nephrotic syndrome: which one would you choose to deal with?

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