nephrotic syndrome: which one would you choose to deal with?
TRANSCRIPT
Dr VS Aithal
Morriston Hospital
Nephrotic syndrome: Which one would you
choose to deal with?
History of Nephrosis
When bubbles settle on the surface of urine, it indicates a disease of the kidney and the disease will be protracted : Hippocrates: 460-360BC
History of Nephrosis
Whole body swelling:
take the tops of elder plant and daneswort, cook in white wine and
wrap the child in hot clothes by applying poultice in whole or part, and so CURE him: Cornelius Roelans from Belgium 1484
History of Nephrosis
1827 Richard Bright and later his colleagues defined nephrotic syndrome as we know it
Steroids first used in early 1950s in Glasgow by Arneil and Wilson
Questions
Is it a T cell disease or B cell disease?
Would a biopsy help in frequently relapsing steroid sensitive nephrotic who had MCD?
Can you clinically distinguish MCD from other nephrotics?
50% develop AKI true or false
10% develop thromboembolic disease true/false
Spontaneous remission is seen in 60% of patients
Questions with answers?
• What dose of steroids?
• When do you decide steroids are ineffective?
• When do you start weaning steroids?
• How do you wean steroids?
• How do you treat a relapse?
• When do you consider a steroid sparing agent?
• Which steroid sparing agent?
• What bone protection?
• Lipid management?
Why is it difficult to prescribe IS
Normal renal functions and probability of ESRD negligible
No other co-morbidities and on very few medications
Side effects from treatment difficult to come to terms with as a clinician
Things to know about MCD
15 -20% nephrotic adults have MCD
Abrupt onset. Sudden onset is specific but not sensitive for MCD
>90% are steroid sensitive
Things to know about MCD
30-50% of FSGS in adults present as steroid sensitive disease
Insidious onset and partial remissions suggest FSGS
<20% of MCD in children show no response at 6 weeks and biopsy suggests FSGS
Repeat biopsy in SSNS in children fails to show FSGS
Adults with relapsing SSNS may have FSGS lesions
Steroid sensitivity rather than microscopic features of FSGS determine long term outcome
New Concepts in MCD
Glucocorticoid receptors on podocytes higher in podocytes with MCD
Presence of two high risk APOL1 allelles in people of African descent – FSGS
Urinary fibrinogen excretion rate increased in FSGS
Increased urinary Vit D binding protein in SRNS vs SSNS
Pathogenesis of MCD: Current views
T cell disorder
Deficiency of T regulatory cells
Alterations in CD80 and CD40/40L
Upregulation of CD80 (podocytic) in response to virus can interact with Neph1 and disrupt slit diaphragm
Locally produced angiopoetin –like 4 could be a permeability factor in MCD and CNIs can downregulate this
TREG, CD80/B7
Tregs suppress activation, proliferation and
cytokine production of CD4+ T cells and
CD8+ T cells, and are thought to suppress
B cells and dendritic cells
Treg functions
T v B: Interesting Observations
Measles helps remission
Atopy and Lymphoma predispose to MCD
T cell hybridoma from patient with MCD released a substance that, when injected into rats, induced proteinuria and foot process effacement
In rat glomeruli, increased permeability to albumin seen after incubation with sera from patient with MCD and Hodgkin lymphoma
Circulating Factor
IL13 produced by Helper T cells (Th2) induces CD80
expression on podocyte leading to podocyte fusion
B cells in MCD express IL13 receptor
When kidneys from a patient with MCD were inadvertently
transplanted into two recipients without significant baseline :
In both recipients, proteinuria was present at the time of
grafting but diminished rapidly and was within the normal
range within six weeks.
Relapsing disease
Relapse rate after successful therapy is 40-65%
Younger age, more severe NS,absence of mesangial hypercelluarity and a short course of steroid therapy increase relapse risk
Initial use of cyclophosphamide with steroids reduced relapse rates
40% develop AKI : proximal tubular injury
9% develop thromboembolic complications and this is increased if they have AKI
Secondary causes
NSAID COX2 I
Lithium
Penicillamine Tiopironin
Bisphosphonates
Sulfasalazine
Antibiotics
Check point inhibitors
Immunisaton
Y interferon
Why you might miss FSGS?
Sclerotic changes occur first in the juxtamedullary glomeruli
May not be present in superficial biopsies that contain only the outer cortex or
In biopsies that contain fewer than eight glomeruli, where sampling error may be important.
Case 1
53 y old lady with no previous medical history
2/52 h/o of progressive oedema and nausea
Urine PCR 1569 Urine Blood 2+
Cr 250 Alb 23 Chol 8.5 HDL 1.5
Progressively oedematous and oligoanuric
Lowest Albumin 15 Peak creatinine 350
Spent 2 months in hospital for fluid management
No response with high dose prednisolone after 2 months
Sister gives a history of recurrent urticarial rash over the last 2-3 yrs
Started on Cyclosporin
Increasing diuresis within 2 weeks
Off all diuretics by week 3
Creatinine normal within 2 months well before Albumin
normalised (Alb 27)
Albumin in the normal range by 4 months
Urine PCR normal 16 months after starting CYA
Minimal change variants
Mesangial proliferation with no immune deposits
C1q deposition nephritis
IgM deposits in mesangium on EM
Case 2
• Young male, no previous medical history
• 10 day history of acute onset oedema
• Urine blood 3+ Prot 4+
• PCR 1366
• Albumin 27. Lowest 18. Peak cholesterol 35
• Oliguric and hyperkalaemic
• HD for 6 weeks
• No response to high dose steroids at 6 weeks
Cyclosporin 100 mgs twice daily added
Increasing urine output
Off HD in 2 weeks
Prednisolone weaned to 10 mgs over the next two months
Prednisolone stopped after a total of 8 months. ALB 36. PCR 482
PCR 280: 4 months later on CYA alone
Severe gingival hypertrophy
Herpes Zoster
Shoulder AVN and bilateral hip AVN
Changed to MMF
PCR around 300-400 for 14 months and then
Severe oedema PCR 817 Alb 10 Cr 80
What do you do now?
Repeat Renal biopsy
15 gloms 9 sclerosed, remaining focal and segmental sclerosis
Restarted on Pred 60mgs and CYA
1 month later acute onset pleuritic chest pain and SOB
Alb 19
What has happened now?
Albumin 28-32
PCR 500
Genital warts
Pneumonia
CYA reduced to 75 bd
2 months later ALB 26 PCR 1000
What can we do now?
Rituximab x 2doses
CYA reduced to 50 bd with Pred 12.5 mg
6 weeks later CYA had to be increased to 100mgs bd
Albumin was 28, Cr 100 when last checked 10months post
rituximab
Local audit MCN results
• 2/14 had AKI at presentation
• None were left with CKD: 0/14
• 8/14 had haematuria
• 6/14 had HTN
• 2/14 were nephrotic in childhood
• 2/14 steroid resistant
• 2/14 are off immunosuppression
• 12/14 are on steroid sparing
No correlation between presence of blood and tendency to relapse.
No correlation with blood and steroid responsiveness.
No correlation between HTN and relapse rates or steroid sensitivity.
Steroids in MCD
80% achieve remission in adults with steroids
50% in 4 weeks, 10-25% may need upto 16 weeks of high
dose steroids
IV vs oral steroids : No difference
Daily vs alternate days no difference in observational cases
Steroids in MCD
Duration: In children rapid taper after remission over 4
weeks vs slow taper over 5 months: Higher incidence of
FR/SD in rapid vs slow 51.7% v 17.6%. Slower taper
received 35% more steroids
In adults no studies have compared rapid v slow wean
5-10mg reduction /wk after remission for a total period of at
least 2 months
Relapses
56-76% relapse in adults
FR 2 or more relapses in 6 months or 4 or more within 1 yr
of achieving remission
SD: 2 or more relapses during steroid taper or within 2 week
of steroid discontinuation
SR: Lack of response after 16 weeks
Cyclophosphamide Mak etal NDT
1996
Oral CYC 2-2.5mgs/kg for 8 weeks in 22 pts
SR(2),SD(9) and FR (5), 1st relapse after steroids (5)
80% SD responded and 50% SR responded. Sustained
remission upto 9yrs seen in 80% of FR (5pts)
86%,74%,63% remission in cyc at 1,3,5 yrs vs
50%,35%,25% in steroid group
IV Cyclophosphamide vs CNI X Li
etal NDT 2007
Tacrolimus level (4-8) vs IV Cyc randomised study 26 pts:
cyc 750mg/m monthly for 24 wks. Pred till remission.
91% Tac and 77% CYC group achieved remission.
Relapse rates 40% CYC and 50% Tac group.
% who remained steroid free similar
CNI vc CYC
Ponticelli randomised 73pts (11 adults, 62 children)
31 pts with MCD with FR/SD
Oral Cyc for 8 weeks or CYA 5mg/kg for 9 months with a 3
month taper
At 9 months 64% on cyc vs 74% on cya were in remission
At 2yrs, 63% on cyc vs 25% on cya were in remission
MMF Sandoval D et al Clin Kid J 2017
29 pts with SD/FR MCD
Dose 2g MMF or 1440 of Myfortic plus pred 15-40 mgs (
10mg after 1 month)
Remission 27/29 (93.1%)
In 20 pts MMF stopped after a mean FU of 32 m (12-108)
11/20 maintained remission at mean FU of 32m
9/20 relapsed but responded to same dose MMF plus pred
Rituximab markedly reduces relapses in steroid dependent
disease
Reconstitution of memory B cells after RTX is associated
with relapse
Use as first line unexplored
Variable results in steroid resistant disease and FSGS. Case
studies positive results
Ofatumumab a fully humanised anti CD 20 ab useful in pts
allergic to RTX
Nephrutix: Randomised double blind placebo vs RTX assessing T cell
subset changes in MCD
PTs with FRNS entered the trial at remission
Relapses occured in all 13 pts on placebo plus maintenance
drugs at a mean of 7 weeks while only 1/10 with RTX had a
relapse
Pts on RTX had a significantly lower burden of other IS drugs
Relapses associated with sig decrease of Treg (CD4
CD25+ FoxP3+)
RTX in paediatric disease Hewins etal
13 pts with FRNS, 10 steroid dependent, 6 were relapsing at
RTX
1-5 doses
Rate of relapse reduced from 4 to 0.4/yr
Median FU 20months after last RTX
Number of additional IS,steroid dependancy and
antihypertensives reduced significantly
RTX for maintenance in FRNS young
adults Trompeter et al
15 adults with FRNS or steroid dependent MCD on a CNI
Two doses RTX 1g 6 months apart
Relapse frequency decreased from 2.6 to 0.4 per year after
RTX
5 of the 7 relapses occured when CD19 counts increased
>100
Amelioration of adverse effects after
RTX Nitta K et al
54 pts with steroid dependent MCD received four 6montly
Ritux 375mg/mt squared
All remained in remission. Pred dose was significantly lower
at 24 months.
Osteoporosis, glycaemic control and HTN were significantly
better at 24 months
Mild infusion reactions in 57%
B cell reconstitution after RTX in MCD
RTX given in 28 paediatric pts with FRNS
Some were on CNI and all on steroids
All pts at baseline had lower levels of mature B cells vs
controls
RTX induced full depletion of B cells (<1% of lymphocytes)
All pts had complete recovery of mature B cells at 1 yr BUT
memory B cells remained depleted
Total T cell conc unchanged but CD4:CD8 ratio increased
14 pts relpased in 24 months
Reconstitution of memory B cells,number of IS drugs and
dose of Tacrolimus predicted relapse in univariate analysis
Delayed reconstitution of memory B cells only
predictor of sustained remission in multivariate
analysis
No evidence that RTX is effective in steroid resistant MCD
RTX in FSGS/SRMCD
High dose RTX 375mg/m weekly for 8 doses, FSGS with no
IS
1/8 responded
Questions ?
Patients with remission on RTX had sig decrease in the
CD4CD45ROCXCR5+ cells and invariant NK cells and
CD4-CD-T cells