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DIFFULCULT TO MANAGE NEPHROTIC SYNDROME

Rajendra Bhimma

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History of NS

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1484 – Cornelus Roelans (Belgium)

‘Whole Body Swelling’ - Dropsy

Treatment

“Take the tops of elder plant and daneswort, cook in white wine and wrap the

child in hot clothes by applying the poultice in whole or in part, and so cure him”

(Pal and Kaskel et al., 2016). Roelans C. Liber de Aegritudinibus Infantium (1484)

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1722 – Theodore Zwinger (Basel in Switzerland)

Theodor Zwinger the Elder - Swiss physician

(2 August 1533 – 10 March 1588)

Noted decreased urine output and attributed this to “obstruction and

compression of the tubules of the kidney”

(Pal and Kaskel et al., 2016). Zwinger T. Anasarca puerorum (1974); vol 5: p 659-66

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200 years later

Morgagni’s disciple William Heberden

‘Dropsy is very rarely an original distemper but generally a symptom

of some other which is too often incurable’

(Pal and Kaskel et al., 2016). Heberden W. Commentaries on the History and Cure of Disease (1802)

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Eighteenth Century

Dependent on morbid viscera

(Liver and heart)

General form

‘inflammation’

DROPSY

(Pal and Kaskel et al., 2016). Contuno D. De ischiade nervosa commentarius (1770)

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Richard Bright - (1789 – 1858)

Proteinuria

Oedema Kidney

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1830 – Christison + John Bostock

Bostock – ‘when protein in the urine was highest, it was lowest in the

serum’

NS of profound albuminuria, hypoalbuminaenia, and oedema,

resulting from diseased kidney confirmed in 1930

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Mid 1900

Advent of steroids, antibiotics, duiretics, and other immunomodulators

leading to effective treatment

1950 – 1960s histological classification

1961 – Ciba Foundation symposium on the use of kidney biopsy

(Pal and Kaskel et al., 2016) Cameron and Hicks., (1997) / Am J Nephrol 1997; 17(3-4):347-58

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Case Definition

Massive proteinuria (>40mg/m2/hr or 50mg/kg/day)

(uP/Cr ratio >2.0)

Hypoalbuminaemia ( ≤ 2.5mg/dl)

Oedema

Supporting characteristics

Hyperlipidaemia (serum cholesterol >200mg/dl or 6.5mmol/l)

Raised alpha2 globulin

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Epidemiology

Commonest glomerular disorder in children

Incidence 2-7 per 100 000 population

Asians have a 3-4 fold higher frequency than Caucasians

Strong geographical bias

Black patients have a high incidence of steroid resistance

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Classification

Aetiology

Age

Steroid Responsiveness

Histopathology

Genetics

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Classification of NS based on Aetiology and Steroid

Response

Primary

FRNS SDNS SRNS

Schulman. J. Paediatric, 1988,113;996-1001

Secondary OR

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Remission Urine albumin nil or trace on dipsticks (or

proteinuria <4mg/m2/h) for 3 conservative early

morning specimens

Relapse Urine albumin 3+or 4+ on dipsticks (or

proteinuria >40mg/m2/h) for 3 conservative early

morning specimens, after having being in

remission

Frequent relapses Two or more relapses in the initial 6-month

period or more than 3 relapses in 12 months

Steroid dependence Two or more consecutive relapses when on

alternate day steroid therapy or within 14 days of

its discontinuation

Steroid resistance Absence of remission despite therapy with daily

prednisone at a dose of 2mg/kg/day for 6 weeks

Primary

Secondary

Clinical Definitions of Nephrotic Syndrome

Pediatric Health Medicine and Therapeutics 2017:8:29-37

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FRNS and SDNS

Approximately 50-70% of children will develop FRNS or SDNS

Increased morbidity from disease complications and treatment

Risk factors for developing FRNS or SDNS

Female

Shorter time to first relapse

Greater number of days to initial remission

Lower age of first presentation (3.5 vs. 8.5 years)

Arch Dis Child 1982;57:544-8

J Am Soc Nephrol 2001;16:1010-1014

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Outcome of FRNS and SDNS

10-20% still show FR or SD during or after additional steroid and

additional immunosuppressive treatment

23% of SRNS develop steroid-sensitive FRNS or SDNS following

immunosuppressive therapy

Long term steroid treatment leads to serious side effects of steroid

treatment

Ishikura K Kidney International, 2008,73;1167-1173

Ijima K,. Lancet ,2014,384;1273-1281

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Standard Therapies for FRNS and SDNS

KDIGO Clinical Practice Guidelines

Alkylating agents (chlorambucil or cyclophosphamide)

Levamisole

Calcineurin inhibition (CyA or tacrolimus)

MMF

Japanese Society for Paediatric Nephrology

CyA

Cyclophosphamide

Mizoribine KDIGD Kidney International 2010;163-171.

Ishikura K Clin Exp Neph, 2015,19,6-33.

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Alternative treatment for SSNS with FR or SD

LAVIMASOLE

20% reduction of relapse rate compared to placebo

FRNS had superior response compared to SDNS

Daily doses resulted in better remission rates compared to

alternate day doses

Grippen M. Paediatr Nephol, 2011,31;1753

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RITUXIMAB

Chimeric anti-CD20 monoclonal Ab

Inhibits CD20-mediated B-cell proliferation and differentiation

Most frequent dose 375mg/m2 (1-4 infusions)

Studies from Japan suggested that continuing treatment with

MMF led to superior remission rates

Ito S Paediatric Nephrol 2013,28;257-264

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.

J. AM Soc Nephrol, 2015, 26;2219-2266

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Rituximab

Prednisone

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SUMMARY

Rituximab allows the complete withdrawal of steroids in SDNS without

adversely affecting clinical outcomes and has an acceptable short-term

adverse event profile

J. AM Soc Nephrol, 2015, 26;2219-2266

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Pediatr Nephrol (2017) 32:2071–2078

DOI 10.1007/s00467-017-3718-0

Long-term outcome of childhood-onset complicated nephrotic

syndrome after a multicenter, double-blind, randomized,

placebo-controlled trial of rituximab

Koichi Kamei et al on behalf of the Rituximab for Childhood-Onset Refractory Nephrotic Syndrome

(RCRNS) Study Group

94% of patients develop relapses after B-cell recovery

90% required immunosuppressive agents or additional rituximab

treatment

Continuation of immunosuppressive agents (such as CyA or MMF)

is necessary to achieve long-term remission in most patients

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MMF

Inhibits the de novo pathway of guanosine nucleotide synthesis

This is important in proliferation of T- and B lymphocytes

Neither nephrotoxic no gonadotoxic

Although remission rate with CSA after 1 year were better (85% vs.

64%), renal function was better with MMF

Patients with adequate MMF exposure (prodrug MPA ˃50ug/hr/ml)

had comparable remission rates to CSA

(Kemper et al., 2017) J. Pediatr Nephrol, 2017.(DOI: 10.1007/500467-017-3780-7)

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SRNS

Therapeutic challenges for the PN

Currently no optimal therapy

Children with refractory proteinuria have a poor prognosis

High propensity for progression to ESKD (>50% within 5-10years)

Urology and Nephrol,,2017, 5(1);00159

(Zagury et al.,2013) J. Bras Nefrol, 35(3):191-199

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Available Drug Therapy

Prolonged oral steroid treatment

High dose intravenous pulse methylprednisolone

Alkylating agents (CYC in combination with IV MP)

CNIs

Cyclosporin

Tacrolimus

Vincristine

MMF

Rituximab

Urology and Nephrol,,2017, 5(1);00159

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Newer Biological

Anti-IL-2 antibodies

Fresolimumab

Abatacept

ACTH

Adalimumab and galactose

Pediatr Nephrol 6 Sept 2017 DOI 10.1007/s00467-017-7

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Non Immunosuppressive Management of

Childhood Nephrotic Syndrome

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Management of Oedema

Paediatr Nephrol (2016): 31; 1383-1402

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Infections

Leading cause of mortality

Annual incidence of invasive bacterial infection 1-2%

Viral infections: RSV, influenza, parainfluenza, VZV, adenovirus

Exposure to measles virus has been associated with disease

remission

Association between EBV and the onset of INS in children

J Paediatric Child Health (1998):34; 314-317

Paediatr Nephrol (2014): 29; 2325-2331

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Management of Infections in Nephrotic Syndrome

Table adapted from Pediatr Nephrol (2016): 31; 1383-1402

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Prevention of Infection

Antibiotic prophylaxis not administered

Routine childhood immunisation is safe

Live virus strains contraindicated during high-dose steroid therapy

(maximum steroid dose not exceed 20mg day)

Differ for 3 months from completion of cytotoxic agents

Provide post-exposure hyperimmunoglobulin for varicella

Pediatr Nephrol (2016): 31; 1383-1402

Pediatrics (2009): 124; 747-757

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Pediatric Nephrol (1999): 13; 77-89

Paediatrics (2009): 124; 747-757

Normalises with abrogation of proteinuria

Persistent dyslipidaemia associated with accelerated

atherosclerosis and increased risk of CVD

AAP recommends treatment if low-density lipoprotein cholesterol

levels persistently between 4.1– 4.9 mmol/l or more

Dyslipidaemia

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Dyslipidaemia

Treatment:

Dietary modification

Lipid-lowering agents

Fibrate therapy

HMG-CoA reductase inhibitors (e.g. simvastatin, atorvastatin)

Paediatr Nephrol (1999): 13; 77-89

Paediatrics (2009): 124; 747-757

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Fracture Risk

Risk increased due to:

• Steroid-induced osteoporosis

• Decrease of 25-hydroxyvitamin D levels secondary to

urinary loss of vitamin D binding protein

The IAP recommends that children with INS receiving

prolonged steroid therapy (>3 months) should receive daily

supplements of oral calcium (250–500 mg) and vitamin D

(125–250 IU)

Lancet (1997): 2; 629-632

Indian Paediatr (2008): 45; 203-204

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Pediatr Nephrol (1994): 8; 412-415

Decreased levels of T4 and T3 levels secondary to urinary loss of

thyroxine-binding globulin

Free throxine (FT4) and thyroidstimulating hormone (TSH) are

usually normal

If proteinuria persistent for >3 weeks despite steroids, measure

serum thyroid hormone concentrations

Thyroid disease

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Paediatr Nephrol (2016): 31; 1383-1402

Low salt diet

Exercise

Weight reduction

Pharmacological management- start with ACEI or ARB

Hypertension

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Role of Genetic Testing in SRNS

Genetic testing preferable in all children ˂2 years old

Cyclosporin therapy more effective in non-genetic forms of SRNS

Key features in a patient with SRNS which suggest the need for

genetic testing:

• Age ˂6 years (esp <2 years)

• FH of NS

• Consanguinity

• Histopathological findings of FSGS or diffuse mesangial sclerosis.

Pediatric Health, Medicine and Therapeutics, 2017,8:29-37

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Conclusion

CNIs and MMF most commonly used in FR or SD steroid-sensitive NS

Rituximab useful in multi-drug dependent SSNS

In SRNS mutations in podocyte genes or other genes confer resistance

to immunosuppressive treatment

Patients must be monitored for adverse effects of immunosuppression

therapy

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