Minimal Change Disease (MCD) is a type of nephrotic syndrome characterized by proteinuria and swelling without significant findings on light microscopy. It is caused by a circulating permeability factor that leads to foot process effacement on electron microscopy. MCD is most common in children and responds well to steroid treatment, though relapses are common. Second line treatments include cyclophosphamide or rituximab if relapses are frequent or the patient is steroid dependent.

1. Minimal Change Disease
Fellows’ Curriculum
Amanda Valliant, MD
Nephrology Fellow
10.17.2012

2. Objectives
Epidemiology
Pathology
Pathogenesis
Etiology/Associations
Diagnosis
Treatment

3. Epidemiology
First described in 1913 by Munk, who called it lipoid
nephrosis due to lipids in tubular epithelial cells and urine
More common in children
70-90% of nephrotic syndromes in kids <10
50% of nephrotic syndromes in kids 10-18
10-15% of primary nephrotic syndromes in adults; 3rd most
common after FSGS and MN
More common in Asia than in North America/Europe
? Biopsy practices? vs genetic or environmental influence

4. Biopsy-Proven Proteinuria Causes (>3g/day)
FIGURE 31-1 Graph depicting the frequencies of different forms of glomerular disease identified in renal
biopsy specimens from patients with proteinuria of more than 3 g of protein per day evaluated at the
University of North Carolina Nephropathology Laboratory. Some diseases that cause proteinuria are
underrepresented because they are not always evaluated by renal biopsy. For example, in many patients steroid-
responsive proteinuria is given a presumptive diagnosis of minimal change glomerulopathy and patients do not
undergo biopsy, and most patients with diabetes and proteinuria are presumed to have diabetic
glomerulosclerosis and do not undergo biopsy.

5. Pathology: Light Microscopy
FIGURE 31-2 Unremarkable light microscopic appearance of a biopsy specimen from a patient with
minimal change glomerulopathy. Glomerular basement membranes are thin, and there is no glomerular
hypercellularity or mesangial matrix expansion. (Jones’ methenamine silver stain, ×300.)
Brenner and Rector’s The Kidney, 9th Ed. CH. 31—Primary Glomerular Disease

6. Pathology: Foot Process Effacement
FIGURE 31-3 Diagrams depicting the ultrastructural features of a normal glomerular capillary loop
(A) and a capillary loop with features of minimal change glomerulopathy (B). The latter has effacement
of epithelial foot processes (arrow) and microvillous projections of epithelial cytoplasm.
Brenner and Rector’s The Kidney, 9th Ed. CH. 31—Primary Glomerular Disease

7. Pathology: Electron Microscopy
 FIGURE 31-4 Electron micrograph of a glomerular capillary wall from a patient with minimal
change glomerulopathy showing extensive foot process effacement (arrows) and microvillous
transformation. (×5000.)
Brenner and Rector’s The Kidney, 9th Ed. CH. 31—Primary Glomerular Disease

8. Pathogenesis—T Cell Dysfunction?
 Likely the result of abnormal regulation of a T-cell subset and
pathologic elaboration of one or more circulating “permeability
factors”
 Circulating factor thought to directly effect the glomerular
capillary wall  foot process effacement and fusion
 Steroids and alkylating drugs (cyclophosphamide) most effective for
remission
 Association with Hodgkins; occurs more frequently than in general pop
 Remission tends to occur during viral illnesses like measles known to modify
cell-mediated immunity
 Transplanting a kidney from a patient with refractory minimal change
disease  rapid disappearance of proteinuria

9. Pathogenesis—B Cells?
Initially thought to be uninvolved or negligible
Recent publications demonstrating response to rituximab
(B20 monoclonal antibody) suggest B cell involvement in
producing permeability factors in circulation

10. Pathogenesis—Does this “permeability
factor” exist?
T-cell hybridoma from MCD patient  proteinuria and foot
process effacement in rats
Isolated rat glomeruli + sera from Hodgkins patient with
MCD  increased permeability to albumin, improved when
Hodgkins treated but NOT with steroids
2 MCD kidneys transplanted into 2 recipients (oops) 
proteinuria at time of grafting decreased to normal in 6
weeks

11. Pathogenesis—What IS this factor?
Hemopexin
Plasma protein with an active isoform that may cause increased
glomerular permeability
Patients with relapsed disease demonstrate increased levels of
hemopexin proteinase activity
Th2-derived cytokine IL-13
Rats with IL-13 overexpression  albuminuria,
hypoalbuminemia, up to 80% foot process fusion on biopsy
Patients with relapsed MCD have increased expression
IL-13 induces CD80 expression in rat podocytes  foot
process fusion and proteinuria

12. Overexpression of Interleukin-13 Induces
Minimal-Change–
Like Nephropathy in Rats
Background
MCD may be a T cell dependent disorder that results in glomerular
podocyte dysfunction
Th2 cytokine bias in patients with MCD
 MCD associated with atopy and allergy
 Relapse MCD with elevated IL-4 and IL-13
Association between MCD and Hodgkins’s disease
 IL-13 known to be an autocrine growth factor for the Reed-Sternberg
JASN 18 : 1476-1485,2007

13. Hypothesis
IL-13 may play an important role in the development of
proteinuria in MCNS by exerting a direct effect on podocytes,
acting through the IL-13 receptors on the podocyte cell surface,
initiating certain signaling pathways that eventually lead to changes
in the expression of podocyte-related proteins (nephrin, podocin,
and dystroglycan)
IL-13 transfected rat was used as a model in this study

14. Mean 24-h urine albumin excretion
(mg/24 h)
Controls n=17
IL 13 n =41

15. Comparison of control, IL-13-transfected mouse
at experiment end (day 70)
Parameter Control Rats Group 1 Grp 2: neprhrotic
(n=17) (proteinuric rats), rats n=7
n=34
Serum albumin 42.7 +/- 1.8 40.7 +/- 1.3 25.5 +/- 2.2
Urine albumin 0.36 +/- 0.04 3.19 +/- 0.98 9.69 +/- 4.07
Serum cholesterol 1.72 +/- 0.05 2.68 +/- 0.18 6.88 +/- 1.09
Serum IL-13 7.1 +/- 1.8 241.4 +/- 69.5 708.6 +/- 257.7
Nephrin 0.16 +/- 0.03 0.11 +/- 0.01 0.01 +/- 0.005
Podocin 0.25+/- 0.05 0.17 +/- 0.02 0.01 +/- 0.005
Yellow = p <0.001 vs control Red = p<0.001 vs control and Grp 1

16. Histopathologic features on day 70
at killing
(A) Glomerulus of IL-13–transfected rat
showing no significant histologic changes
(periodic acid-Schiff stain).
(B) Glomerulus of IL-13–transfected rat
showing fusion of podocyte foot processes
(arrows).
(C) Glomerulus of control rat showing
normal individual podocyte foot processes
along the glomerular basement membrane
(GBM; arrows).

17. Control IL-13 infected
nephrin
Immunofluorescence staining of
glomeruli for protein expression
of nephrin, podocin, dystroglycan,
podocin and synaptopodin
dystroglycan
synaptopodin

18. Summary
IL-13-transfected rats
Developed minimal change like GN, as evidence by LM and EM changes
Decrease in the expression of nephrin, podocin, and dystroglycan
associated with increased urinary albumin excretion and podocyte foot
process effacement
 suggesting that these proteins are essential in maintaining the filtration barrier, thus
controlling glomerular permeability
 decrease was not due to loss of podocytes (glomerular expression of WT-1 and
synaptopodin showed no difference between control and IL-13 transfected rats)

19. Pathogenesis—How does the GBM
factor in?
 3 structures separate the capillary lumen from Bowman’s space
Fenestrated endothelium
Glomerular Basement Membrane (GBM)
Epithelium with a slit diaphragm between podocyte foot processes
 Endothelium and GBM are strongly anionic—negative charges from
sialic acid and heparin sulfate
Normally (-) charge repulses circulating albumin
Theory is that the circulating permeability factor diminishes the anionic
property of the GBM
 Slit diaphragm plays a critical role with visible defects on EM in MCD
patients but pathophysiology not understood

20. 

21. Pathophysiology of MCD
UNC
UNC Medical Center

23. Etiology--Drugs
 NSAIDs and selective COX-2 Inhibitors
Antimicrobials (ampicillin, rifampicin, cephalosporins)
Lithium
D-penicillamine, sulfasalazine (any 5-ASA derivative)
Pamidronate (and presumably other bisphosphonates)
Gamma interferon
Immunizations

24. Etiology—Neoplastic Associations
Hodgkin Lymphoma (0.4%)
Non-Hodgkin Lymphoma and Leukemia
Cases of MCD associated with solid tumors are rare but have
been reported
MCD diagnosis may precede signs and symptoms of the
malignancy
Proteinuria typically resolves with treatment of the
malignancy

25. Etiology—Infectious Associations
Rare associations with syphyllis, tuberculosis, mycoplasma,
ehrlichiosis, Hep C, echinococcus
MCD has been described in HIV infection but collapsing
FSGS much more commonly seen

26. Etiology—Allergy Associations
History of allergy described in up to 30% of cases
Multiple allergens described (fungi, cat fur, poison ivy,
pollen, bee stings, house dust)
Onset and relapses have been triggered by bee stings and
allergic reactions
Limited evidence for involvement of food allergy but one
small dietary study suggested an association (oligoantigenic
diet???)

27. Etiology—Other Glomerular Diseases
Association with IgA Nephropathy, with mesangial IgA
deposits and mild mesangial proliferation seen in
concurrence with MCD on biopsy
Reports of MCD occurring with the following, but rare:
Systemic Lupus Erythematosus
Type 1 Diabetes
Polycystic Kidney Diseases

28. MCD Presentation
Typically sudden onset, over days to a week or two
Weight gain, edema, “frothy” urine
Proteinuria >3 g daily and sometimes 15-20 g/day
Hypoalbuminemia, often <2 g/dL
Most cases also demonstrate hyperlipidemia
Microscopic hematuria fairly common in adults, found in 20-
25% of children
AKI not an infrequent complication in adults, creatinine
elevation typically 30-40% > baseline
40-50% will have hypertension at the time of diagnosis

29. MCD Diagnosis
Renal biopsy needed prior to treatment in adults; children
can be treated presumptively with steroids
Need to demonstrate ALL of the following on biopsy:
Normal glomerular findings on light microscopy
Absence of complement or Ig deposits on immunflourescence
Characteristic diffuse effacement of epithelial foot processes on
EM

30. MCD vs FSGS
Primary FSGS diagnosis requires biopsy findings of segmental
glomerusclerosis in at least 1 glomerulus in addition to
diffuse foot process effacement
Sclerotic changes appear first at the juxtamedullary
glomeruli, which may not be seen in a biopsy sample
containing only outer cortex or with <8 glomeruli on biopsy
Some cases that respond poorly to steroids and progress to
ESRD are thought to have been missed FSGS rather than
MCD at initial diagnosis

31. Odds & Ends
 Diagnosis in the elderly may be challenging as changes of aging
may suggest primary FSGS rather than MCD superimposed on
aging glomerulosclerosis of aging should be focal and global
rather than focal and segmental
 Nephrotic syndrome + AKI  also should consider collapsing
FSGS (idiopathic or HIV), crescentic GN superimposed on
membranous nephropathy, nephrotic syndrome due to
monoclonal Ig deposition (cast nephropathy)
 Renal vein thrombosis may occur as a complication of MCD but is
typically CHRONIC in nature and does not cause renal failure due
to collateral circulation

32. MCD Treatment
Glucocorticoid therapy is treatment of choice initially
Prednisone 1 mg/kg daily (max 80 mg daily)
Complete response and remission defined as reduction of
proteinuria to 300 mg/day
Relapse defined as return to 3.5g/day or more after previous
remission
Frequent relapsers defined as 3 or more relapses per year
Remission occurs in 85-90% with steroids but may take several
months to remit in adults (25% take longer than 3-4 months)
Response to initial steroid therapy most important prognostic
indicator

33. MCD Treatment
 Glucocorticoid dependance considered relapse on therapy or patients who must
stay on steroids to maintain remission
 Glucocorticoid resistane refers to little to no reduction in proteinuria after 16
weeks of adequate prednisone tehrapy
 Remissions as well as relapses usually abrupt, occurring within 1-2 weeks 
“all or nothing” response
 Partial response = ? Diagnosis ?
 Relapses may be triggered by infection or allergy
 Most relapses occur within one year of stopping therapy but have been known
to occur up to 25 years later

34. MCD Treatment
Diuretics + salt-free diet also important in treatment due to
severe edema + hypertension typically present
If patient remains hypertensive, ARB or ACEI should be
considered for further treatment
Steroid taper should not be started for minimum of 8 weeks
or 1-2 weeks after complete remission
Very slow taper recommended to prevent relapse

35. Treatment—Glucocorticoids
 There is only one randomized control treatment trial in
adults with MCD that compared prednisone with no
therapy (n=31).
- 75 % of prednisone treated patients had remission to
<1g/day of proteinuria within 6 months.
- In the untreated group, 50% were in remission at 18
months and approximately 70% at three years.
 There are no randomized control trials comparing
prednisone to other agents for the initial therapy in adults
with MCD.
Black DA et al. BMJ 3:p421, 1970.

36. Second Line Therapy
Reasonable to repeat steroid course in patients who relapse off
of steroids
Relapsing while on steroids or frequent relapsers may need
additional treatment
Alkylating agents such as cyclophosphamide can be used but must
be monitored closely
Antimetabolites (azathioprine, mycophenolate mofetil) are often
helpful
CNIs such as cyclosporine or tacrolimus effective but may cause
renal injury
 Direct antiproteinuric effect on the podocyte
Continuous low-dose prednisone often considered but must
discuss long-term side effects

37. Second Line Therapy
 Cyclosporine tends to achieve a more rapid remission, but
between 60-90% of patients relapse after discontinuation making
cyclosporine dependence a major issue.
 Both cyclophosphamide and cyclosporine reported to induce and
maintain remission in up to 60% of MCD patients, less so in
steroid resistant cases (10%).
No prospective trials on second-line treatment; all have been
retrospective observational reports.

38. Sources
www.uptodate.com
“Etiology, clinical features, and diagnosis of minimal change
disease in adults”
“Treatment of minimal change disease in adults”
Greenburg, A. Primer on Kidney Diseases,5th Edition.
NKF, 2009. Chapter 17, Minimal Change Nephrotic
Syndrome, pp. 160-164.
Brenner and Rector’s The Kidney, 9th Edition. CH. 31,
Primary Glomerular Diseases.
www.slideshare.com

39. Thank You!
Questions?