Minimal change disease

1. MINIMAL CHANGE DISEASE
MANAGEMENT
Dr Mohammed H. E, Dr.s Adamu mohammad
Nephrology unit
27.05.22

2. TABLE OF CONTENT
• INTRODUCTION
• EPIDERMIOLOGY
• ETIOLOGY
• PATHOPHYSIOLOGY
• PATHOLOGY
• CLINICAL MANIFESTATION
WORK UP
• DIFFERENTIAL DIAGNOSIS
• TREATMENT
• DEFINITIONS OF RESPONSE
• COMPLICATIONS
• PROGNOSIS
• CONCLUSION
• REFERENCES
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3. INTRODUCTION
• First described in 1913 by munk, who called it lipoid nephrosis due to
lipids in the tubular epithelial cells and urine.
• More common in children
• - 70 – 90 % cause of nephrrotic syndrome in kids < 10 yrs
• 50% of nephrotic syndrome in children 10 – 18yrs
• 10 – 20% of primary nephrotic syndrome in adults, 3rd most
common after FSGS and MN.
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4. • NS is generally divided into primary or idiopathic, secondary, and
congenital, with idiopathic (INS) being the most common form
observed in 90%
• Glomerular lesions associated with INS include multiple histologic
types
• MCD usually presents as primary renal disease but can be asssociated
with several other conditions such as
• Hodgkins disease
• Allergies
• Use of NSAIDS
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5. Epidermiology
• The reported incidence of MCD in children varies between two and
seven new cases per 100,000 children.
• The exact prevalence is not known, but on the basis of disease
evolution and average age of onset, it can be estimated at
approximately 10–50 cases per 100,000 children.
• The disease is slightly more common in Asia and has a male
predominance (approximately 2:1) in young children that disappears
in adolescents and adults .
• MCD is much less frequent in adults, but the exact incidence in this
population is less well documented
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8. • Clinical and morphologic characteristics of idiopathic nephrotic
syndrome by wasiu A. oluwa et al UCH IBadan . A non randomized
prospective study of cases conducted over 9 yr period showed MPGN
44.4 %, FSGS 25.9% , MCD 18.5%
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9. SECONDARY CAUSES OF MCD
• Allergy
• Pollen
• Dust
• Fungi
• Bee sting
• Cat fur
• Food allergens (cow’s milk, egg)
• 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
• Mercury
• Gold
• Tiopronin
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10. • Infections
• Viral
• Parasitic
• Mycoplasma pneumoniae
• Autoimmune disorders
• SLE
• Diabetes mellitus
• Myasthenia gravis
• Autoimmune pancreatitis
• Celiac disease
• Allogeneic stem cell transplantation
• Immunizations
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11. Pathophysiology
• The pathogenesis of proteinuria in MCD is unknown. Shalhoub, in
1974, proposed that MCD is caused by a circulating factor, thought to
be a cytokine, that increases the permeability of the glomerular
basement membrane (GBM) to plasma proteins.
• He suggested that MCD might represent a T cell disorder based on
the lack of immune deposits,
• The rapid response to corticosteroids,
• the association with Hodgkin disease (a T cell neoplasm), and the
observation that remission often occurred during resolution of
measles infection, which is associated with a transient inhibition of
cell-mediated immunity
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12. Circulating Factor(s)
• Several candidate molecules have been considered as possible
circulating factors.
• Cytokines,
• interleukin-8 (IL-8),
• IL-13
• Hemopexin; synthesized in the liver and is present in human plasma
of patients with MCD
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13. • Microbial Products
• A role for microbial products as circulating factors is attractive
because 70% of MCD patients with relapse have documented viral or
bacterial respiratory infections.
• Two Toll-like receptor (TLR) ligands ;TLR-4 and TLR-3 on podocytes
• Lipopolysaccharide (LPS)
• polyinosinic-polycytidylic acid (poly IC), a viral-like particle
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14. Mechanism(s) of Proteinuria
• 1. Loss of Anionic Charges in the Glomerular Filtration Barrier
as a Cause of Minimal Change Disease
• Proteinuria in MCD has been proposed to result from a loss of
proteins carrying negative charges in the glomerular capillary wall,
resulting in disruption of the charge barrier
• Heparan sulfate proteoglycans, which are the major source of anionic
sites in the GBM, are reported to be low or normal in the GBM of
MCD patients
• 2. Podocyte Dysfunction as a Cause of Minimal Change Disease
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15. • Alteration of slit diaphragm proteins such as reduced nephrin
phosphorylation and alteration in integrin-mediated podocyte
adhesion
• Podocyte expression of two molecules, CD80 (also known as B7.1)
and angiopoietin-like-4 (Angptl-4) also have been proposed
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16. CD80
• CD80 is a costimulatory molecule present on antigen-presenting cells
that was found to be expressed on podocytes in children with MCD.
• It also can be induced in podocytes both in vitro and in vivo by TLR
ligands
• High levels of CD80 also can be found in the urine of children with
steroid-sensitive MCD, and levels decrease to normal with remission.
• CD80 is regulated by cytotoxic T lymphocyte–associated antigen 4
(CTLA-4), which is a molecule also expressed by podocytes.
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17. • The administration of CTLA-4 immunoglobulin to a child with
recurrent steroid-dependent MCD resulted in rapid decrease in
urinary CD80, with the development of remission within 72 hours
• These observations led to the hypothesis that MCD relapse may
develop after viral infection in which viral components stimulate TLR-
3 podocyte receptors, resulting in overexpression of podocyte CD80
• Because of an inadequate CTLA4 response by the podocyte, the
increased expression of CD80, by interfering with phosphorylation of
nephrin, could lead to changes in podocyte shape affecting the “size
barrier,” allowing protein to pass through larger physical gaps.
• And others consistent with this hypothesis
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18. Angptl-4.
• Angptl-4 is a glycoprotein that has been proposed as a mediator of
proteinuria in MCD
• glomerular overexpression of angptl4 and podocin, associated with
marked loss of GBM heparan sulfate proteoglycans, podocyte foot
process effacement, and albuminuria
• Nevertheless, data on angptl4 in MCD are scarce
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19. PATHOLOGY
• MCD received its name because of the minimal, if any, glomerular
abnormalities present by light microscopy.
• Mild changes such as as light increase in mesangial matrix and
hypercellularity may occasionally be observed
• By immunofluorescence, immunoglobulins or complement deposits
are rarely found. If present, deposits are limited to the mesangium.
• There is a small subset of patients who have IgM deposits, which has
been considered by some clinicians to represent an entity distinct
from MCD, known as IgM nephropathy and characterized by a poorer
clinical outcome
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20. • Electron microscopy demonstrates podocyte foot process effacement
or fusion. Although fusion of foot processes is observed in other
nephrotic conditions, in the absence of light microscopy glomerular
changes, the finding is pathognomonic for MCD.
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21. CLINICAL MANIFESTATIONS
• Edema is the first sign and is noticeable after a weight gain of at least
5% to 7% of a patient’s dry weight
• Edema may be mild and associated only with fatigue or may be
severe, presenting as anasarca with pleural effusions and ascites
• In contrast with other glomerular diseases, MCD is associated with
normal blood pressure. Some patients may develop transient renin
mediated hypertension during relapse from hypovolemia and renal
hypoperfusion
• Paradoxically, blood pressure will normalize after albumin infusion as
the intravascular compartment is restored
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22. • Macroscopic hematuria is not seen in MCD unless there is a
complication
• Less commonly, patients with MCD may develop “white nails,”
sometimes in bands (Muehrcke lines) correlating with periods of
clinical relapse
• Adults may develop xanthomas and xanthelasmas, especially on the
eyelids
• Renal function is commonly normal. Some patients have transient
acute kidney injury (AKI) with oliguria during relapse secondary to
reduction of intravascular compartment.
• AKI is more common in adolescents and young adults than children
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23. URINALYSIS
• Frothy urine
• Profound proteinuria 3+ or more ( >3.5g/d/1.73mˆ2)
• SG maybe high due to proteinuria
• Microscopic hematuria

24. URINE SEDIMENT EXAMINATION
• Waxy casts
• Oval fat bodies and fatty casts
• Maltese cross under polarized light

25. WORK UP
• Urinary protein measurement; timed or single spot
• 24hour urinary protein; more tedious!!!
• Urinay PCR/ACR; much easier. uPCR > 2g/g corresponds to 3g of urinary protein / day or more
• Albumin levels (classically low <3.5g/dl)
• FLP- Hyperlipidemia (predominantly hypercholesterolaemia)
• EUCr (usually normal to modest decline in renal function)
• FBC + Diff (may show elevated Hb and HCT due to plasma volume contraction)
• Serology (Viral, ANA, Complements and Cryoglobulins); normal
• Renal sonogram; normal to increased renal echogenicity

26. WORK UP
• Renal Biopsy
• Should be performed in all adult patients with NS before initiating
treatment
• Adequate biopsy specimen (10 - 20 glomeruli)
• Must go deep to get sample of corticomedullary glomeruli to avoid
missing early FSGS
• Histology
• Light Microscopy; usually normal with no obvious glomerular
lesion
• Immunofluorescent; usually negative for deposits, occasionally
showing small amounts of IgM in the mesangium
• Electron microscopy! ‘Hallmark‘

27. LIGHT MICROSCOPY MCD

28. ELECTRON MICROSCOPY (EM)
• Consistently demonstrates effacement of the foot processes
supporting the epithelial podocytes with weakening of the slit-pore
membranes
• Vacuolation in some cases and appearance of microvilli

29. Normal – Left Vs MCD – Right (EM)

30. Urinary CD80
• Increasing interest on using urinary levels of CD80 as a possible
biomarker in MCD
• Helps differentiate MCD from FSGS
• Predicts responsiveness to corticosteroids
• Patients have long-term preservation of renal function

31. DIFFERENTIAL DIAGNOSIS
• Membranous GN
• Focal segmental glomerulosclerosis
• Membranoproliferative GN
• IgA nephropathy
• Heart failure
• Chronic kidney disease

32. TREATMENT (GENERAL in all patients)
• Patient Education
• Dietary sodium restriction
• Blood pressure control
• Anticoagulation (in selected patients)
• Dietary protein restriction
• RAAS inhibition to treat proteinuria
• Statins to treat dyslipidemia
• Control oedema
• Maintenance of adequate nutrition
• Daily weighing
• Withdrawing offending agent/effective treatment of underlying disease
• NB; this approach is consistent with the 2021 KDIGO Clinical Practice Guideline for the
Management of Glomerular diseases

33. TREATMENT (SPECIFIC)
• Corticosteroids (Prednisolone) are treatment of choice 1st line
therapy
• Glucocorticoid monotherapy leads to complete remission inover 80%
of adults with MCD, though time course may be prolonged (up to 4
months)
• Most glucocorticoid responsive patients will respond by 16 weeks

34. Dosing and duration of Steroid
• Initial dose (for minimum of 4 weeks);
• Oral Prednisolone at 1mg/kg of body weight (maximum dose, 80mg/day), OR
• Alternate day Prednisolone at 2mg/kg every other day (maximum dose of
120mg)
• Give as a single dose upon awakening (usually between 7am and 9am) in an
attempt to minimize adrenal suppression
• Tapering
• Slow (to sustain remission and avoid adrenal suppression)
• Taper rapidly? relapse!
• Primary responders, start tapering Prednisolone 1 to 2 weeks after complete
remission is attained
• Reduce daily dose by 5 to 10mg per week over 16 to 20 weeks

35. Glucocorticoid-sparing regimens
• Steroid-sparing therapy are saved for;
• Frequent relapsers,
• Steroid dependent,
• Steroid resistant,
• Patients with drug-related adverse effects
• Patients with contraindications to steroid therapy or those who do
not wish to take high dose steroids
• CNIs- (Tacrolimus, Cyclosporine), Cyclophosphamide, Chlorambucil,
MMF, Rituximab

36. Glucocorticoid-sparing regimens
• If CNI-based regimen is used as initial therapy and as monotherapy, either
cyclosporine or tacrolimus is a reasonable choice
• Cyclosporine; initial dose 5mg/kg per day in 2 divided doses to maintain
whole blood trough levels between 150 and 200ng/ml
• Tacrolimus; 0.05 – 0.1mg/kg per day in 2 divided doses to maintain whole
blood troughs between 4 and 7ng/ml
• Once complete remission is achieved we continue these doses for an
additional 12 weeks and gradually taper over 8 weeks
• Total duration is approximately 6 months
• MMF can be administered with reduced steroids (low as 0.5mg/kg per day)
and gradually taper

37. Monitoring response to therapy

38. Monitoring response to therapy
• Assess patient‘s clinical response closely
• uPCR, serum albumin, and serum Cr monthly
• Remissions are typically abrupt with patient being free from
proteinuria within 2 to 3 weeks from time of initial response
• In majority of MCD, response is an ‘all or nothing‘ type
• Partial responses are not characteristic of MCD, when seen, suspect a
misdiagnosis (usually FSGS)

39. DEFINITIONS OF RESPONSE
• Complete Remission; a reduction in proteinuria to <300mg/day, stable
serum creatinine, and serum albumin >3.5g/dl
• Partial Remission; reduction in proteinuria of >50%, with absolute
values between 300mg and 3.5mg/dl
• Primary responders; are patients who have complete remission after
a single course of prednisolone
• Steroid dependent; relapse occuring when the steroid dose is tapered
or within 2 weeks of completing glucocorticoid therapy

40. RELAPSE

41. Relapsing Disease
• Disease relapse is defined as a return of proteinuria to >3.5g/day in
patients who had previously undergone complete remission
• May be triggered by allergies or infections
• Approximately 50 – 70% of glucocorticoid sensitive adults will have a
relapse
• Frequent or Infrequent relapse
• Patients can self-diagnose relapse when they notice foamy urine or
oedema
• Re-institue therapy
• Glucocorticoid dependence is seen in 25 – 30 %

42. Glucocorticoid-Resistant MCD
• Glucocorticoid resistance refers to the persistence of proteinuria >3.5g/day
with less than or equal to 50% reduction from baseline after 16 weeks of
adequate glucocorticoid therapy
• Approximately 5 – 10% of patients with MCD are glucocorticoid resistant
• Causes; inadequate initial therapy, incorrect diagnosis, minimal change
variants
• Glucocorticoid resistant MCD may have FSGS on repeat biopsy
• Repeat kidney biopsy?!
• Treatment; generally CNIs +/- low dose Prednisolone

43. COMPLICATIONS
• Hypovolaemic shock
• Hypertension
• Thromboembolic events, may lead to gangrene, pulmonary emboli
• Bacterial infections
• Cardiovascular disease
• ESRD

44. PROGNOSIS
• Most important prognostic factor apears to be the initial response to glucocorticoid
therapy
• Some untreated patients eventually undergo remission, but are exposed to
complications
• Less favourable prognosis when steroid resistance or acute kidney injury occurs
• Long term effects of cytotoxic and steroid therapy
• AKI; some may not recover requiring dialysis
• ESRD is rare. Mostly seen in glucocorticoid-resistant cases
• Overall prognosis is good, 1/3rd have just 1 episode, 1/3rd have infrequent relapses,
1/3rd have frequent relapses

45. CONCLUSION
• MCD is a cause of nephrotic syndrome in adults
• Podocytopathy is the hallmark pathogenic mechanism
• Goal of therapy is to significantly reduce proteinuria and induce
remission with immunosuppressives
• Untreated MCD is associated with potentially fatal outcomes

46. REFERENCES
• Johnson RJ, Feehally J, Floege J, Marcello T. Comprehensive Clinical
Nephrology. 5e. Philadelphia, PA; Elsevier/Saunders 2015
• Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds.
Harrison‘s Principles of Internal Medicine, 18e. New York; McGraw
Hill; 2012.
• Nolasco F, Cameron JS, Heywood EF, et al. Adult Onset Minimal
Change Nephrotic Syndrome; a long-term follow up. Kidney Int 1986;
29:1215.
• Korbet SM, Schwartz MM, Lewis EJ. Minimal Change Glomerulopathy
of Adulthood. Am J Nephrol 1988; 8:291

47. THANK YOU