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 -

Overexpression of CD 80 in MCD

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%.

Could steroid have Could steroid have more direct effect in more direct effect in

kidney?kidney?

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