MINIMAL CHANGE DISEASERichard McCrorySpR Seminar 19th March 2014

Minimal Change Disease - OutlinePathophysiology

IL-13, ANGPTL4, CD80

EpidemiologyEvidence Base for Treatment

What to do in ‘exceptional circumstances’

MCD in AKIMCD in Other Renal Disease

Case 1

57 year old woman B/G Hypothyroidism on 50mcg T4 Otherwise very well

Attends GP after New Year ‘14 Ankle puffiness Weight Gain Fatigue

Blood Test Sept ’13 Jan ‘14

TSH 1.46 22.13

T4 - 12.6

Cholesterol

4.8 mmol/L

11.6 mmol/L

Triglycerides

0.66 mmol/L

2.56 mmol/L

Case 1

2 weeks later Leg swelling getting

worse Started on

Furosemide by GP

The following week… Urine Dipstick 4+

protein PCR >350mg/mmol

Serum Albumin 18 g/L

Light microscopy of glomerulus in MCD

Distribution of Biopsy Proven Nephrotic Syndrome from one US pathology lab

Pathophysiology

Associations with MCD

Tumours Hodgkin’s lymphoma ThymomaDrugs and Toxins NSAIDs Lithium Bisphosphonate Rarely: ampicillin, rifampicin, interferonOther Atopy/Eczema Chronic graft versus host disease

Pathophysiology

“The Shalhoub Hypothesis” (1974)

Remissions occur in the setting of viral associated immunosuppression (Measles)

MCD occurs more frequently in patient’s with lymphoma.

MCD is responsive to steroids and alkylating drugs.

Atopic individuals at higher risk of developing MCD.

Is MCD immunologically mediated?

Pathophysiology

A “Permeability Factor”

T-cell hybridoma made from patient with MCD released a substance that when injected into rats

Proteinuria and foot process effacement.

Young deceased donor with presumed MCD Transplanted into two recipients without baseline

proteinuria. Proteinuria absent by week six.

Koyama A et al. KI 40: p453, 1991.Ali AA et al. Transplantation 58: p849, 1994.

IL-13

Cytokine involved with development of TH2 cells in atopic reactions

IL-13 expression upregulated in T cells in children with steroid sensitive nephrotic syndrome who were in relapse.

Podocytes possess IL-13R & stimulation of cultured monolayers of podocytes with IL-13 lead to decreased transepithelial electrical resistance. Glucocorticoids can reverse this effect through

stabilisation of nephrin at slit diaphragm

Yap HK et al. JASN 10: p 529, 1999.Van den Berg JG et al. JASN 11: p413, 2000.

Tan M J et al. Mol Cancer Res 2012;10:677-688

Angiopoetin Like Protein (ANGPTL4)

• First identified as vascular factor influencing tumour mobility & survival

• Prompts signalling through integrin molecules

• Inhibits lipoprotein lipase• Unifies finding

of proteinuria with hypertriglyceridaemia

Protein B7-1 (aka. CD80)

Commonly found on antigen presenting cells Co-stimulatory signal for T-cells depending on

ligand it binds to CD28 – stimulatory / CTLA-4 - regulatory

Not expressed by normal podocytesBut podocyte expression of B7-1 induced in transgenic models of proteinuria overexpressing interleukin-13

B7-1 Stains Strongly in Native Biopsies of: Membranous Nephropathy

(Regardless of PLA2R status) Primary FSGS Minimal Change Disease

Wei C , and Reiser J Nephrol. Dial. Transplant. 2011;26:1776-1777

© The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Treatment Strategies

KDIGO Glomerulonephritis Guidelines June 2012

“Helping clinicians know and better understand the evidence

(or lack of evidence) that determines current practice.”

Treatment of initial episode of adult MCD (KDIGO 2012)

“We recommend that corticosteroids be given for initial treatment of nephrotic syndrome. (1C)”

“We suggest:Prednisone or prednisolone given at a daily single dose of 1 mg/kg (maximum 80 mg) or alternate-day single dose of 2 mg/kg (maximum 120 mg). (2C)Maintained for a minimum period of 4 weeks if complete remission is achieved, and for a maximum period of 16 weeks if complete remission is not achieved. (2C)”

“For patients with relative contraindications or intolerance to high-dose corticosteroids (e.g., uncontrolled diabetes, psychiatric conditions, severe osteoporosis), we suggest oral cyclophosphamide or CNIs as discussed in frequently relapsing MCD. (2D)”

Back to Case 1

As of 7th March

Creatinine 84 umol/L Albumin 42g/L & ACR <3.5mg/mmol

Prednisolone cut from 40mg/d to 30mg/d Off Furosemide

Glucocorticoids – The Evidence

One RCT in adults (in 1970) 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 (still) no randomized control trials comparing prednisolone to other agents for the initial therapy in adults with MCD.

MCD Treatment - Definitions

Complete response and remission Reduction of proteinuria to <300 mg/day

Glucocorticoid resistance Little to no reduction in proteinuria after 16 weeks of

adequate prednisolone therapy Relapse

Return to 3.5g/day or more after previous remission Frequent relapser

3 or more relapses per year Response to initial steroid therapy most important

prognostic indicator

Steroid Tapering in MCD

Waldman et al. CJASN 2007 95 cases in one referral centre

Majority (>80%) of patients receiving remission within 16 weeks

No optimal corticosteroid taper protocol in adults

In children with MCD Fast tapers associated with

Increased frequency of relapse and/or SD vs. slow-taper group at both 6 months (51.7% vs 17.6%) and last follow-up (34.5% vs. 5.9%).

But total cumulative steroid dose similar

Case 2

55 year old manPresented with nephrotic syndrome

15 grams proteinuria Albumin 17g/L at presentation

Biopsied Minimal Change Disease

Started on Prednisolone 80mg daily Albumin 17 → 32g/L but proteinuria persisted Started on Perindopril + uptitrated Prompt relapse in hypoalbuminaemia when

steroids cut below 20mg/day

KDIGO Guidelines for Frequent Relapsing / Steroid Dependent MCD

“We suggest: Oral cyclophosphamide 2–2.5 mg/kg/d for 8

weeks. (2C) Reported to induce and maintain remission in

up to 60% of MCD patients, less so in steroid resistant cases (10%).

CNI for 1–2 years for FR/SD MCD patients who have relapsed despite cyclophosphamide, or for people who wish to preserve their fertility. (2C) Between 60-90% of patients relapse after

discontinuation MMF 500–1000 mg twice daily for 1–2 years for

patients who are intolerant of corticosteroids,cyclophosphamide, and CNIs. (2D)”

No prospective trials on second-line treatment; all have been retrospective

observational reports.

Challenges with Second Line Therapies for Minimal Change

Is a revision of diagnosis required? Sampling Error on Biopsy

Variations Physician Practice Extrapolation from Paediatric Studies Predicting response to Therapy

Case 2 - Clinical Course

Escalated to oral cyclophosphamide for 6 months 2 LRTIs and one episode of transient AKI needing to stop

ACEi for a bit Albumin slowly rose to 34 g/L maximum Partial response to proteinuria (ACR 800)

Further relapse in hypoalbuminaemia 2 months post cessation of cyclophosphamide

High dose steroids work at cost to: Blood Sugars / Weight Gain Skin Problems

“What about Rituximab?”

Rituximab & Proteinuric Kidney Dx

Chimeric Monoclonal Antibody Strong evidence for use in immune

depletion for primary membranous nephropathy

2006 Rituximab found to bind to podocytes,

despite no evidence of CD20 expression Binds to amino acid sequence found on

the protein SMPDL-3b

Relevance of SMPDL-3b to Proteinuric Kidney Diseases

SMPDL-3b depleted podocytes seen in post re-perfusion biopsies who developed recurrent FSGS

Treatment with rituximab leads to an increase in SMPDL-3b expression and subsequent reduction in proteinuria Proposed mechanism – stabilise SMPDL-3b

+ stops downstream signallingFornoni et al 2011 

Results

At 6 months (Dose 1 rituximab)9 off steroidsMean steroid dose - 8mg/dayMean Urine Protein – 0.4±0.02 g / 24h

At 12 months (Post 2 doses Rituximab)21 off steroidsMean steroid dose – 1.1mg/dayMean Urine Protein – 0.5±2.2g / 24h

The Pharmacist says…

‘Sorry, you can’t have Rituximab…’

Individual Funding Requests

What constitutes an IFR?

1. The patient’s clinical condition represents an unusual or rare circumstance and one likely to occur very infrequently.

2. The treatment requested is a new or developing treatment not normally commissioned or funded by the HSCB.

3. The treatment is commissioned or funded in N. Ireland in certain circumstances but not applicable to the circumstances that apply to the IFR (i.e. “Off-Label” Requests).

4. The treatment may not be commissioned or funded in Northern Ireland e.g. lack of evidence to recommend in national guidance.

“Allocating Resources to fairly & efficiently

meet healthcare

needs”

Fiduciary Propriety

Collegial Propriety

Bureaucratic

Propriety

From Shale “Moral Leadership in Medicine” (2013)

Exceptionality

“An individual whose clinical circumstances are outside the range of clinical circumstances presented by at least 95% of patients with the same medical condition at the same stage of progression as the named patient”

AND

Is likely to gain significantly more benefit for the intervention than might normally be expected for patients with that condition.

Case 2 - Continued

June 2013 Received single dose rituximab (800mg)

Proteinuria fell from 12.5g/24hr to 2.7g/24hr within 3 weeks ACR August 2013 – 0.1mg/mmol

Creatinine 95 umol/L and now <10mg/day Prednisolone

Hot off the press…

AKI with Minimal Change Disease

Case 3

77 year old male One week history of abrupt onset leg

oedema + shortness of breath O/E

Hypertensive (BP Periorbital Oedema, Severe Leg & Flank

Oedema Relevant Chemistry

Creatinine 167 (previously N) ACR >900mg/mmol, Albumin 22g/L

Clinical Course

Biopsy – Minimal Change & Florid ATN Started on Prednisolone & High Dose Diuretics

One week later: Poor response to diuretics, worsening renal

function (Cre >480 umol/L), symptomatic uraemia

Started on Haemodialysis and remained HD-dependent for 30 days.

Serial improvement in urine output, renal function & proteinuria

Currently: Creatinine 100 umol/L, ACR 70 mg/mmol

AKI complicating MCD

Waldman et al. CJASN 2007 95 cases in one referral centre

24 presentations associated with AKI

Tended to be: Older Males Hypertensive Worse Serum Albumin / Proteinuria

Progression to ESRD – 4 cases 3 re-biopsied (FSGS) 1 frequent relapser + 2 episodes of AKI remaining HD

dependent

MCD in other renal diseases

Case 4

58 year old male, presented March 2002. Marked ankle oedema and weight gain for last 2-3 weeks Recent sore throat

PMHx: Bronchiectasis; Intermittent Non-blanching skin rash for one year.

BP= 150/64 mmHgMarked oedema to above kneesFew areas of non-blanching purpuraUrinalysis – 4+ protein, 1+ blood

Bloods: Renal Screen – Negative / Albumin 20g/L / Creatinine 78 umol/L

Renal Pathology

Prominent global mesangial expansion and mildly increased cellularity

Immunofluorescence Positive for IgA /

C3

Diagnosis IgA Nephropathy

Clinical Course

Given 60mg/day prednisolone Remittance of Proteinuria within 3 weeks Has relapsed frequently with complete

remission on oral steroid At 10 year follow-up

Continues to have normal renal function despite proteinuric flares

No further rash flares & No Haematuria Bronchiectasis occasionally problematic with

maintenance steroid, now on azithromycin prophylaxis

IgA Nephropathy / MCD Overlap Subset of patients with IgA where steroids appear

to be of more benefit Sudden onset nephrotic syndrome No haematuria Minimal glomerular changes on light microscopy Treatment essentially that of minimal change disease

HOWEVER IgA / IgM deposition on IF in biopsies deemed

‘minimal change’ on light microscopy don’t have the same favourable prognostic response as MCD.

Summary

MCD mediated by systemic (IL-13) + local (ANGPTL4) influences on podocyte structure/function

Corticosteroid sensitivity helps define response & prognosis

Robust evidence lacking on second line therapies Rituximab presents a promising treatment option

for patients with challenging MCD Remember your Individual Funding Request

MCD + AKI – recovery the rule rather than exception MCD + IgA – the exception rather than the rule!