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Minimal Change Disease,Minimal Change Disease,Some new updates!Some new updates!
Deepti Torri M.DDeepti Torri M.D
North Shore-LIJ NephrologyNorth Shore-LIJ Nephrology
Hofstra Medical SchoolHofstra Medical School
IntroductionIntroduction Most common cause of the nephrotic Most common cause of the nephrotic
syndrome in children, MCD contributes to 90 syndrome in children, MCD contributes to 90 % of cases.% of cases.
~10-15% of nephrotic syndrome in adults, ~10-15% of nephrotic syndrome in adults, third most common after MN and FSGSthird most common after MN and FSGS More common in Hispanics, Asians, Arabs and More common in Hispanics, Asians, Arabs and
CaucasiansCaucasians clinical and pathologicalclinical and pathological entity defined by entity defined by
selective proteinuria and hypoalbuminemiaselective proteinuria and hypoalbuminemia
that occurs in the that occurs in the absenceabsence of of cellular glomerular infiltratescellular glomerular infiltrates or or immunoglobulin depositsimmunoglobulin deposits
Pathogenesis - “Intrinsic Pathogenesis - “Intrinsic factor”factor”
Genetic basis for hereditary NSGenetic basis for hereditary NS NS of the Finnish typeNS of the Finnish type Autosomal-recessive steroid-resistant NSAutosomal-recessive steroid-resistant NS Familial forms of FSGSFamilial forms of FSGS Diffuse mesangila sclerosis associated with Diffuse mesangila sclerosis associated with
Denys-Drash syndrome and with Frasier Denys-Drash syndrome and with Frasier syndromesyndrome
NS associated with nail-patella syndromeNS associated with nail-patella syndrome Help elucidate molecular aspect of FSGSHelp elucidate molecular aspect of FSGS Not clear for MCDNot clear for MCD
Molecular anatomy of the Molecular anatomy of the podocyte foot process podocyte foot process
cytoskeletoncytoskeleton
Nature Genetics 24, 333 - 335 (2000)
Pathogenesis – extrinsic Pathogenesis – extrinsic factor, better explanation factor, better explanation
for MCDfor MCD Clinical Observations - Shalhoub’s hypothesisClinical Observations - Shalhoub’s hypothesis
MCD frequently remits with measles infectionMCD frequently remits with measles infection Corticosteroids and alkylating drugs cause a remissionCorticosteroids and alkylating drugs cause a remission Association of MCD with Hodgkin diseaseAssociation of MCD with Hodgkin disease
Experimental ObservationsExperimental Observations T cell hybridoma (Koyama KI 1991 (40): 453-460)T cell hybridoma (Koyama KI 1991 (40): 453-460) Removal of glomerular permeability factor leads to Removal of glomerular permeability factor leads to
normal kidney (Ali Transplantation 1994 Oct normal kidney (Ali Transplantation 1994 Oct 15;58(7):849-52)15;58(7):849-52)
““circulating factor”circulating factor” possible link between T-cell response and possible link between T-cell response and
glomerular diseaseglomerular disease
Overexpression of Interleukin-Overexpression of Interleukin-13 Induces Minimal-Change–13 Induces Minimal-Change–
Like Nephropathy in RatsLike Nephropathy in Rats BackgroundBackground
MCD may be a T cell dependent MCD may be a T cell dependent disorder disorder that results in glomerular podocyte that results in glomerular podocyte dysfunctiondysfunction
Th2 cytokine bias in patients with MCDTh2 cytokine bias in patients with MCD MCD associated with atopy and allergyMCD associated with atopy and allergy Relapse MCD with elevated IL-4 and IL-13Relapse MCD with elevated IL-4 and IL-13
Association between MCD and Hodgkins’s Association between MCD and Hodgkins’s diseasedisease
IL-13 known to be an autocrine growth factorIL-13 known to be an autocrine growth factor for for the Reed-Sternberg the Reed-Sternberg
JASN 18 : 1476-1485,2007
HypothesisHypothesis
IL-13 may play an important role in the IL-13 may play an important role in the development ofdevelopment of proteinuria in MCNS by proteinuria in MCNS by exerting a direct effect on podocytes,exerting a direct effect on podocytes,
acting through the IL-13 receptors on the acting through the IL-13 receptors on the podocyte cell surface,podocyte cell surface, initiating certain initiating certain signaling pathways that eventually lead signaling pathways that eventually lead toto changes in the expression of podocyte-changes in the expression of podocyte-related proteins (nephrin, podocin, and related proteins (nephrin, podocin, and dystroglycan)dystroglycan)
IL-13 transfected rat was used as a modelIL-13 transfected rat was used as a model
Mean 24-h urine albumin Mean 24-h urine albumin excretion (mg/24 h)excretion (mg/24 h)
Controls n=17
IL 13 n =41
Comparison of control, IL-13-Comparison of control, IL-13-transfected mouse at transfected mouse at
experiment end (day 70)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 +/- 241.4 +/- 69.569.5
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 Histopathologic features on day 70 at killingon day 70 at killing
(A) Glomerulus of (A) Glomerulus of IL-13IL-13––transfected rat showing no transfected rat showing no significant histologic significant histologic changes (periodic acid-Schiff changes (periodic acid-Schiff stain). stain).
(B) Glomerulus of (B) Glomerulus of IL-13IL-13––transfected rat showing transfected rat showing fusion of podocyte foot fusion of podocyte foot processes (arrows). processes (arrows).
(C) Glomerulus of control rat (C) Glomerulus of control rat showing normal individual showing normal individual podocyte foot processes podocyte foot processes along the glomerular along the glomerular basement membrane (GBM; basement membrane (GBM; arrows).arrows).
Immunofluorescence Immunofluorescence staining of glomeruli for staining of glomeruli for protein expression of protein expression of nephrin, podocin, nephrin, podocin, dystroglycan, and dystroglycan, and synaptopodinsynaptopodin
nephrin
podocin
dystroglycan
synaptopodin
Control IL-13 infected
SummarySummary
IL-13-transfected ratsIL-13-transfected rats Developed minimal change like GN, as Developed minimal change like GN, as
evidence by LM and EM changesevidence by LM and EM changes decrease in the expression of nephrin, decrease in the expression of nephrin,
podocin,podocin, and dystroglycan associated with and dystroglycan associated with increased urinary albumin excretion and increased urinary albumin excretion and podocytepodocyte foot process effacementfoot process effacement suggesting that these proteins aresuggesting that these proteins are essential in essential in
maintaining the filtration barrier, thus maintaining the filtration barrier, thus controllingcontrolling glomerular permeabilityglomerular permeability
decrease was not due to loss ofdecrease was not due to loss of podocytes - podocytes -
EtiologiesEtiologies
Idiopathic (80-90% of cases) Idiopathic (80-90% of cases)
SecondarySecondary Drugs – NSAIDs, gold, rifampin, penicillins, Drugs – NSAIDs, gold, rifampin, penicillins,
trimethadionetrimethadione Toxins - mercury, leadToxins - mercury, lead Atopic agents - bee stings, poison ivy, pollenAtopic agents - bee stings, poison ivy, pollen Infection – Syphilis, Infectious mononucleosis, HIVInfection – Syphilis, Infectious mononucleosis, HIV Tumor - Hodgkin lymphoma (most commonly), other Tumor - Hodgkin lymphoma (most commonly), other
lymphoproliferative diseases, carcinomaslymphoproliferative diseases, carcinomas
Glassock R. NDT 18:p vi52, 2003.
How does steroid work in How does steroid work in MCD?MCD?
Widely used in treatment but their Widely used in treatment but their mode of action is poorly understood mode of action is poorly understood
What is its effectiveness in MCD What is its effectiveness in MCD where there is no evident where there is no evident inflammationinflammation
Steroid – quick overviewSteroid – quick overview
Inhibitory effects on both innate and Inhibitory effects on both innate and acquired immunologic functionacquired immunologic function
Innate Immune functionInnate Immune function Reduced Inflammatory response:Reduced Inflammatory response:
inhibit transmigration of leukocytesinhibit transmigration of leukocytes attenuate the generation of inflammatory attenuate the generation of inflammatory
exudatesexudates Phospholipase A2 suppresionPhospholipase A2 suppresion COX-2 suppressionCOX-2 suppression
Acquired Immune functionAcquired Immune function Antigen presenting cells, B cell and T cellsAntigen presenting cells, B cell and T cells
Treatment - GlucocorticoidsTreatment - Glucocorticoids Glucocorticoid therapy remains the mainstay Glucocorticoid therapy remains the mainstay
of treatment with complete remission in 75-of treatment with complete remission in 75-97% of adults with MCD.97% of adults with MCD.
There is only one randomized control There is only one randomized control treatment trial in adults with MCD that treatment trial in adults with MCD that compared prednisone with no therapy compared prednisone with no therapy (n=31). (n=31).
- 75 % of prednisone treated patients had 75 % of prednisone treated patients had remission to <1g/day of proteinuria within 6 remission to <1g/day of proteinuria within 6 months.months.
- In the untreated group, 50% were in In the untreated group, 50% were in remission at 18 months and approximately remission at 18 months and approximately 70% at three years.70% at three years.
There are no randomized control trials There are no randomized control trials comparing prednisone to other agents for the comparing prednisone to other agents for the initial therapy in adults with MCD.initial therapy in adults with MCD.
Black DA et al. BMJ 3:p421, 1970.
Treatment - GlucocorticoidsTreatment - Glucocorticoids
StudyStudy Korbet et alKorbet et alNolasco et Nolasco et alal Mak et alMak et al
Fujimoto et Fujimoto et alal
Nakayama et Nakayama et alal
Waldman et Waldman et alal ISKDCISKDC
Number of Number of PatientsPatients 4040 8989 5151 3333 6262 9595 401401
RemissionRemission 98%98% 91%91% 92%92% 97%97% 98%98% 92%92% 95%95%
CompleteComplete 91%91% 78%78% 76%76% 97%97% 93%93% 75%75% 95%95%
PartialPartial 7%7% 13%13% 16%16% 5%5% 17%17%
Steroid Steroid ResistanceResistance 2%2% 9%9% 8%8% 3%3% 2%2% 8%8% 5%5%
Initial response to steroids (1-1.5mg/kg/day) in adult onset minimal change disease.Complete remission defined as < 0.3 g/d of proteinuria.Partial remission defined as >50% reduction of proteinuria from baseline.
Glucocorticoid Treatment Glucocorticoid Treatment ResponseResponse
There were no features at presentation that There were no features at presentation that predicted a response (or lack thereof) to predicted a response (or lack thereof) to steroids.steroids.
Responders tended to have a slightly lower Responders tended to have a slightly lower serum creatinine at presentation compared with serum creatinine at presentation compared with nonresponders but this was not statistically nonresponders but this was not statistically significant (1.3 vs 1.6mg/dl).significant (1.3 vs 1.6mg/dl).
Of note, seven steroid resistant patients Of note, seven steroid resistant patients underwent repeat biopsy in the Waldman study, underwent repeat biopsy in the Waldman study, FSGS was identified in six cases. (whether the FSGS was identified in six cases. (whether the diagnosis of FSGS was missed on initial biopsy diagnosis of FSGS was missed on initial biopsy or there was progression to FSGS is uncertain).or there was progression to FSGS is uncertain).
Waldman et al. CJASN 2: p445, 2007.
RelapsesRelapses
Study Korbet et al Nolasco et al Mak et alFujimoto et al
Nakayama et al
Waldman et al ISKDC
Number of Patients 40 89 51 33 62 95 401Total Relapses
65% 76% 70% 37% 62% 73% 71%Frequent-relapsers
16% 26% 27% 44%Steroid-dependent
40% 14% 50% 10% 18%
Relapse defined as resumption of nephrotic range proteinuria (>3.5 g/d).Frequent relapsers defined as >3 relapses in 1 year period.Steroid dependent defined as relapse upon tapering steroid therapy or within 4 weeks of discontinuation of steroids.
Second Line TreatmentSecond Line Treatment For frequent relapsers and steroid-dependent For frequent relapsers and steroid-dependent
patients.patients.
No prospective treatment trials, all No prospective treatment trials, all retrospective observational reports.retrospective observational reports.
Both cyclophosphamide and cyclosporine Both cyclophosphamide and cyclosporine reported to induce and maintain remission in reported to induce and maintain remission in up to 60% of MCD patients, less so in steroid up to 60% of MCD patients, less so in steroid resistant cases (10%).resistant cases (10%).
Cyclosporine tends to achieve a more rapid Cyclosporine tends to achieve a more rapid remission, but between 60-90% of patients remission, but between 60-90% of patients relapse after discontinuation making relapse after discontinuation making cyclosporine dependence a major issue.cyclosporine dependence a major issue.
Meyrier A et al. NDT 18:p vi79, 2003.Ponticelli et al. KI 43:p1377, 1993.
Second Line TreatmentSecond Line Treatment
Although small retrospective case series Although small retrospective case series have used azathioprine, mycophenolate have used azathioprine, mycophenolate mofetil, and tacrolimus, the data is very mofetil, and tacrolimus, the data is very limited.limited.
LemivasoleLemivasole- An immunomodulator which enhances An immunomodulator which enhances
antibody production and phagocytic antibody production and phagocytic activity of PMNs and monocytes, has been activity of PMNs and monocytes, has been used in children with frequent relapses used in children with frequent relapses and steroid-dependence with increasing and steroid-dependence with increasing rates of steroid free remissions. rates of steroid free remissions.
- A few case reports in adults suggesting A few case reports in adults suggesting possible role in the treatment of MCD.possible role in the treatment of MCD.
RituximabRituximab
PrognosisPrognosis
StudyStudyKorbet et Korbet et
alalNolasco Nolasco
et alet al Mak et alMak et alFujimoto Fujimoto
et alet alNumber Number of of PatientsPatients 4040 8989 5151 3333
Follow Follow up (mo)up (mo)
5454 9191 169169 4646
NephrotiNephroticc
20%20% 6%6% 2%2% 3%3%
ESRDESRD 5%5% 1%1% 2%2%
DeathDeath 8%8% 17%17% 2%2% 3%3%
Complications of Complications of nephrotic syndrome nephrotic syndrome have been reported in have been reported in 21% of adults in long 21% of adults in long term follow up term follow up including:including:
- Thrombotic events 13%Thrombotic events 13%- Life threatening Life threatening
infections 11%infections 11%- Myocardial infarction Myocardial infarction
9%9%
Mortality rate is higher Mortality rate is higher in adults as compared in adults as compared to children which is to children which is approximately 3%.approximately 3%.
Direct effects of Direct effects of dexamethasone on human dexamethasone on human
podocyte – Xing, Saleem, et alpodocyte – Xing, Saleem, et al
Hypothesis:Hypothesis: Glucocorticoid exert direct protection of Glucocorticoid exert direct protection of
podocytes from injury and/or promotion podocytes from injury and/or promotion of repairof repair Nephrin: podocyte specific proteinNephrin: podocyte specific protein
mutation of NPHS2 gene - cause congenital mutation of NPHS2 gene - cause congenital nephrotic syndrome of Finnish typenephrotic syndrome of Finnish type
Studies show possible downregulation of nephrin Studies show possible downregulation of nephrin in MCDin MCD
KI (2006) 70, 1038-1045
Result – effects of Result – effects of dexamethasone on podocyte dexamethasone on podocyte
maturation at 37 C and maturation at 37 C and expression of nephrinexpression of nephrin
Quantificaton of
nephrin
Immunofluorescent staining
SummarySummary
Dexamethasone enhanced and Dexamethasone enhanced and accelerated podocyte maturation, accelerated podocyte maturation, with a particulary striking effect on with a particulary striking effect on expression of nephrinexpression of nephrin
Other steroid responseOther steroid responseIn disease In disease statestate
With With dexamethasonedexamethasone
p21p21 UpregulatedUpregulated downregulation downregulation allow podocyte to allow podocyte to enter the cell cycle enter the cell cycle – enhance ability to – enhance ability to repairrepair
VEGVEGFF
a mitogen for a mitogen for vascular vascular endotheila endotheila cellscells
DownregulatedDownregulated
p52p52 Induces Induces apoptosisapoptosis
downregulateddownregulated