Minimal Change Disease     Fellows’ Curriculum     Amanda Valliant, MD      Nephrology Fellow          10.17.2012
ObjectivesEpidemiologyPathologyPathogenesisEtiology/AssociationsDiagnosisTreatment
EpidemiologyFirst described in 1913 by Munk, who called it lipoid  nephrosis due to lipids in tubular epithelial cells an...
Biopsy-Proven Proteinuria Causes (>3g/day)FIGURE 31-1 Graph depicting the frequencies of different forms of glomerular dis...
Pathology: Light Microscopy FIGURE 31-2 Unremarkable light microscopic appearance of a biopsy specimen from a patient with...
Pathology: Foot Process Effacement FIGURE 31-3 Diagrams depicting the ultrastructural features of a normal glomerular cap...
Pathology: Electron Microscopy FIGURE 31-4 Electron micrograph of a glomerular capillary wall from a patient with minimal...
Pathogenesis—T Cell Dysfunction? Likely the result of abnormal regulation of a T-cell subset and  pathologic elaboration ...
Pathogenesis—B Cells?Initially thought to be uninvolved or negligibleRecent publications demonstrating response to ritux...
Pathogenesis—Does this “permeability          factor” exist?T-cell hybridoma from MCD patient  proteinuria and foot  pro...
Pathogenesis—What IS this factor?Hemopexin  Plasma protein with an active isoform that may cause increased   glomerular ...
Overexpression of Interleukin-13 Induces            Minimal-Change–        Like Nephropathy in RatsBackground  MCD may b...
HypothesisIL-13 may play an important role in the development of  proteinuria in MCNS by exerting a direct effect on podo...
Mean 24-h urine albumin excretion           (mg/24 h)                                    Controls n=17                    ...
Comparison of control, IL-13-transfected mouse          at experiment end (day 70)Parameter           Control Rats    Grou...
Histopathologic features on day 70              at killing (A) Glomerulus of IL-13–transfected ratshowing no significant h...
Control           IL-13 infected            nephrin                                    Immunofluorescence staining of     ...
SummaryIL-13-transfected rats  Developed minimal change like GN, as evidence by LM and EM changes  Decrease in the expr...
Pathogenesis—How does the GBM                  factor in? 3 structures separate the capillary lumen from Bowman’s space  ...

Pathophysiology of MCDUNCUNC Medical Center
Etiology--Drugs NSAIDs and selective COX-2 InhibitorsAntimicrobials (ampicillin, rifampicin, cephalosporins)LithiumD-p...
Etiology—Neoplastic AssociationsHodgkin Lymphoma (0.4%)Non-Hodgkin Lymphoma and LeukemiaCases of MCD associated with so...
Etiology—Infectious AssociationsRare associations with syphyllis, tuberculosis, mycoplasma,  ehrlichiosis, Hep C, echinoc...
Etiology—Allergy AssociationsHistory of allergy described in up to 30% of casesMultiple allergens described (fungi, cat ...
Etiology—Other Glomerular DiseasesAssociation with IgA Nephropathy, with mesangial IgA  deposits and mild mesangial proli...
MCD PresentationTypically sudden onset, over days to a week or twoWeight gain, edema, “frothy” urineProteinuria >3 g da...
MCD DiagnosisRenal biopsy needed prior to treatment in adults; children  can be treated presumptively with steroidsNeed ...
MCD vs FSGSPrimary FSGS diagnosis requires biopsy findings of segmental  glomerusclerosis in at least 1 glomerulus in add...
Odds & Ends Diagnosis in the elderly may be challenging as changes of aging  may suggest primary FSGS rather than MCD sup...
MCD TreatmentGlucocorticoid therapy is treatment of choice initially  Prednisone 1 mg/kg daily (max 80 mg daily)Complet...
MCD Treatment Glucocorticoid dependance considered relapse on therapy or patients who must   stay on steroids to maintain...
MCD TreatmentDiuretics + salt-free diet also important in treatment due to  severe edema + hypertension typically present...
Treatment—Glucocorticoids  There is only one randomized control treatment trial in   adults with MCD that compared predni...
Second Line TherapyReasonable to repeat steroid course in patients who relapse off of steroidsRelapsing while on steroid...
Second Line Therapy Cyclosporine tends to achieve a more rapid remission, but  between 60-90% of patients relapse after d...
Sourceswww.uptodate.com  “Etiology, clinical features, and diagnosis of minimal change   disease in adults”  “Treatment...
Thank You!Questions?
Minimal Change Disease
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  • 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
  • Minimal Change Disease

    1. 1. Minimal Change Disease Fellows’ Curriculum Amanda Valliant, MD Nephrology Fellow 10.17.2012
    2. 2. ObjectivesEpidemiologyPathologyPathogenesisEtiology/AssociationsDiagnosisTreatment
    3. 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. 4. Biopsy-Proven Proteinuria Causes (>3g/day)FIGURE 31-1 Graph depicting the frequencies of different forms of glomerular disease identified in renalbiopsy specimens from patients with proteinuria of more than 3 g of protein per day evaluated at theUniversity of North Carolina Nephropathology Laboratory. Some diseases that cause proteinuria areunderrepresented 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 notundergo biopsy, and most patients with diabetes and proteinuria are presumed to have diabeticglomerulosclerosis and do not undergo biopsy.
    5. 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. 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. 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. 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. 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. 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. 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. 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. 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. 14. Mean 24-h urine albumin excretion (mg/24 h) Controls n=17 IL 13 n =41
    15. 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=34Serum albumin 42.7 +/- 1.8 40.7 +/- 1.3 25.5 +/- 2.2Urine albumin 0.36 +/- 0.04 3.19 +/- 0.98 9.69 +/- 4.07Serum cholesterol 1.72 +/- 0.05 2.68 +/- 0.18 6.88 +/- 1.09Serum IL-13 7.1 +/- 1.8 241.4 +/- 69.5 708.6 +/- 257.7Nephrin 0.16 +/- 0.03 0.11 +/- 0.01 0.01 +/- 0.005Podocin 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. 16. Histopathologic features on day 70 at killing (A) Glomerulus of IL-13–transfected ratshowing no significant histologic changes (periodic acid-Schiff stain). (B) Glomerulus of IL-13–transfected ratshowing fusion of podocyte foot processes (arrows). (C) Glomerulus of control rat showingnormal individual podocyte foot processesalong the glomerular basement membrane (GBM; arrows).
    17. 17. Control IL-13 infected nephrin Immunofluorescence staining of glomeruli for protein expression of nephrin, podocin, dystroglycan, podocin and synaptopodin dystroglycan synaptopodin
    18. 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. 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. 20.
    21. 21. Pathophysiology of MCDUNCUNC Medical Center
    22. 22. 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
    23. 23. 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
    24. 24. 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
    25. 25. 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???)
    26. 26. 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
    27. 27. 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
    28. 28. 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
    29. 29. 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
    30. 30. 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
    31. 31. 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
    32. 32. 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
    33. 33. 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
    34. 34. 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.
    35. 35. 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
    36. 36. 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.
    37. 37. 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
    38. 38. Thank You!Questions?
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