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 inpatients with nephrotic syndrome and may exacerbate hypertension;
therefore, it is not recommended for this condition. However, in cases ofsevere 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 theireffectiveness in reducing the urinary protein level is not clear. We suggestthat 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 reducethe 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 cholesterollevels, 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 theremoval of body fluids in refractory edema and ascites that are difficult tocontrol using drug-based therapy (CQ30).

9. Trimethoprim-sulfamethoxazole combination

In patients with nephrotic syndrome, we recommend treatment with thetrimethoprim-sulfamethoxazole
combinationforpreventing
pneumocystis pneumonia during immunosuppressive therapy (CQ31).

10. Immunoglobulin supplyIn nephrotic syndrome, we suggest supplying immunoglobulin to patientswith 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).

6) Lifestyle and dietary instruction
1. Screening for cancer

The incidence of cancer in patients with membranous nephropathy is nothigher in Japan than in Europe and the United States. However, it isunclear 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 patientswith 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 ofinfection to patients with nephrotic syndrome (CQ37).

4. Steroid-induced femoral head necrosis (FHN)

No study has investigated the preventive measures against FHN inpatients with nephrotic syndrome. The use of only the essential dose ofsteroid may prevent the development of steroid-induced FHN (CQ38).

5. Avoidance of mental stressIn steroid-dependent and/or frequently relapsing nephrotic syndrome inchildren, 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 forpreventing the relapse of nephrotic syndrome in adults (CQ39).

6. Fat-restricted diet

We recommend providing fat-restricted diet for the treatment ofdyslipidemia in patients with nephrotic syndrome. It is not clear whether
a fat-restricted diet improves the prognosis of nephrotic patients (CQ40).

Reference
I. Disease entity・Definition(Pathogenesis)

1. Russo LM, et al. The normal kidney filters nephrotic levels of albumin
retrieved by proximal tubule cells：retrieval is disrupted in nephrotic states.
Kidney Int 2007；71：504—13.
II. Diagnosis
1. Symptomatology・Clinical manifestation
1. Abdel—Hafez M, et al. Idiopathic nephrotic syndrome and atopy：Is there
a common link? Am J Kidney Dis 2009；54：945—53.
2. Yokoyama H, et al ； On the behalf of the Committee for theStandardization of Renal Pathological Diagnosis and for Renal Biopsy andDisease Registry in the Japanese Society of Nephrology. Membranous
nephropathy in Japan：analysis of the Japan Renal Biopsy Registry（J—RBR）. Clin Exp Nephrol 2012；16：557—63.
3. Andoh D, et al. Loss of nocturnal decline of blood pressure in non—diabetic patients with nephrotic syndrome in the early and middle stagesof chronic kidney disease. Hypertens Res 2009；32：364—8.
4. Mahmoodi BK, et al. High absolute risks and predictors of venous andarterial thromboembolic events in patients with nephrotic syndrome ：results from a large retrospective cohort study. Circulation 2008；117：224—
30.
5. Witz M, et al. Renal vein occlusion：diagnosis and treatment. Isr Med
Assoc J 9：402—5, 2007.
6. Glassock RJ. Attending rounds ： an older patient with nephrotic
syndrome. Clin J Am Soc Nephrol 2012；7：665—70.
2. Laboratory findings
1. Ginsberg JM, et al. Use of single voided urine samples to estimate
quantitative proteinuria. N Engl J Med 1983；309：1543—6.
2. Bazzi C, et al. A modern approach to selectivity of proteinuria andtubulointerstitial damage in nephrotic syndrome.Kidney Int 2000；58：
1732—41.
3. Vaziri ND ： Molecular mechanisms of lipid disorders in nephrotic
syndrome. Kidney Int 2003；63：1964—76.

4. Joven J, et al. Abnormalities of lipoprotein metabolism in patients with
the nephrotic syndrome. N Engl J Med 1990；323：579—84.
5. Kerlin BA, et al. Epidemiology and pathophysiology of nephrotic
syndrome — associated thromboembolic disease. Clin J Am Soc Nephrol
2012；7：513—20.
6. Rabelink TJ, et al. Thrombosis and hemostasis in renal disease. Kidney
Int 1994；46：287—96.
7. Singhal R, et al. Thromboembolic complications in the nephrotic
syndrome：pathophysiology and clinical management. Thromb Res 2006；
118：397—407.
8. Mahmoodi BK, et al. High absolute risks and predictors of venous andarterial thromboembolic events in patients with nephrotic syndrome ：results from a large retrospective cohort study. Circulation 2008；117：224—30.
9. Bates SM, et al. Antithrombotic Therapy and Prevention of Thrombosis,
9th ed：American College of Chest Physicians Evidence—Based Clinical
Practice Guidelines. Chest 2012；141：e351S—418S.
10. Wells PS, et al. Value of assessment of pretest probability of deep—vein
thrombosis in clinical management. Lancet 1997；350：1795—8.
11. Ogi M, et al. Risk factors for infection and immunoglobulin replacement
therapy in adult nephrotic syndrome. Am J Kidney Dis 1994；24：427—36.
III. Epidemiology・Prognosis
1. Incidence・Prevalence・Recurrence rate
1. Yokoyama H, et al；the Committee for the Standardization of Renal
Pathological Diagnosis and for Renal Biopsy and Disease Registry in theJapanese Society of Nephrology. Membranous nephropathy in Japan ：analysis of the Japan Renal Biopsy Registry（J—RBR）. Clin Exp Nephrol
2012；16：557—63.
2. Fujimoto S, et al. Minimal change nephrotic syndrome in adults ：response to corticosteroid therapy and frequency of relapse. Am J Kidney
Dis 1991；17：687—92.
3. Yokoyama H, et al；the Committee for the Standardization of Renal
Pathological Diagnosis and for Renal Biopsy and Disease Registry of theJapanese Society of Nephrology, and the Progressive Renal Disease
Research of the Ministry of Health, Labour and Welfare of Japan. Renaldisease in the elderly and the very elderly Japanese：analysis of the Japan
Renal Biopsy Registry（J—RBR）. Clin Exp Nephrol 2012；16：903—20.
4. Takei T, et al. The characteristics of relapse in adult—onset minimal—change nephrotic syndrome. Clin Exp Nephrol 2007；11：214—7.
5. Nakayama M, et al. Steroid responsiveness and frequency of relapse in
adult—onset minimal change nephrotic syndrome. Am J Kidney Dis 2002；
39：503—12.
6. Ponticelli C, et al. Posttransplant recurrence ofglomerulonephritis. Clin J Am Soc Nephrol 2010；5：2363—72.

primary

7. Cattran DC, et al. A randomized trial of cyclosporine in patients withsteroid — resistant focal segmental glomerulosclerosis. North America
Nephrotic Syndrome Study Group. Kidney Int 1999；56：2220—6.
8. Waldman M, et al. Controversies in the treatment of idiopathic
membranous nephropathy. Nat Rev Nephrol 2009；5：469—79.
9. Kalliakmani P, et al. Benefit and cost from the long — term use of
cyclosporine — A in idiopathic membranous nephropathy. Nephrology（Carlton） 2010；15：762—7.
2. Remission rate・Nonresponsive rate・Renal prognosis
1. Fujimoto S, et al. Minimal change nephrotic syndrome in adults ：response to corticosteroid therapy and frequency of relapse. Am J Kidney
Dis 1991；17：687—92.
2. Nakayama M, et al. Steroid responsiveness and frequency of relapse in
adult—onset minimal change nephrotic syndrome. Am J Kidney Dis 2002；
39：503—12.
3. Tse KC, et al. Idiopathic minimal change nephrotic syndrome in older
adults ： steroid responsiveness and pattern of relapses. Nephrol Dial
Transplant 2003；18：1316—20.
4. Imbasciati E, et al. Controlled trial of methylprednisolone pulses andlow dose oral prednisone for the minimal change nephrotic syndrome. Br
Med J（Clin Res Ed）1985；291：1305—8.
5. Takei T, et al. The characteristics of relapse in adult—onset minimal—change nephrotic syndrome. Clin Exp Nephrol 2007；11：214—7.
6. Matsumoto H, et al. Favorable outcome of low—dose cyclosporine after
pulse methylprednisolone in Japanese adult minimal—change nephrotic
syndrome. Intern Med 2004；43：668—73.

7. Lee HY, et al. The efficacy of cyclosporine A in adult nephrotic syndrome
with minimal change disease and focal—segmental glomerulosclerosis：amulticenter study in
Korea. Clin Nephrol 1995；43：375—81.
8. Shibasaki T, et al. A randomized open — label comparative study of
conventional therapy versus mizoribine onlay therapy in patients withsteroid—resistant nephrotic syndrome（postmarketing survey）. Clin Exp
Nephrol 2004；8：117—26.
9. Fujinaga S, et al. Single daily high—dose mizoribine therapy for children
with steroid — dependent nephrotic syndrome prior to cyclosporine
administration. Pediatr Nephrol 2011；26：479—83.
10. Muso E, et al. Low density lipoprotein apheresis therapy for steroid—
resistant nephrotic syndrome. Kansai—FGS—Apheresis Treatment （K—FLAT）Study Group. Kidney Int Suppl 1999；71：S122—5.
11. Matalon A, et al. Treatment of focal segmental glomerulosclerosis.
Semin Nephrol 2000；20：309—17.
12. Korbet SM. Treatment of primary focal segmental glomerulosclerosis.
Kidney Int 2002；62：2301—10.
13. Kirpekar R, et al. Clinicopathologic correlates predict the outcome inchildren with steroid—resistant idiopathic nephrotic syndrome treated withpulse methylprednisolone therapy. Am J Kidney Dis 2002；39：1143—52.
14. Chang JW, et al. Low — dose methylprednisolone pulse therapy in
Chinese children with steroid resistant focal segmental glomerulosclerosis.
Pediatr Int 2007；49：349—54.
15. Pena A, et al. Steroid — resistant nephrotic syndrome ： long — term
evolution after sequential therapy. Pediatr Nephrol 2007；22：1875—80.
16. Meyrier AY. Treatment of focal segmental glomerulosclerosis withimmunophilin modulation：when did we stop thinking about pathogenesis?
Kidney Int 2009；76：487—91.
17. Meyrier A. An update on the treatment options for focal segmental
glomerulosclerosis. Expert Opin Pharmacother 2009；10：615—28.
18. Tojo K, et al. Possible therapeutic application of low density lipoprotein
apheresis（LDL—A） in conjunction with double filtration plasmapheresis（DFPP）in drug - resistant nephrotic syndrome due to focal glomerularsclerosis（FGS）. Jpn J Nephrol 1988；30：1153-60.

19. Hattori M, et al. A combined low - density lipoprotein apheresis andprednisone therapy for steroid—resistant primary focal segmental
glomerulosclerosis in children. Am J Kidney Dis 2003；42：1121-30.
20. Muso E, et al. Beneficial effect of low - density lipoprotein apheresis（ LDL-A ） on refractory nephrotic syndrome （ NS ） due to focal
glomerulosclerosis（FGS）. Clin Nephrol 2007；67：341-4.
21. Shiiki H, et al. Prognosis and risk factors for idiopathic membranous
nephropathy with nephrotic syndrome in Japan. Kidney Int 2004；65：
1400-7.
22. Kida H, et al. Long - term prognosis of membranous nephropathy. Clin
Nephrol 1986；25：64-9.
23. Troyanov S, et al. Idiopathic membranous nephropathy：definition andrelevance of a partial remission. Kidney Int 2004；66：1199-205.
24. Bazzi C, et al. A modern approach to selectivity of proteinuria andtubulointerstitial damage in nephrotic syndrome. Kidney Int 2000；58：
1732-41.
25. Schieppati A, et al. Prognosis of untreated patients with idiopathic
membranous nephropathy. N Engl J Med 1993；329：85-9.
26. Cattran DC, et al. Cyclosporin in idiopathic glomerular diseaseassociated with the nephrotic syndrome ： workshop recommendations.
Kidney Int 2007；72：1429-47.
27. Neary JJ, et al. Linkage of a gene causing familial
membranoproliferative glomerulonephritis type Ⅲ to chromosome 1. J
Am Soc Nephrol 2002；13：2052—7.
28. Smith RJ, et al. New approaches to the treatment of dense deposit
disease. J Am Soc Nephrol 2007；18：2447—56.
29. Little MA, et al. Severity of primary MPGN, rather than MPGN type,determines renal survival and post — transplantation recurrence risk.
Kidney Int 2006；69：504—11.
30. Cameron JS, et al. Idiopathic mesangiocapillary glomerulonephritis.
Comparison of types Ⅰ and Ⅱ in children and adults and long —term
prognosis. Am J Med 1983；74：175—92.
31. Zäuner I, et al. Effect of aspirin and dipyridamole on proteinuria in
idiopathic membranoproliferative glomerulonephritis ： a multicentre
prospective clinical trial. Collaborative Glomerulonephritis Therapy Study
Group（CGTS）. Nephrol Dial Transplant 1994；9：619—22.

32. Jones G, et al. Treatment of idiopathic membranoproliferative
glomerulonephritis with mycophenolate mofetil and steroids. Nephrol Dial
Transplant 2004；19：3160—4.
33. Waldman M, et al. Adult minimal — change disease ： clinicalcharacteristics, treatment, and outcomes. Clin J Am Soc Nephrol 2007；2：
445—53.
34. Mak SK, et al. Long—term outcome of adult—onset minimal—change
nephropathy. Nephrol Dial Transplant 1996；11：2192—201.
35. Bohle A, et al. The long — term prognosis of the primary
glomerulonephritides. A morphological and clinical analysis of 1747 cases.
Pathol Res Pract 1992；188：908—24.
36. Takeda Y, et al. Two cases of nephrotic syndrome（NS）— induced acutekidney injury（AKI）associated with renal hypouricemia. Clin Nephrol
2011；76：78—82.
37. Chen CL, et al. Increased endothelin 1 expression in adult — onset
minimal change nephropathy with acute renal failure. Am J Kidney Dis
2005；45：818—25.
38. Ehrich JH, et al. Long versus standard prednisone therapy for initial
treatmentofidiopathic
nephrotic
syndromeinchildren.
Arbeitsgemeinschaft für Pädiatrische Nephrologie. Eur J Pediatr 1993；
152：357—61.
39. Thomas DB, et al. Clinical and pathologic characteristics of focal
segmental glomerulosclerosis pathologic variants. Kidney Int 2006；69：
920—6.
3. Incidence of complication
1. Ordoñez JD, et al. The increased risk of coronary heart diseaseassociated with nephrotic syndrome. Kidney Int 1993；44：638—42.
2. Lechner BL, et al. The risk of cardiovascular disease in adults who
have had childhood nephrotic syndrome. Pediatr Nephrol 2004；19：744—
8.
3. Ogi M, et al. Risk factors for infection and immunoglobulin replacement
therapy in adult nephrotic syndrome. Am J Kidney Dis 1994；24：427—36.
4. Wu HM, et al. Interventions for preventing infection in nephrotic
syndrome. Cochrane Database Syst Rev 2012；4：CD003964.
5. Uncu N, et al. Primary peritonitis in children with nephrotic syndrome：
results of a 5—year multicenter study. Eur J Pediatr 2010；169：73—6.

6. Citak A, et al. Hemostatic problems and thromboembolic complications
in nephrotic children. Pediatr Nephrol 2000；14：138—42.
7. Kayali F, et al. Venous thromboembolism in patients hospitalized withnephrotic syndrome. Am J Med 2008；121：226—30.
8. Mahmoodi BK, et al. High absolute risks and predictors of venous andarterial thromboembolic events in patients with nephrotic syndrome：
results from a large retrospective cohort study. Circulation 2008；117：224—30.
9. Lionaki S, et al. Venous thromboembolism in patients with membranous
nephropathy. Clin J Am Soc Nephrol 2012；7：43—51.
10. Kerlin BA, et al. Epidemiology and risk factors for thromboembolic
complications of childhood nephrotic syndrome ： a Midwest Pediatric
Nephrology Consortium（MWPNC） study. J Pediatr 2009；155：105—10.
11. Kerlin BA, et al. Epidemiology and pathophysiology of nephrotic
syndrome—associated thromboembolic disease. Clin J Am Soc Nephrol
2009；7：513—20.
12 Singhal R, et al. Thromboembolic complications in the nephrotic
syndrome：pathophysiology and clinical management. Thromb Res 2006；
118：397—407.
13. Cherng SC, et al. The role of lung scintigraphy in the diagnosis ofnephrotic syndrome with pulmonary embolism. Clin Nucl Med 2000；25：
167—72.
14. Burstein DM, et al. Membranous glomerulonephritis and malignancy.
Am J Kidney Dis 1993；22：5—10.
15. Lefaucheur C, et al. Membranous nephropathy and cancer ：Epidemiologic evidence and determinants of high—risk cancer association.
Kidney Int 2006；70：1510—7.
16. Bjorneklett R, et al. Long—term risk of cancer in membranous
nephropathy patients. Am J Kidney Dis 2007；50：396—03.
17. Zeng CH, et al. Etiology and clinical characteristics of membranous
nephropathy in Chinese patients. Am J Kidney Dis 2008；52：691—8.
18. Yokoyama H, et al. Membranous nephropathy in Japan：Analysis of theJapan Renal Biopsy Registry（J—RBR）. Clin Exp Nephrol 2012；16：557—
63.
19. Smith JD, et al. Reversible renal failure in the nephrotic syndrome. Am
J Kidney Dis 1992；19：201—13.

IV. Treatment
1. Clinical questions for treatment
1) Minimal change nephrotic

syndrome ・Focal

segmental

glomerulosclerosis
CQ 1. Is oral steroid recommended for reducing urinary protein level andpreventing the decline of renal function in minimal change nephrotic
syndrome?
1. Gipson DS, et al. Pediatrics 2009；124：747—57. (Level 2)
2. Hodson EM, et al. Cochrane Database Syst Rev 2007：CD001533 (Level
2)
3. Black DA, et al. Br Med J 1970；3：421—6. (Level 2)
4. Coggins CH. Trans Am Clin Climatol Assoc 1986；97：18—26. (Level 2)
5. Mak SK, et al. Nephrol Dial Transplant 1996；11：2192—201. (Level 4)
6. Tse KC, et al. Nephrol Dial Transplant 2003；18：1316—20. (Level 4)
7. Palmer SC, et al. Cochrane Database Syst Rev 2008：CD001537 (Level2)
8. Fujimoto S, et al. Am J Kidney Dis 1991；17：687—92. (Level 4)
9. Nakayama M, et al. Am J Kidney Dis 2002；39：503—12. (Level 4)
10. Nolasco F, et al. Kidney Int 1986；29：1215—23. (Level 4)
11. Al—Khader AA, et al. Clinical Nephrology 1979；11：26—30. (Level 4)
12. Imbasciati E, et al. Br Med J 1985；291：1305—8. (Level 2)
13. Fukudome K, et al. Nephrology 2012；17：263—8. (Level 4)
14. Tojo S, et al. Kidney and Dialysis. 1994；36：1053—64. (Level 2)
15. Nagasawa K, et al. Lupus 2005；14：385—90. (Level 3)
CQ 2 . Is cyclosporine recommended for reducing urinary protein level andpreventing the decline of renal function in minimal change nephrotic
syndrome?
1. Hodson EM, et al. Cochrane Database Syst Rev 2010：CD003594 (Level
2)
2. Durkan AM, et al. Kidney Int 2001；59：1919—27. (Level 1)
3. Ponticelli C, et al. Nephrol Dial Transplant 1993；8：1326—32. (Level 2)
4. Niaudet P. Pediatr Nephrol 1992；6：1—3. (Level 2)
5. Ishikura K, et al. Kidney Int 2008；73：1167—73. (Level 2)
6. Eguchi A, et al. Nephrol Dial Transplant 2010；25：124—9. (Level 2)

CQ 3. Is steroid therapy recommended for reducing urinary protein andpreventing the decline of renal function in focal segmental
glomerulosclerosis?
1. Troyanov S, et al. J Am Soc Nephrol 2005；16：1061—8. (Level 4)
2. Goumenos DS, et al. Nephron Clin Pract 2006；104：c75—82. (Level 4)
3. Pei Y, et al. Am J Med 1987；82：938—44. (Level 4)
4. Stirling CM, et al. QJM 2005；98：443—9. (Level 4)
5. Korbet SM, et al. Am J Kidney Dis 1994；23：773—83. (Level 2)
6. Banfi G, et al. Clin Nephrol 1991；36：53—9. (Level 4)
7. Cattran DC, et al. Am J Kidney Dis 1998；32：72—9. (Level 4)
8. Rydel JJ, et al. Am J Kidney Dis 1995；25：534—42. (Level 4)
9. Hari P, et al. Pediatr Nephrol 2001；16：901—5. (Level 4)
10. Kirpekar R, et al. Am J Kidney Dis 2002；39：1143—52. (Level 4)
11. Chang JW, et al. Pediatr Int 2007；49：349—54. (Level 4)
12. Pena A, et al. Pediatr Nephrol 2007；22：1875—80. (Level 4)
13. Tune BM, et al. J Am Soc Nephrol 1997；8：824—32. (Level 4)
CQ 4. Is cyclosporine recommended for reducing urinary protein level andpreventing the decline of renal function in focal segmental
glomerulosclerosis?
1. Hodson EM, et al. Cochrane Database Syst Rev 2010（11）：CD003594(Level 1)
2. Durkan AM, et al. Kidney Int 2001；59：1919—27. (Level 1)
3. Ponticelli C, et al. Nephrol Dial Transplant 1993；8：1326—32. (Level 2)
4. Niaudet P, et al. Pediatr Nephrol 1992；6：1—3. (Level 2)
5. Ishikura K, et al. Kidney Int 2008；73：1167—73. (Level 2)
6. Ponticelli C, et al. Kidney Int 1993；43：1377—84. (Level 2)
7. Cattran DC, et al. Kidney Int 1999；56：2220—6. (Level 2)
8. Eguchi A, et al. Nephrol Dial Transplant 2010；25：124—9. (Level 2)
9. Braun N, et al. Cochrane Database Syst Rev 2008 (3)：CD003233 (Level
1)
10. Heering P, et al. Am J Kidney Dis 2004；43：10—8. (Level 2)
CQ 5. Is the addition of immunosuppressive agents recommended for
reducing urinary protein level or preventing the decline of renal function infrequently relapsing nephrotic syndrome?
1. Ponticelli C, et al. Nephrol Dial Transplant 1993；8：1326—32. (Level 2)
2. Mak SK, et al. Nephrol Dial Transplant 1996；11：2192—201. (Level 4)
3. Nolasco F, et al. Kidney Int 1986；29：1215—23. (Level 4)
4. Yoshioka K, et al. Kidney Int 2000；58：317—24. (Level 2)
5. Fujieda M, et al. Clin Nephrol 2008；69：179—84. (Level 5)
6. Doi T, et al. Clin Nephrol 2008；69：433—5. (Level 5)
CQ 6. Are immunosuppressive agents administered in conjunction withsteroids recommended for reducing urinary protein and preventing thedecline of renal function in steroid-resistant focal segmental
glomerulosclerosis?
1. Braun N, et al. Cochrane Database Syst Rev 2008(3): CD003233 (Level
1)
2. Cattran DC, et al. Kidney Int 1999；56：2220—6. (Level 2)
3. Heering P, et al. Am J Kidney Dis 2004；43：10—8. (Level 2)
4. Gipson DS, et al. Kidney Int 2011；80：868—78. (Level 2)2) Membranous nephropathy
CQ 7. Is no treatment or supportive treatment alone without
immunosuppressive agents recommended for reducing urinary protein leveland preventing the decline of renal function in membranous nephropathy
with nephrotic syndrome?
1. Polanco N, et al. J Am Soc Nephrol 2010；21：697—704. (Level 4)
2. Gansevoort RT, et al. Nephrol Dial Transplant 1992；7（Suppl 1）：91—
6. (Level 3)
3. Praga M, et al. Am J Kidney Dis 1992；20：240—8. (Level 5)
4. Shiiki H, et al. Kidney Int 2004；65：1400—7. (Level 4)
CQ 8. Is steroid-alone treatment recommended for reducing urinary protein
level and preventing the decline of renal function in membranous
nephropathy?
1. Coggins CH, et al. N Engl J Med 1979；301：1301—6. (Level 2)
2. Cattran DC, et al. N Engl J Med 1989；320：210—5. (Level 2)
3. Cameron JS, et al. QJM 1990；74：133—56. (Level 2)
4. Shiiki H, et al. Kidney Int 2004；65：1400—7. (Level 4)

5. Ponticelli C, et al. N Engl J Med 1992；327：599—603. (Level 2)
6. Pahari DK, et al. J Assoc Physicians India 1993；41：350—1. (Level 3)
7. Cattran DC, et al. Kidney Int 2001；59：1484—90. (Level 2)
CQ 9. Is cyclosporine recommended for reducing urinary protein level andpreventing the decline of renal function in membranous nephropathy?
1. Schieppati A, et al. Cochrane Database Syst Rev 2004（4）：CD004293(Level 2)
2. Perna A, et al. Am J Kidney Dis 2004；44：385—401. (Level 1)
3. Cattran DC, et al. Kidney Int 2001；59：1484—90. (Level 2)
4. Alexopoulos E, et al. Nephrol Dial Transplant 2006；21：3127—32. (Level
4)
5. Naumovic R, et al. Biomed Pharmacother 2011；65：105—10. (Level 2)
6. Satio T, et al. Clin Exp Nephrol, in press (Level 2)
CQ 10. Is mizoribine recommended for reducing urinary protein level andpreventing the decline of renal function in membranous nephropathy?
1. Shibasaki T, et al. Clin Exp Nephrol 2004；8：117—26. (Level 3)
CQ 11. Are alkylating agents recommended for reducing urinary protein
level and preventing the decline of renal function in membranous
nephropathy?
1. Schieppati A, et al. Cochrane Database Syst Rev 2004（4）：CD004293(Level 2)
2. Perna A, et al. Am J Kidney Dis 2004；44：385—401. (Level 1)
3. Ponticelli C, et al. N Engl J Med 1992；327：599—603. (Level 2)
4. Falk RJ, et al. Ann Intern Med 1992；116：438—45. (Level 2)
5. Shiiki H, et al. Kidney Int 2004；65：1400—7. (Level 4)
6. Hofstra JM, et al. Nephrol Dial Transplant 2008；23：3534—8. (Level 4)
7. Naumovic R, et al. Biomed Pharmacother 2010；64：633—8. (Level 4)
8. Eriguchi M, et al. Nephrol Dial Transplant 2009；24：3082—8. (Level 1)
9. Bizzarri D, et al. Contrib Nephrol 1993；105：65—70. (Level 4)
10. Branten AJ, et al. Am J Kidney Dis 2007；50：248—56. (Level 3)
11. Ponticelli C, et al. J Am Soc Nephrol 1998；9：444—50. (Level 2)
CQ 12. Are conservative treatments recommended for reducing urinaryprotein level and preventing the decline of renal function in membranous
nephropathy showing a non-nephrotic range of proteinuria?
1. Hladunewich MA, et al. Clin J Am Soc Nephrol 2009；4：1417—22. (Level
4)3) Membranoproliferative glomerulonephritis
CQ 13. Is steroid treatment recommended for reducing urinary protein
level and preventing the decline of renal function in idiopathic
membranoproliferative glomerulonephritis showing nephrotic syndrome?
1. Tarshish P, et al. Pediatr Nephrol 1992；6：123—30. (Level 2)
2. McEnery PT. J Pediatr 1990；116：S109—14. (Level 4)
3. Warady BA, et al. J Pediatr 1985；107：702—7. (Level 4)
4. Emre S, et al. Acta Paediatr Jpn 1995；37：626—9. (Level 4)
5. Bergstein JM, et al. Pediatr Nephrol 1995；9：268—71. (Level 4)
6. Ford DM, et al. Kidney Int 1992；41：1606—12. (Level 4)
7. Donadio JV Jr, et al. Am J Kidney Dis 1989；14：445—51. (Level 5)4) Steroid treatment
CQ 14. Is oral steroid treatment recommended during intervals between
steroid pulse treatments (i.e., at days when no steroid pulse treatment isgiven)?
CQ 15. Is the increase of oral steroid doses or the change of administrationroutes recommended for patients with systemic edema?
1. Frey FJ, et al. Am J Kidney Dis 1984；3：339—48. (Level 4)
2. Bergrem H. Kidney Int 1983；23：876—81. (Level 4)
CQ 16. Is alternate-day administration as a means of steroid dose reduction
effective for inhibiting the incidence of adverse effects?
1. Mak SK, et al. Nephrol Dial Transplant 1996；11：2192—201. (Level 4)
2. Waldman M, et al. Clin J Am Soc Nephrol 2007；2：445—53. (Level 4)
3. Carter ME, et al. Ann Rheum Dis 1972；31：379—83. (Level 4)
4. Kimura Y, et al. J Rheumatol 2000；27：2018—24. (Level 4)
5. Byron MA, et al. J R Soc Med 1983；76：452—7. (Level 4)
CQ 17. Is reducing the steroid dose compared with that of the firsttreatment recommended for the treatment of recurrent nephrotic syndrome?
1. Fujimoto S, et al. Am J Kidney Dis 1991；17：687—92. (Level 4)
2. Nakayama M, et al. Am J Kidney Dis 2002；39：503—12. (Level 4)
3. Takei T, et al. Clin Exp Nephrol 2007；11：214—7. (Level 4)
4. Imbasciati E, et al. Br Med J 1985；291：1305—8. (Level 2)
CQ 18. Is there a standard period for steroid maintenance therapy after
nephrotic syndrome has remitted?
1. Huang JJ, et al. Am J Nephrol 2001；21：28—34. (Level 4)
2. Mak SK, et al. Nephrol Dial Transplant 1996；11：2192—201. (Level 4)
3. Waldman M, et al. Clin J Am Soc Nephrol 2007；2：445—53. (Level 4)
4. Korbet SM, et al. Am J Kidney Dis 1994；23：773—83. (Level 2)
5. Banfi G, et al. Clin Nephrol 1991；36：53—9. (Level 4)
6. Cattran DC, et al. Am J Kidney Dis 1998；32：72—9. (Level 4)
7. Rydel JJ, et al. Am J Kidney Dis 1995；25：534—42. (Level 4)
8. Tarshish P, et al. Pediatr Nephrol 1992；6：123—30. (Level 2)
9. McEnery PT. J Pediatr 1990；116：S109—14. (Level 4)
10. Warady BA, et al. J Pediatr 1985；107：702—7. (Level 4)
11. Bergstein JM, et al. Pediatr Nephrol 1995；9：268—71. (Level 4)5) Immunosuppressive agents not allowed by medical insurance (at the timeof description of this guideline in 2013)
CQ 19. Is rituximab recommended for reducing urinary protein level andpreventing the decline of renal function in nephrotic syndrome?
1. Sugiura H, et al. Nephron Clin Pract 2011；117：c98—105. (Level 5)
2. Fernandez—Fresnedo G, et al. Clin J Am Soc Nephrol 2009；4：1317—23.
(Level 4)
3. Ravani P, et al. Clin J Am Soc Nephrol 2011；6：1308—15. (Level 2)
4. Bomback AS, et al. Clin J Am Soc Nephrol 2009；4：734—44. (Level 5)
5. Segarra A, et al. Clin J Am Soc Nephrol 2009；4：1083—8. (Level 5)
6. Fervenza FC, et al. Clin J Am Soc Nephrol 2010；5：2188—98. (Level 5)
CQ 20. Is mycophenolate mofetil recommended for reducing urinary protein
level and preventing the decline of renal function in nephrotic syndrome?
1. Lee YH, et al. Lupus 2010；19：703—10. (Level 2)
2. Zhu B, et al. Nephrol Dial Transplant 2007；22：1933—42. (Level 1)

3. Dorresteijn EM, et al. Pediatr Nephrol 2008；23：2013—20. (Level 2)
4. Ito S, et al. Pediatr Nephrol 2011；26：1823—8. (Level 3)
5. Senthil Nayagam L, et al. Nephrol Dial Transplant 2008；23：1926—30.
(Level 2)
6. Dussol B, et al. Am J Kidney Dis 2008；52：699—705. (Level 2)
7. Branten AJ, et al. Am J Kidney Dis 2007；50：248—56. (Level 3)
8. Chan TM, et al. Nephrology（Carlton） 2007；12：576—81. (Level 2)
CQ 21. Is azathioprine recommended for reducing urinary protein level andpreventing the decline of renal function in nephrotic syndrome?
1. Sharpstone P, et al. Br Med J 1969；2：535—9. (Level 2)
2. Cade R, et al. Arch Intern Med 1986；146：737—41. (Level 4)
3. Hiraoka M, et al. Pediatr Nephrol 2000；14：776—8. (Level 5)
4. Goumenos DS, et al. Nephron Clin Pract 2006；104：c75—82. (Level 4)
5. Abramowicz M, et al. Lancet 1970；（1 7654）：959—61. (Level 2)
6. Adeniyi A, et al. Arch Dis Child 1979；54：204—7. (Level 2)
7. Habashy D, et al. Pediatr Nephrol 2003；18：906—12. (Level 2)
8. Colquitt JL, et al. Health Technol Assess 2007；11：iii—iv, ix—xi, 1—93.
(Level 2)
9. Western Canadian Glomerulonephritis Study Group, et al. Can Med
Assoc J 1976；115：1209—10. (Level 2)
10. Ahuja M, et al. Am J Kidney Dis 1999；34：521—9. (Level 2)
11. Goumenos DS, et al. Clin Nephrol 2006；65：317—23. (Level 3)
12. Brown JH, et al. Nephrol Dial Transplant 1998；13：443—8. (Level 4)
13. Williams PS, et al. Nephrol Dial Transplant 1989；4：181—6. (Level 4)
14. Naumovic R, et al. Biomed Pharmacother 2011；65：105—10. (Level 2)6) Nephrotic syndrome in the elderly
CQ 22. Are immunosuppressive agents recommended for elderly patientswith nephrotic syndrome?
1. Deegens JK, et al. Drugs Aging 2007；24：717—32. (Level 5)
2. Passerini P, et al. Nephrol Dial Transplant 1993；8：1321—5. (Level 3)
3. Bizzarri D, et al. Contrib Nephrol 1993；105：65—70. (Level 5)
4. Nolasco F, et al. Kidney Int 1986；29：1215—23.
5. Tse KC, et al. Nephrol Dial Transplant 2003；18：1316—20. (Level 4)
6. Al—Khader AA, et al. Clin Nephrol 1979；11：26—30. (Level 4)

7. Nagai R, et al. Clin Nephrol 1994；42：18—21. (Level 4)
8. Zent R, et al. Am J Kidney Dis 1997；29：200—6. (Level 4)
9. Branten AJ, et al. QJM 1998；91：359—66. (Level 4)
10. Ponticelli C, et al. J Am Soc Nephrol 1998；9：444—50. (Level 2)
11. Quaglia M, et al. Drugs 2009；69：1303—17. (Level 5)7) Adjunctive and supportive treatments
CQ 23. Are renin-angiotensin system (RAS) inhibitors recommended for
reducing urinary protein level in nephrotic syndrome?
1. The GISEN group. Lancet 1997；349：1857—63. (Level 2)
2. Polanco N, et al. J Am Soc Nephrol 2010；21：697—704. (Level 2)
3. Kosmadakis G, et al. Scand J Urol Nephrol 2010；44：251—6. (Level 2)
4. Giri S, et al. J Assoc Physicians India 2002；50：1245—9. (Level 2)
5. Usta M, et al. J Intern Med 2003；253：329—34. (Level 2)
6. Cheng J, et al. Int J Clin Pract 2009；63：880—8. (Level 1)
7. Kincaid—Smith P, et al. Nephrol Dial Transplant 2002；17：597—601.
(Level 2)
8. Tomino Y, et al. J Nephrol 2009；22：224—31. (Level 4)
9. Nakamura T, et al. Am J Hypertens 2007；20：1195—201. (Level 2)
10. Parving HH, et al. N Engl J Med 2008；358：2433—46. (Level 2)
11. Navaneethan SD, et al. Clin J Am Soc Nephrol 2009；4：542—51. (Level1)
12. Parving HH, et al. N Engl J Med 2012；367：2204—13. (Level 2)
CQ 24. Are diuretics recommended for reducing edema in nephrotic
syndrome?
1. Nakahama H, et al. Nephron 1988；49：223—7. (Level 4)
2. Kapur G, et al. Clin J Am Soc Nephrol 2009；4：907—13. (Level 4)
3. Ostermann M, et al. Nephron Clin Pract 2007；107：c70—6. (Level 2)
4. Felker GM, et al. N Engl J Med 2011；364：797—805. (Level 2)
5. Fliser D, et al. Kidney Int 1999；55：629—34. (Level 4)
6. Akcicek F, et al. BMJ 1995；310：162—3. (Level 4)
CQ 25. Is albumin administration recommended
hypoalbuminemia in nephrotic syndrome?
1. Fliser D, et al. Kidney Int 1999；55：629—34. (Level 4)

toimprove2. Ghafari A, et al. Saudi J Kidney Dis Transpl 2011；22：471—5. (Level 4)
3. Na KY, et al. J Korean Med Sci 2001；16：448—54. (Level 2)
4. Dharmaraj R, et al. Pediatr Nephrol 2009；24：775—82. (Level 4)
5. Haws RM, et al. Pediatrics 1993；91：1142—6. (Level 4)
6. Yoshimura A, et al. Clin Nephrol 1992；37：109—14. (Level 4)
CQ 26. Are antiplatelet and anticoagulant agents recommended for
reducing urinary protein level and preventing thrombosis in nephrotic
syndrome?
1. Kamei K, et al. Clin J Am Soc Nephrol 2011；6：1301—7. (Level 2)
2. Taji Y, et al. Clin and Exp Nephrol 2006；10：268—73. (Level 1)
3. Nakamura T, et al. Nephron 2001；88：80—2. (Level 2)
4. Nakamura T, et al. Diabetes Care 2000；23：1168—71. (Level 2)
5. Liu XJ, et al. Intern Med 2011；50：2503—10. (Level 1)
6. Tojo S, et al. Contrib Nephrol 1978；9：111—27. (Level 4)
7. Zäuner I, et al. Nephrol Dial Transplant 1994；9：619—22. (Level 2)
8. Lilova MI, et al. Pediatr Nephrol 2000；15：74—8. (Level 4)
9. Sarasin FP, et al. Kidney Int 1994；45：578—85. (Level 4)
CQ 27. Are statins recommended to improve dyslipidemia and life
prognosis in nephrotic syndrome?
1. Ordoñez JD, et al. Kidney Int 1993；44：638—42. (Level 4)
2. Valdivielso P, et al. Nephrology（Carlton） 2003；8：61—4. (Level 2)
3. Fried LF, et al. Kidney Int 2001；59：260—9. (Level 4)
4. Gheith OA, et al. Nephron 2002；91：612—9. (Level 2)
5. Sandhu S, et al. J Am Soc Nephrol 2006；17：2006—16. (Level 4)
6. Rayner BL, et al. Clin Nephrol 1996；46：219—24. (Level 2)
7. Dogra GK, et al. Kidney Int 2002；62：550—7. (Level 4)
CQ 28. Is ezetimibe recommended to improve lipid metabolism
abnormalities and life prognosis in nephrotic syndrome?
1. Baigent C, et al. Lancet 2011；377：2181—92. (Level 2)
2. Nakamura T, et al. Pharmacol Res 2010；61：58—61. (Level 2)
CQ 29. Is low-density lipoprotein (LDL) apheresis recommended for
reducing urinary protein levels in refractory nephrotic syndrome?

1. Tojo K, et al. Jpn J Nephrol 1988；30：1153—60. (Level 5)
2. Muso E, et al. Nephron 2001；89：408—15. (Level 4)
3. Muso E, et al. Clin Nephrol 2007；67：341—4. (Level 4)
4. Hattori M, et al. Am J Kidney Dis 2003；42：1121—30. (Level 5)
CQ 30. Is the extracorporeal ultrafiltration method (ECUM) recommended
for refractory edema and ascites in nephrotic syndrome?
1. Smith DE, et al. J Pharm Sci 1985；74：603—7. (Level 5)
2. Keller E, et al. Clin Pharmacol Ther 1982；32：442—9. (Level 5)
3. Asaba H, et al. Acta Med Scand 1978；204：145—9. (Level 5)
4. Fauchald P, et al. Acta Med Scand 1985；217：127—31. (Level 5)
CQ 31. Is the trimethoprim-sulfamethoxazole combination recommended
for preventing infectious disease during immunosuppressive therapy innephrotic syndrome?
CQ 32. Is immunoglobulin supply recommended for preventing infectious
disease in nephrotic syndrome?
1. Wu HM，et al. Cochrane Database Syst Rev 2012；4：CD003964．(Level
1)
2. Ogi M，et al. Am J Kidney Dis 1994；24：427—36. (Level 4)
CQ 33. Is treatment with antitubercular agents recommended forpreventing tuberculous infection in nephrotic syndrome?
1. Gulati S, et al. Pediatr Nephrol 1995；9：431—4. (Level 4)
2. Gulati S, et al. Pediatr Nephrol 1997；11：695—8. (Level 4)
3. Currie AC, et al. Transplantation 2010；90：695—704. (Level 1)
4. Naqvi R, et al. Nephrol Dial Transplant 2010；25：634—7. (Level 2)
CQ 34. Is immunosuppressive therapy recommended for patients with
hepatitis B-positive nephrotic syndrome?
8) Lifestyle and dietary instruction
CQ 35. Is the prevalence rate of cancer in patients with membranous
nephropathy higher than that in the general population?
1. Bjørneklett R, et al. Am J Kidney Dis 2007；50：396—403. (Level 4)
2. Lefaucheur C, et al. Kidney Int 2006；70：1510—7. (Level 4)

3. Burstein DM, et al. Am J Kidney Dis 1993；22：5—10. (Level 5)
CQ 36. Is bed rest/exercise restriction recommended in nephrotic
syndrome?
1. Fuiano G, et al. Am J Kidney Dis 2004；44：257—63. (Level 5)
CQ 37. Is vaccination recommended in patients with nephrotic syndromeduring treatment with corticosteroids and immunosuppressive drugs?
1. Fuchshuber A, et al. Nephrol Dial Transplant 1996；11：468—73. (Level
4)
2. Collins AJ, et al. Am J Kidney Dis 2008；51：S1—320. (Level 4)
CQ 38. Are there any preventive measures against steroid-induced femoral
head necrosis in nephrotic syndrome?
1. Nagasawa K, et al. Lupus 2006；15：354—7. (Level 3)
2. Ajmal M, et al. Orthop Clin North Am 2009；40：235—9. (Level 4)
3. Lai KA, et al. J Bone Joint Surg Am 2005；87：2155—9. (Level 2)
4. Wang CJ, et al. Arch Orthop Trauma Surg 2008；128：901—8. (Level 2)
CQ 39. Is the avoidance of mental stress recommended to prevent the onset
and relapse of nephrotic syndrome?
1. Takahashi S, et al. J Jpn Pediatr Soc 1996；100：72—7. (Level 4)
2. Takahashi S, et al. Pediatr Nephrol 2007；22：232—6. (Level 4)
CQ 40. Is a fat-restricted diet recommended to improve dyslipidemia andlife prognosis in nephrotic syndrome?
1. D’Amico G, et al. Clin Nephrol 1991；35：237—42. (Level 4)
2. D’Amico G, et al. Lancet 1992；339：1131—4. (Level 4)
2. Dietary instruction
1. Rodriguez—Iturbe B, et al. Atrial natriuretic factor in theacute nephritic
and nephrotic syndromes. Kidney Int 1990；38：512—7.
2. Kaysen GA, et al. Effect of dietary protein intake on albumin
homeostasis in nephrotic patients. Kidney Int 1986；29：572—7.
3. D’Amico G, et al. Effect of dietary proteins and lipids in patients withmembranous nephropathy and nephrotic syndrome. Clin Nephrol 1991；

35：237—42.
4. Walser M, et al. Treatment of nephrotic adults with a supplemented,
very low—protein diet. Am J Kidney Dis 1996；28：354—64.
5. D’Amico G, et al. Effect of vegetarian soy diet on hyperlipidaemia in
nephrotic syndrome. Lancet 1992；339：1131—4.
6. Kopple JD, et al. Effect of energy intake on nitrogen metabolism in
nondialyzed patients with chronic renal failure. Kidney Int 1986；29：
734—42.
7. Kaysen GA, et al. Effect of dietary protein intake on albumin
homeostasis in nephrotic patients. Kidney Int 1986；29：572—7.
8. Maroni BJ, et al. Mechanisms permitting nephrotic patients to achieve
nitrogen equilibrium with a protein—restricted diet. J Clin Invest 1997；
99：2479—87.
9. Lim VS, et al. Leucine turnover in patients with nephrotic syndrome：evidence suggesting body protein conservation. J Am Soc Nephrol 1998；
9：1067—73.
10. Fouque D, et al. A proposed nomenclature and diagnostic criteria forprotein—energy wasting in acute and chronic kidney disease. Kidney Int
2008；73：391—8.
11. Kendirli T, et al. Vitamin B6 deficiency presenting with low alanine
aminotransferase in a critically ill child. Pediatrics Int 2009；51：597—
9.
12. Nishida M, et al. Wernicke’s encephalopathy in a patient with nephrotic
syndrome. Eur J Pediatr 2008；168：731—4.
13. Banerjee S, et al. Vitamin D in nephrotic syndrome remission：a case—control study. Pediatr Nephrol 2013；28：1983—9.
14. El—Melegy NT, et al. Oxidative Modification of Low—Density
Lipoprotein in Relation to Dyslipidemia and Oxidant Status in Children
With Steroid Sensitive Nephrotic Syndrome. Pediatr Res 2008；63：404—
9.
3. Treatment Interpretation and Treatment AlgorithmTable1. Clinical definition of adult nephrotic syndrome
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)
Notes:
1) The above urine protein and hypoalbuminemia are indispensable prerequisites for theclinical diagnosis of nephrotic syndrome.
2) Edema is not an indispensable prerequisite but an important finding for nephrotic
syndrome.
3)

Dyslipidemia is not an indispensable prerequisite for nephrotic syndrome.

4)

Oval fat body is helpful for diagnosis of nephrotic syndrome.

Table2. Therapeutic evaluation for nephrotic syndrome
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
Notes:
1) The diagnosis of nephrotic syndrome and therapeutic evaluation should be done by 24hour urine collection. If to collect 24-hour urine is impossible, the ratio of urine protein
and urine creatinine (g/gCr) at spot urine is available for the diagnosis of nephrotic
syndrome and therapeutic evaluation.
2) In principle, the evaluation of complete remission or incomplete remission at 6 months
after the initiation of treatment includes the improvement of clinical finings and serum
albumin.
3) The evaluation of relapse is the condition that urine protein ≥ 1 g/gCr (1g/gCr) runs or ≥(2+) continues 2～3 times in a row.
4) In Europe and the United States partial remission defines 50% or more of the reductionof urine protein, while the Japanese evaluation does not use this definition.

Table3. The classification by the response to treatment of nephrotic syndrome
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 andimmunosuppressive 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 todiscontinue, 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 betreated by steroid or immunosuppressive agents over 2 years.

Table4. The definition of nephrotic syndrome in children
1. Nephrotic syndrome: Massive proteinuria
hypoalbuminemia (serum albumin ≤ 2.5 g/dL)(40≥

mg/h/m2)+

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.

Table5. Examination findings of primary nephrotic syndrome
Examination

Measurement items

Major findings

Urinalysis

urine volume, urine protein(24-h collection or spot urine)
fraction of urine protein
occult blood, urinary sediments
granular cast, waxy castselectivity of urine protein(clearance ration of IgG andtransferrin)
peripheral blood examination
biochemical examination

increase: urine protein, albuminemia
fatty cast, oval fat body

Blood examination

lipid examination

coagulation test
immunological test
Chest X-ray

Ultrasonography
Renal biopsy

cardiothoratic ratio,
pulmonary vascular shadow
cost-phrenic angle
shadow of lung fielddeep vein thrombosis in lower extremities
light microscopy
immunofluorescence microscopy
electron microscopy

sometimes decrease: red blood cell, hemoglobin
decrease: total protein, albuminsometimes decrease: Na, vitamin D, GFR
sometimes increase: BUN, Cr
increase: total cholesterol, LDL, VLDL,La(a)ApoB, ApoCⅡ, HDL-3
stable: HDL
decrease: HDL-2
increase: fibrinogen, FDP, D-dimer
decrease: antithrombin Ⅲ, plasminogendecrease: IgG and other immunoglobulins,
complements
sometimes: pulmonary congestion

collapse of venous system due to decrease of
circular blood volume
The definitive diagnosis is usually determinedby renal biopsy.

Notes: When secondary nephrotic syndrome is suspected from patient’s conditions, the examinations according toeach baseline disease should be added. (For example; In the case of lupus nephritis, the examinations concerning
collagen diseases should be done as additional items.)

Table6. Examination findings of secondary nephrotic syndrome
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 caseswith infectious diseases ad vasculitis
blood sugar markers such as blood glucose,
HbA1c, and glycoalbumin in diabetic
nephropathy.
CRP and inflammatory reactions increase inin vasculitis and purpura nephritis.
Paraprotein or cryoglobumin is confirmed inin the cases with paraproteinemia.
The abnormality of IDL or ApoE is confirmed
in lipoprotein glomerulopathy.
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 inbacterial culture and antigen/antibody
detection for pathogenic microbes.

biochemical examination

lipid examination
immunological examination

Renal biopsy

The specific findings are observed in eachsecondary disease, thus the renal biopsy
is useful for the definitive diagnosis ofsecondary 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