A 10-year-old female student presented with nephrotic syndrome. She responded well to oral prednisone treatment but after 2 years of remission, presented with edema and increased proteinuria. Her renal function was normal. An elevated urinary albumin:protein ratio would be suggestive of relapse of her nephrotic syndrome. The document then discusses definitions, pathogenesis, management and treatment guidelines for minimal change disease in children.

1. MCD
CPC PRESENTED BY
DR RAHEEL AHMED

2. MCQ
 A 10-year-old female student with NS (10 g/day)
 She is started on oral prednisone with good response (proteinuria
250 mg/day) in 9 weeks.
 Prednisone is slowly tapered to 5 mg every other day.
 After 2 years of remission, she presents to the clinic with
peripheral edema, and urinary protein excretion increased to 6.5
g/day. Her renal function is normal.
 Which one of the following urinary findings is SUGGESTIVE of
relapse of her nephrotic syndrome?
A. Urinary albumin: protein ratio
B. Urinary neutrophil gelatinase-associated lipocalin (NGAL)
C. Monocyte chemo attractant protein-1 (MCP-1)
D. Urinary CTLA-4
E. Urinary CD80

3. LEARNING OBJECTIVES
 VARIOUS DEFINITIONS RELEVANT TO NS
 LARGEST STUDY ON NS IN CHILDREN ISKDC
 SECONDARY CAUSES & CLINICAL FEATURES OF MCD
 HYPOTHETICAL ASPECTS OF PATHOGENESIS OF MCD
 MANAGEMENT OF MCD IN CHILDREN IN LIGHT OF KDIGO GUIDELINES

4. Major cause of idiopathic Nephrotic syndrome
• Characterized by intense proteinuria leading to edema and
intravascular volume depletion
• In children >1 year of age >>> MCD accounts for 80% of cases
• In Adults >>> 10%-20% of cases of NS
• Around 3rd Decade and later on, membranous nephropathy,
become more frequent

7. 10–50 cases per 1,00,000 children
More common in Asia
Epidemiology
10–50 cases per 1,00,000 children
It is more common in Asians and Native Americans
Much rarer in African Americans, in whom NS is much more
likely to be caused by FSGS.
Male predominance (approximately 2:1)
MCD is much less frequent in adults But ( M:F 1:1)
Seasonal influence incidence Higher during winter

8. INTERNATIONAL STUDY OF KIDNEY DISEASE IN CHILDREN (ISKDC)
The largest and Very OLD study carried out in children with Nephrotic syndrome
Between January, 1967, and April, 1976,
521 CHILDREN WITH THE NEPHROTIC SYNDROME WERE ALLOCATED
(age range 12 weeks to 16 years of age)
All patients satisfied the following criteria:
(1) Heavy proteinuria > 40 mg/ hour/m 2, determined quantitatively on an
overnight collection;
(2) Hypoalbuminemia < 2.5 gm/dl;
(3) Age > 12 weeks and < 16 years;
(4) No prior treatment with steroids or other cytotoxic immunosuppressive
agents; and
(5) No evidence of underlying systemic disease or exposure to agents known to
be associated with the Nephrotic syndrome.
ALL CHILDREN WERE BIOPSIED

9. Of the 521 Children in (ISKDC) study idiopathic nephrotic syndrome
between 1967 and 1974, the following findings were made based upon
kidney biopsy
● MCD − 77 percent MOST COMMON
● MPGN − 8 percent
● FSGS − 7 percent
● Proliferative glomerulonephritis − 2 percent
● Mesangial proliferation − 2 percent
● Focal and global glomerulosclerosis − 2 percent
● Membranous glomerulonephropathy − 2 percent

10. Age (Yrs) Total N Pts with MCD Pts with other lesions
n (n/N)100 n (n/N)100
All Ages 471 363 77 108 23
<6 ===== 332 289 87 43 13
>6 ===== 139 74 53 65 47
RESPONDERS 92% WERE MCD
All Ages 368 338 92 30 8
<6 ===== 284 266 94 18 6
>6 ===== 84 72 85 12 15
NON RESPONDERS 75 % WERE NON-MCD
All Ages 103 25 25 78 75
<6 ===== 48 23 48 25 52
>6 ===== 55 2 4 53 96
MCD and other histopathological categories according to age and
response to prednisone AT EIGHT WEEKS (50 RAN AWAY)

11. ● Age younger than ten years of age
●Absence of hypertension
●Absence of hematuria
●Normal complement levels
●Normal kidney function
One exception to the age criterion is onset of Nephrotic
syndrome in the first year of life, particularly the first three
months of life,
more likely to be due to a gene mutation and to be
resistant to glucocorticoids.
After ISKDC Study
An initial trial of steroid therapy is generally administered to
children who are likely to have MCD based upon clinical
diagnosis, THEREBY AVOIDING KIDNEY BIOPSY.

21. I N C H I L D R E N with NS
it is clinically important to differentiate as early as
possible in the course of the disease between patients
with MCD and those with other glomerular lesions.
Decisions concerning
• The need for renal biopsy,
• Optimal initial treatment, and
• Predictions concerning prognosis depend upon this
differentiation.

22. PARENTS ARE WORRIED AND CONCERNED
 PARENTS OF CHILDREN WITH MCNS CAN BE TOLD
 That the prognosis for complete RECOVERY IS EXCELLENT,
 That a renal biopsy probably will NOT BE NECESSARY, and
 That Prednisone can in most instances SUPPRESS THE SYMPTOMS
 IN CONTRAST
PARENTS OF CHILDREN WITH OTHER LESIONS MUST KNOW
 That the disease may progress to ESRD,
 That ONE OR MORE renal biopsies may be required, and
 That, at present, there is NO KNOWN DEFINITIVE treatment?.

23. SECONDARY CAUSES OF MINIMAL CHANGE DISEASE
Allergy
Pollen
Dust
Fungi
Bee sting
Cat fur
Food allergens (cow’s milk, egg)
Infections
Viral
Parasitic
Mycoplasma pneumoniae

24. Malignancies
Hodgkin disease
Non-Hodgkin lymphoma
Leukemia
Multiple myeloma
Thymoma
Bronchogenic cancer
Colon cancer
Eosinophilic lymphoid
granuloma (Kimura disease)
Drugs
Nonsteroidal anti-
inflammatory drugs
Salazopyrin
D-penicillamine (WILSON)
Tiopronin (WILSON)
Gold
Mercury
Lithium
Tyrosine-kinase inhibitors

25. DEFINITIONS..
Nephrotic Syndrome
Edema
Massive proteinuria (>40 mg/m2 per h in children, >3.5 g/d in adults)
uPCR ≥2000 mg/g
Hypoalbuminemia (<2.5 g/dl)
Remission
Resolution of edema WITH Marked reduction in proteinuria
Normalization of serum albumin (≥3.5 g/dl)
COMPLETE REMISSION (<4 mg/m2 per h or negative dipstick in children, <0.3
g/d in adults) uPCR <200 mg/g
PARTIAL REMISSION Reduction by ≥50% ; uPCR between 200 and
2000mg/g and serum albumin ≥2.5 g/dl in children, 0.21 g/day and 3.4 g/day and
decreased by ≥50% in adults)

26. Relapse
Recurrence of massive proteinuria uPCR ≥2000 mg/g in children, >3.5 g/d in adults)
Positive urine dipstick (≥3+ for 3 d or positive for 7 d, usually applicable to children)
±Edema
Steroid-Sensitive Nephrotic Syndrome
Initial responder Attainment of complete remission within initial 4 wk of
corticosteroid therapy BEST PROGNOSIS
Response to PDN 60 mg/m2 per d within 4–6 wk ±MPD boluses in children
Response to PDN 1 mg/kg per d or 2 mg/kg every other d, within 16 wk in adults

27. Most patients who are to respond to steroids do so within 4 weeks.
50% of children achieve remission within 8 days of RECOMMENDED
steroid treatment
90% of Children Achieve Remission following Steroids.
However Relapses tend to be more rapid in children
In both populations, MCD has a high tendency to relapse
In contrast, in adults the median time to remission exceeds 2 months

28. NONRELAPSING NS VERY GOOD PROGNOSIS
No relapses for >2 yr. after the end of therapy for the first episode of
Nephrotic syndrome (applicable to children, not yet defined in
adults)
Infrequently Relapsing Nephrotic Syndrome
<2 relapses per 6 months (or <4 relapses per 12 months)
Frequently Relapsing Nephrotic Syndrome
≥2 relapses per 6 months (or ≥4 relapses per 12 months)

29. STEROID-DEPENDENT NEPHROTIC SYNDROME
Two consecutive relapses DURING STEROID THERAPY, or
WITHIN 14 DAYS of discontinuation of steroid therapy
STEROID-RESISTANT NEPHROTIC SYNDROME
In children No response to PDN 60 mg/m2 per d within 08 wk.
In adults No response to PDN 1 mg/kg/d or 2 mg/kg EOD within 16wk.

30. WHEN TO BIOPSY???
In adults EARLY KIDNEY BIOPSY is crucial
The indications for renal biopsy in CHILDREN are
Onset, age <1 or >12 years
Gross hematuria
Low serum C3
Marked hypertension
Renal failure without severe hypovolemic
Positive history for secondary cause
Steroid resistance or therapy with Calcineurin inhibitors

31. • By LM, NOTHING IN LIGHT MICROSCOPY (NIL DISEASE)
• Sometimes- mild focal meningeal prominence not
exceeding three or four cells per segment are seen.
HISTOPATHOLOGY

32. Immunofluorescence is USUALLY NEGATIVE.
• However, low-intensity mesangial IgM (sometimes
accompanied by C3 or C1q) staining can be found.
• MCD is occasionally accompanied by glomerular IgA
deposits-IgA nephropathy with MCD 5% Of IgA
• Focal segmental distribution of IgM and C3
staining should strongly suggest FSGS
IMMUNOFLUORESCENCE

33. Electron Microscopy
Foot Process
Effacement

37. o Edema- Periorbital, scrotum or labia and lower extremities
o Edema increases RAPIDLY and becomes detectable when
fluid retention exceeds 3 to 5 percent of body weight.
o Severe infections such as Sepsis, Pneumonia, and Peritonitis
o Bowel edema may manifest as Abd Pain & diarrhea
o Intravascular volume depletion and oliguria - AKI, which is
more frequently seen in adults.
o Rarely, AKI with gross hematuria followed by anuria -
secondary to bilateral renal vein thrombosis.
CLINICAL MANIFESTATIONS

38. IN CONTRAST TO OTHER GLOMERULAR DISEASES
MCD is associated with NORMAL BLOOD PRESSURE.
Some patients may develop transient renin mediated hypertension during
relapse from hypovolemia and renal hypo perfusion.
Paradoxically, blood pressure will normalize after albumin infusion as the intravascular
compartment is restored.
Hypertension also can be iatrogenic, secondary to use of STEROIDS, AND CNIS.
Sustained hypertension QUESTIONS YOUR DIAGNOSIS .

39. LAB VALUES
• Urinalysis, with urinary dipstick showing 3+/4+ proteinuria
• Nephrotic-range proteinuria > 50 mg/kg/day or
> 40 mg/m2/hour
• Urine PCR >200 mg/mmol in children and
• Urine proteins >3.5 g/d in adults
• Serum albumin<2 g/dl
• Urinalysis relatively inactive urine sediment (ie, oval fat bodies
and hyaline casts, but few red cells and no red cell or other
cellular casts).
• Lipid Profile
• IgG is markedly decreased

40. NONIMMUNE GENERAL MEASURES These Include
 Prevention of infection –
Pneumococcal, INFLUENZA and varicella vaccines.
AVOID LIVE VACCINATIONS DURING RELAPSE
 Identification and treatment of suspected infections (pneumonia, cellulitis,
sepsis, peritonitis) as these patients are immunosuppressed.
 Management of edema with avoidance of excessive fluid intake, moderate
restriction of dietary salt, elevation of extremities, and judicious use of
diuretics.
 IV ALBUMIN HAS TWO ROLES
 1) Prevention of venous thromboembolism and
 2) Avoidance of intravascular hypovolemia
 Maintenance of adequate protein intake (130 to 140 percent of the
recommended daily allowance)
MANAGEMENT

41. WHAT KDIGO GUIDELINES RECOMMEND
NOMENCLATURE AND DESCRIPTION FOR RATING GUIDELINE RECOMMENDATIONS
Within each recommendation,
STRENGTH OF RECOMMENDATION is indicated as Level 1 or Level 2,
QUALITY OF THE SUPPORTING EVIDENCE is shown as A, B, C, or D.

42. Grade
Implications
Clinicians Patients
Level 1
“We recommend”
MOST CLINICIANS in your
situation would want the
recommended course of action,
and only a small proportion
would not.
Most patients should
receive the
recommended course of
action.
Level 2
“We suggest”
MAJORITY OF PEOPLE in your
situation would want the
recommended course of action,
but many would not.
Different choices will be
appropriate for different
patients. Each patient needs help
to arrive at a management
decision consistent with her or
his values and preferences.

43. Grade Quality of evidence Meaning
A High We are confident that the true effect lies close to
the estimate of the effect.
B Moderate The true effect is likely to be close to the estimate
of the effect.
C Low The true effect may be substantially different from
the estimate of the effect.
D Very low The estimate of effect is very uncertain, and often
will be far from the truth.

44. 3.1.1: We recommend that corticosteroid therapy (prednisone or
prednisolone)* be given for at least 12 weeks. (1B) <=
 3.1.1.1: We recommend that oral prednisone be administered as a single
daily dose (1B) <= starting at 60 mg/m2 /d or 2 mg/kg/d to a maximum
60 mg/d. (1D)
3.1.1.2: We recommend that daily oral prednisone be given for 4–6 weeks
(1C) followed by alternate-day medication as a single daily dose starting at 40
mg/m2 or 1.5 mg/kg (maximum 40 mg on alternate days) (1D) and continued
for 2–5 months with tapering of the dose. (1B) <=
3.1: Treatment of CHILDREN INITIAL EPISODE

45. 3.2: Treatment of Infrequent Relapsing SSNS
USUALLY SHORT COURSE OF STEROIDS WILL SUFFICE
3.2.1: Corticosteroid therapy for children with INFREQUENT RELAPSES :
3.2.1.1:
We suggest that infrequent relapses of SSNS in children be treated with a
single-daily dose of prednisone 60 mg/m2 or 2 mg/kg (maximum of 60 mg/d)
until the child has been in complete remission for at least 3 days. (2D) <==
3.2.1.2:
We suggest that, after achieving complete remission, children be given
prednisone as a single dose on alternate days (40 mg/m2 per dose or 1.5
mg/kg per dose: maximum 40 mg on alternate days) for at least 4 weeks.
(2C)

46. 3.2.2: Treatment of CHILDREN FR and SD SSNS
BE AWARE OF ADVERSE AFFECTS (LONGER COURSE IS REQUIRED)
 3.2.2.1: We suggest that relapses in children with FR or SD SSNS be treated
with daily prednisone until the child has been in remission for at least 3 days, followed
by alternate-day prednisone for at least 3 months. (2C)
 3.2.2.2: We suggest that prednisone be given on alternate days in the lowest
dose to maintain remission without major adverse effects in children with FR and SD
SSNS. (2D)
 3.2.2.3: We suggest that daily prednisone at the lowest dose be given to
maintain remission without major adverse effects in children with SD SSNS where
alternate-day prednisone therapy is not effective(2D)
 3.2.2.4: We suggest that daily prednisone be given during episodes of upper
respiratory tract and other infections to reduce the risk for relapse in children with FR
and SD SSNS already on alternate-day prednisone. (2C)

47. 3.3: Treatment of CHILDREN FR and SD SSNS
TREATMENT WITH CORTICOSTEROID-SPARING AGENTS
3.3.1: We recommend that corticosteroid-sparing agents be prescribed for children with
FR SSNS and SD SSNS, who develop steroid-related adverse effects. (1B) <=
 3.3.2: We recommend that alkylating agents, cyclophosphamide or chlorambucil, be
given as corticosteroid-sparing agents for FR SSNS. (1B) <=
We Suggest that alkylating agents, cyclophosphamide or chlorambucil, be given as
corticosteroid-sparing agents for SD SSNS. (2C)
 3.3.2.1: We suggest that cyclophosphamide (2 mg/kg/d) be given for 8–12 weeks
(maximum cumulative dose 168 mg/kg). (2C)
 3.3.2.2: We suggest that cyclophosphamide not be started until the child has achieved
remission with corticosteroids. (2D)
 3.3.2.3: We suggest that chlorambucil (0.1–0.2 mg/kg/d) may be given for 8 weeks
(maximum cumulative dose 11.2 mg/kg) as an alternative to cyclophosphamide. (2C)
 3.3.2.4: We suggest that Second Course Of Alkylating Agents NOT Be Given.
(2D)

48. 3.3.3: We recommend that levamisole be given as a corticosteroid-
sparing agent. (1B) <=
3.3.3.1: We suggest that levamisole be given at a dose of 2.5 mg/kg on alternate
days (2B) for at least 12 months (2C) as most children will relapse when
levamisole is stopped.
3.3: Treatment of CHILDREN (FR) and SD SSNS
TREATMENT WITH CORTICOSTEROID-SPARING AGENTS

49. 3.3.4: We recommend that the Calcineurin Inhibitors cyclosporine or
tacrolimus be given as corticosteroid-sparing agents. (1C)
3.3.4.1: We suggest that cyclosporine be administered at a dose of 4–5 mg/kg/d
(starting dose) in two divided doses. (2C)
3.3.4.2: We suggest that tacrolimus 0.1 mg/kg/d (starting dose) given in two divided
doses be used instead of cyclosporine when the cosmetic side-effects of cyclosporine
are unacceptable. (2D)
3.3.4.3: Monitor CNI levels during therapy to limit toxicity. (Not Graded)
3.3.4.4: We suggest that CNIS BE GIVEN FOR AT LEAST 12 MONTHS, as most children
will relapse when CNIs are stopped. (2C)

50. 3.3.5: We suggest that MMF be given as a corticosteroid-sparing
agent. (2C)
3.3.5.1: We suggest that MMF (starting dose 1200 mg/m2 /d) be given in two
divided doses for at least 12 months, as most children will relapse when MMF is
stopped. (2C)
3.3.6: We suggest that rituximabbe considered only in children with SD SSNS
who have continuing frequent relapses despite optimal combinations of prednisone
and corticosteroid-sparing agents, and/or who have serious adverse effects of
therapy. (2C)
3.3.8: We recommend that azathioprine not be used as a
corticosteroid-sparing agent in FR and SD SSNS. (1B)

51. SUMMARY OF (1B) <==> RECOMMENDATIONS
 3.1.1: We recommend that corticosteroid therapy (prednisone or
prednisolone)* be given for at least 12 weeks. (1B) <=
 3.1.1.1: We recommend that oral prednisone be administered as a single
daily dose (1B) <=
 3.1.1.2: We recommend that daily oral prednisone be continued for 2–5
months with tapering of the dose. (1B) <=
 3.3.1: We recommend that corticosteroid-sparing agents be prescribed for
children with FR SSNS and SD SSNS, who develop steroid-related adverse effects.
(1B) <=
 3.3.2: We recommend that alkylating agents, cyclophosphamide or
chlorambucil, be given as corticosteroid-sparing agents for FR SSNS. (1B) <=
 3.3.3: We recommend that levamisole be given as a corticosteroid-sparing
agent. (1B) <=

52. 3.4: Indication for kidney biopsy
3.4.1: Indications for kidney biopsy in children with SSNS are (Not Graded):
 Late failure to respond following initial response to corticosteroids;
 A high index of suspicion for a different underlying pathology;
 Decreasing kidney function in children receiving CNIs.

53. 3.5: Immunizations in children with SSNS
3.5.1: To reduce the risk of serious infections in children with SSNS (Not Graded):
Give pneumococcal vaccination to the children.
Give influenza vaccination annually to the children and their household contacts.
Defer vaccination with live vaccines until prednisone dose is below either 1 mg/kg
daily (o20 mg/d) or 2 mg/kg on alternate days (o40 mg on alternate days).
Live vaccines are contraindicated in children receiving corticosteroid-sparing
immunosuppressive agents. K
Immunize healthy household contacts with live vaccines to minimize the risk of
transfer of infection to the immunosuppressed child but avoid direct exposure of
the child to gastrointestinal, urinary, or respiratory secretions of vaccinated
contacts for 3–6 weeks after vaccination.
Following close contact with Varicella infection, give nonimmune children on
immunosuppressive agents varicella zoster immune globulin, if available.

54. TREATMENT IN CHILDREN STEROID-RESISTANT NS
4.1.1: We suggest a minimum of 8 weeks treatment with corticosteroids to define steroid
resistance. (2D)
4.1.2: The following are required to evaluate the child with SRNS (Not Graded):
 a diagnostic kidney biopsy;
 evaluation of kidney function by GFR or eGFR;
 quantitation of urine protein excretion.
4.2: Treatment recommendations for SRNS
o 4.2.1: We recommend using a calcineurin inhibitor (CNI) as initial therapy for
children with SRNS. (1B) <==
o 4.2.1.1: We suggest that CNI therapy be continued for a minimum of 6 months and
then stopped if a partial or complete remission of proteinuria is not achieved. (2C)
o 4.2.1.2: We suggest CNIs be continued for a minimum of 12 months when at least
a partial remission is achieved by 6 months. (2C)
o 4.2.1.3: We suggest that low-dose corticosteroid therapy be combined with CNI
therapy. (2D)

55. 4.2.2: We recommend treatment with ACE-I or ARBs for children with SRNS. (1B)
4.2.3: In children who fail to achieve remission with CNI therapy:
4.2.3.1: We suggest that mycophenolate mofetil (2D), high-dose corticosteroids
(2D), or a combination of these agents (2D) be considered in children who fail to
achieve complete or partial remission with CNIs and corticosteroids.
4.2.3.2: We suggest that cyclophosphamide not be given to children with SRNS. (2B)
4.2.4: In patients with a relapse of nephrotic syndrome after complete remission,
we suggest that therapy be restarted using any one of the following options: (2C)
 Oral corticosteroids (2D);
 Return to previous successful immunosuppressive agent (2D);
 An alternative immunosuppressive agent to minimize potential cumulative
toxicity (2D).

56. • After remission of the first episode of nephrosis, about
 30% NEVER RELAPSE for 18–24 months,
 20%–30% progress to infrequent relapses
 The remaining 40%–50%, more frequently children <5
years of age, will have a frequently relapsing or steroid-
dependent course
• Initially steroid-sensitive disease will develop secondary
steroid resistance. • This clinical feature is highly predictive
of post-transplant recurrence
In Children,
In adults, relapses are frequent, occurs in about 56%–76%.
Overall Outcome

57. ANSWER
E. Urinary CD80
Urinary CD80 levels are increased during
relapse and normalizes during remission in
children with minimal change disease. Garin
et al.
Unlike CD80, the urinary levels of soluble CTLA-4
are not elevated during relapse of minimal change
disease. However, the ratio of CD80/CTLA-4 is
elevated. Thus, option D is incorrect.


58. THANK YOU