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
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
Mean 24-h urine albumin excretion (mg/24 h) of control rats ( n = 17) and IL-13 –transfected rats ( n = 41) measured at 14-d intervals. Data are means ± SEM.
Immunofluorescence examination showed that nephrin, podocin, and dystroglycan all stained strongly as a continuous granular pattern along the GBM in the control rats . This was in contrast to the nephrotic rats, in which the fluorescence signal was much weaker and in a discontinuous, and sometimes segmental, granular pattern along the GBM Of note, there was no significant difference between the control and nephrotic rats in the expression of synaptopodin, which showed strong and continuous staining along the GBM. In FSGS usually podocytopenia results where there’s decrease in the number of podocyte 2/2 stress, injury, intrinsic factor. IN MCD, there’s a phenotypic change with decrease in absolute no of podocyte.
… . , because the glomerular expression of WT-1 and synaptopodin, which are specific cell surface markers of podocytes, showed no significant difference between the control rats and the IL-13 –transfected rats