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
EpidemiologyFirst described in 1913 by Munk, who called it lipoid nephrosis due to lipids in tubular epithelial cells and urineMore 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 MNMore 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 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.
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
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 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
Pathogenesis—B Cells?Initially thought to be uninvolved or negligibleRecent 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 ratsIsolated rat glomeruli + sera from Hodgkins patient with MCD increased permeability to albumin, improved when Hodgkins treated but NOT with steroids2 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 activityTh2-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 RatsBackground 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
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)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
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).
Control IL-13 infected nephrin Immunofluorescence staining of glomeruli for protein expression of nephrin, podocin, dystroglycan, podocin and synaptopodin dystroglycan synaptopodin
SummaryIL-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)
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
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 LeukemiaCases of MCD associated with solid tumors are rare but have been reportedMCD diagnosis may precede signs and symptoms of the malignancyProteinuria typically resolves with treatment of the malignancy
Etiology—Infectious AssociationsRare associations with syphyllis, tuberculosis, mycoplasma, ehrlichiosis, Hep C, echinococcusMCD 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 biopsyReports of MCD occurring with the following, but rare: Systemic Lupus Erythematosus Type 1 Diabetes Polycystic 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 steroidsNeed 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
MCD vs FSGSPrimary FSGS diagnosis requires biopsy findings of segmental glomerusclerosis in at least 1 glomerulus in addition to diffuse foot process effacementSclerotic 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 biopsySome cases that respond poorly to steroids and progress to ESRD are thought to have been missed FSGS rather than MCD at initial diagnosis
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
MCD TreatmentGlucocorticoid 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/dayRelapse defined as return to 3.5g/day or more after previous remissionFrequent 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
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
MCD TreatmentDiuretics + salt-free diet also important in treatment due to severe edema + hypertension typically presentIf patient remains hypertensive, ARB or ACEI should be considered for further treatmentSteroid taper should not be started for minimum of 8 weeks or 1-2 weeks after complete remission Very 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 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
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.
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