“The Shalhoub Hypothesis” (1974)
Remissions occur in the setting of viral associated
MCD occurs more frequently in patient’s with
MCD is responsive to steroids and alkylating drugs.
Atopic individuals at higher risk of developing MCD.
Is MCD immunologically mediated?
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.
Cytokine involved with development ofTH2 cells in atopic
IL-13 expression upregulated inT 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
• First identified as
mobility & survival
• Prompts signalling
• Inhibits lipoprotein
• Unifies finding of
Protein B7-1 (aka. CD80)
Commonly found on antigen presenting cells
Co-stimulatory signal forT-cells depending on ligand it binds to
CD28 – stimulatory / CTLA-4 - regulatory
Not expressed by normal podocytes
But podocyte expression of B7-1 induced in transgenic models of
proteinuria overexpressing interleukin-13
B7-1 Stains Strongly in Native Biopsies of:
(Regardless of PLA2R status)
Minimal Change Disease
KDIGO Glomerulonephritis Guidelines
“Helping clinicians know and better understand
the evidence (or lack of evidence) that determines
Treatment of initial episode of adult
MCD (KDIGO 2012)
“We recommend that corticosteroids be given for initial treatment of
nephrotic syndrome. (1C)”
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
“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
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
MCD Treatment - Definitions
Complete response and remission
Reduction of proteinuria to <300 mg/day
Little to no reduction in proteinuria after 16 weeks of adequate
Return to 3.5g/day or more after previous remission
3 or more relapses per year
Response to initial steroid therapy most important prognostic
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
55 year old man
Presented with nephrotic syndrome
15 grams proteinuria
Albumin 17g/L at presentation
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
KDIGO Guidelines for Frequent
Relapsing / Steroid Dependent MCD
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
Extrapolation from Paediatric Studies
Predicting response toTherapy
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
High dose steroids work at cost to:
Blood Sugars /Weight Gain
Rituximab & Proteinuric Kidney Dx
Strong evidence for use in immune depletion for primary
Rituximab found to bind to podocytes, despite no
evidence of CD20 expression
Binds to amino acid sequence found on the protein
Relevance of SMPDL-3b to Proteinuric
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
Proposed mechanism – stabilise SMPDL-3b + stops
Fornoni et al 2011
At 6 months (Dose 1 rituximab)
9 off steroids
Mean steroid dose - 8mg/day
Mean Urine Protein – 0.4±0.02 g / 24h
At 12 months (Post 2 doses Rituximab)
21 off steroids
Mean steroid dose – 1.1mg/day
Mean Urine Protein – 0.5±2.2g / 24h
The Pharmacist says…
‘Sorry, you can’t
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
From Shale “Moral Leadership in Medicine”(2013)
“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”
Is likely to gain significantly more benefit for the intervention
than might normally be expected for patients with that
Case 2 - Continued
Received single dose rituximab (800mg)
Proteinuria fell from 12.5g/24hr to 2.7g/24hr within 3
ACR August 2013 – 0.1mg/mmol
Creatinine 95 umol/L and now <10mg/day
77 year old male
One week history of abrupt onset leg oedema +
shortness of breath
Periorbital Oedema, Severe Leg & Flank Oedema
Creatinine 167 (previously N)
ACR >900mg/mmol,Albumin 22g/L
Biopsy – Minimal Change & FloridATN
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 withAKI
Tended to be:
Worse Serum Albumin / Proteinuria
Progression to ESRD – 4 cases
3 re-biopsied (FSGS)
1 frequent relapser + 2 episodes of AKI remaining HD dependent
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 mmHg
Marked oedema to above knees
Few areas of non-blanching purpura
Urinalysis – 4+ protein, 1+ blood
Bloods: Renal Screen – Negative / Albumin 20g/L / Creatinine 78 umol/L
mesangial expansion and
Positive for IgA / C3
Given 60mg/day prednisolone
Remittance of Proteinuria within 3 weeks
Has relapsed frequently with complete remission on oral
At 10 year follow-up
Continues to have normal renal function despite proteinuric
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
Sudden onset nephrotic syndrome
Minimal glomerular changes on light microscopy
Treatment essentially that of minimal change disease
IgA / IgM deposition on IF in biopsies deemed‘minimal
change’ on light microscopy don’t have the same favourable
prognostic response as MCD.
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!