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Fellows’ CurriculumAmanda Valliant, MDNephrology Fellow
10.17.2012
Minimal Change Disease
Objectives
EpidemiologyPathologyPathogenesisEtiology/AssociationsDiagnosisTreatment
EpidemiologyFirst described in 1913 by Munk, who called it
lipoid nephrosis due to lipids in tubular epithelial cells and urine
More common in children70-90% of nephrotic syndromes in kids <1050% of nephrotic syndromes in kids 10-1810-15% 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
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.
Pathology: Light MicroscopyFIGURE 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
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
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
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 fusionSteroids and alkylating drugs (cyclophosphamide) most
effective for remissionAssociation with Hodgkins; occurs more frequently than in
general popRemission tends to occur during viral illnesses like measles
known to modify cell-mediated immunityTransplanting a kidney from a patient with refractory minimal
change disease rapid disappearance of proteinuria
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
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
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
Overexpression of Interleukin-13 Induces Minimal-Change–Like Nephropathy in Rats
BackgroundMCD may be a T cell dependent disorder that
results in glomerular podocyte dysfunctionTh2 cytokine bias in patients with MCD
MCD associated with atopy and allergyRelapse MCD with elevated IL-4 and IL-13
Association between MCD and Hodgkins’s diseaseIL-13 known to be an autocrine growth factor for the Reed-
Sternberg
JASN 18 : 1476-1485,2007
HypothesisIL-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
Mean 24-h urine albumin excretion (mg/24 h)
Controls n=17
IL 13 n =41
Comparison of control, IL-13-transfected mouse at experiment end (day 70)
ParameterParameter Control Rats Control Rats (n=17)(n=17)
Group 1 Group 1 (proteinuric (proteinuric rats), n=34rats), n=34
Grp 2: Grp 2: neprhrotic neprhrotic rats n=7rats n=7
Serum Serum albuminalbumin
42.7 +/- 1.842.7 +/- 1.8 40.7 +/- 1.340.7 +/- 1.3 25.5 +/- 2.225.5 +/- 2.2
Urine albuminUrine albumin 0.36 +/- 0.040.36 +/- 0.04 3.19 +/- 0.983.19 +/- 0.98 9.69 +/- 4.079.69 +/- 4.07
Serum Serum cholesterolcholesterol
1.72 +/- 0.051.72 +/- 0.05 2.68 +/- 0.182.68 +/- 0.18 6.88 +/- 1.096.88 +/- 1.09
Serum IL-13Serum IL-13 7.1 +/- 1.87.1 +/- 1.8 241.4 +/- 69.5241.4 +/- 69.5 708.6 +/- 708.6 +/- 257.7257.7
NephrinNephrin 0.16 +/- 0.030.16 +/- 0.03 0.11 +/- 0.010.11 +/- 0.01 0.01 +/- 0.0050.01 +/- 0.005
PodocinPodocin 0.25+/- 0.050.25+/- 0.05 0.17 +/- 0.020.17 +/- 0.02 0.01 +/- 0.0050.01 +/- 0.005Yellow = p <0.001 vs control Red = p<0.001 vs control and Grp 1
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).
Immunofluorescence staining of glomeruli for
protein expression of nephrin, podocin, dystroglycan, and
synaptopodin
nephrin
podocin
dystroglycan
synaptopodin
Control IL-13 infected
Summary
IL-13-transfected ratsDeveloped minimal change like GN, as evidence by
LM and EM changesDecrease in the expression of nephrin, podocin, and
dystroglycan associated with increased urinary albumin excretion and podocyte foot process effacementsuggesting 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)
Pathogenesis—How does the GBM factor in?
3 structures separate the capillary lumen from Bowman’s spaceFenestrated endotheliumGlomerular 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 sulfateNormally (-) charge repulses circulating albuminTheory 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
Pathophysiology of MCDUNC
UNC Medical Center
Etiology--Drugs NSAIDs and selective COX-2 InhibitorsAntimicrobials (ampicillin, rifampicin,
cephalosporins)LithiumD-penicillamine, sulfasalazine (any 5-ASA
derivative)Pamidronate (and presumably other
bisphosphonates)Gamma interferonImmunizations
Etiology—Neoplastic AssociationsHodgkin 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
Etiology—Infectious AssociationsRare associations with syphyllis,
tuberculosis, mycoplasma, ehrlichiosis, Hep C, echinococcus
MCD has been described in HIV infection but collapsing FSGS much more commonly seen
Etiology—Allergy AssociationsHistory of allergy described in up to 30% of
casesMultiple allergens described (fungi, cat fur,
poison ivy, pollen, bee stings, house dust)Onset and relapses have been triggered by
bee stings and allergic reactionsLimited evidence for involvement of food
allergy but one small dietary study suggested an association (oligoantigenic diet???)
Etiology—Other Glomerular DiseasesAssociation 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 ErythematosusType 1 DiabetesPolycystic Kidney Diseases
MCD PresentationTypically sudden onset, over days to a week or
twoWeight gain, edema, “frothy” urineProteinuria >3 g daily and sometimes 15-20
g/dayHypoalbuminemia, often <2 g/dLMost cases also demonstrate hyperlipidemiaMicroscopic hematuria fairly common in adults,
found in 20-25% of childrenAKI not an infrequent complication in adults,
creatinine elevation typically 30-40% > baseline40-50% will have hypertension at the time of
diagnosis
MCD DiagnosisRenal 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
immunflourescenceCharacteristic diffuse effacement of epithelial
foot processes on EM
MCD vs FSGSPrimary 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
Odds & EndsDiagnosis 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
MCD TreatmentGlucocorticoid therapy is treatment of choice
initiallyPrednisone 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 yearRemission 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
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” responsePartial 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
MCD TreatmentDiuretics + 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 remissionVery slow taper recommended to prevent relapse
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.
Second Line TherapyReasonable to repeat steroid course in
patients who relapse off of steroidsRelapsing while on steroids or frequent
relapsers may need additional treatmentAlkylating agents such as cyclophosphamide
can be used but must be monitored closelyAntimetabolites (azathioprine, mycophenolate
mofetil) are often helpfulCNIs such as cyclosporine or tacrolimus
effective but may cause renal injuryDirect antiproteinuric effect on the podocyte
Continuous low-dose prednisone often considered but must discuss long-term side effects
Second Line TherapyCyclosporine 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.
Sourceswww.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.
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