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.

www.slideshare.com

Thank You!

Questions?