Challenging Nephrotic Syndrome

Dr Richard McCroryST3 Renal Medicine

BCH Physician’s Meeting

Outline

• A patient with a challenging case history • Key clinical features of nephrotic syndrome• Some recent research• Some hope for the patient (at the end!)

Our Challenging Case - Ms LF

19 year old femalePresented January 2005 to Local Hospital3 week history of:

– lower limb swelling to mid thigh– polyuria

GP dipped urine - ++++ protein on dipstick

Lab Results at Presentation

Hb 161 g/LWhite Cells 8.7Platelets 419

Total protein 47 g/L, Albumin 12g/L24 hour Urinary Protein – 5.4 g/24h

Cholesterol 10 mmol/l

140 4.4 7.4103 28 71

Clinical diagnosis – nephrotic syndrome

• Oedema• Hypoalbuminaemia• Proteinuria (> 3.5 g/24hr)

• Frequent associations with nephrotic syndrome– hyperlipidaemia– thromboembolism

Glomerular structure facilitating ultrafiltration

The Glomerular Filtration Barrier

Ronco P. JCI. 2007 117(8):2079-82.

Failure of the Filtration Barrier in Nephrotic Syndrome

Why is there oedema with nephrotic syndrome?

Plasma colloid oncotic pressure↓ Oedema and Intravascular volume↓

Intravascular volume↓® Stimulation of antidiuretic hormone (ADH )

® H2O and Na+ retention® GFR ↓

® Activation of Renin Angiotensin Aldosterone H2O and Na+ retention

H2O and Na+ Retention → Aggravates Oedema

Classifying Nephrotic Syndrome

Diseases with antibody-mediated mechanismse.g., lupus erythematosus, membranous nephropathy

Diseases that are associated with metabolic disorderse.g., diabetes, plasma cell disorders, amyloidosis

Diseases caused by abnormal glomerular cell functione.g. minimal change glomerulonephritis

Differential diagnosis of nephrotic syndrome in an adult1

• Membranous nephropathy• Minimal change disease• Focal segmental glomerulosclerosis (FSGS)• Lupus nephritis• Membranoproliferative nephritis• IgA nephropathy• Amyloidosis

• Adults with nephrotic syndrome need a renal biopsy to establish a diagnosis

1Rivera F, et al. Spanish Registry of Glomerulonephritis.Kidney Int. 2004;66(3):898

Management: Feb-Mar 2005

• oral prednisolone 60mg daily• rash with captopril, switched to candesartan.• initial rapid reduction in proteinuria 5g/24h to 1.6g/24h• serum albumin improved from 12g/L to 36g/L• stable kidney function

Rationale for ACEi / ARB in treating Proteinuric Renal Disease

PAng II

Ang II

An

g I

I

Efferent arteriolar vasoconstriction

Podocyte Injury and Cytoskeleton Remodelling

May 2005

• prednisolone reduced to 60mg alternate days– proteinuria promptly relapsed (>5g/24 hours)– serum albumin fell to 18 g/L

• nephrotic syndrome remitted again with increasing steroid– albumin rose to 33 g/L– but becoming cushingoid– candesartan dose escalated up to 8mg daily and prednisolone reduced– decision made to perform native renal biopsy

June 2005 – Biopsy Report

• ‘The biopsy shows a mild degree of mesangial proliferation…however, it still falls within the category of minimal change disease.’

• ‘There is no evidence of tubular atrophy or acute tubular necrosis. There is no interstitial inflammation or fibrosis.’

Pathological diagnosis – minimal change disease

• No obvious histological features on light microscopy despite clinical problems associated with nephrotic syndrome

Minimal change disease

• Usually idiopathic• Associations with NSAID use and lymphoma

• Management of oedema and proteinuria– Loop diuretics– ACE inhibitor (or ARB)

• Immunosuppression if symptomatic and protracted– Steroids

June 2005 – June 2006

• Unable to get below 17.5mg prednisolone / day without return of hypoalbuminaemia– candesartan increased to 16mg– frank nephrotic syndrome in November

• Eventually...– urinary Protein <1g/24h– no limb oedema for ~4 months

However - August 2006

++++ Protein on DipstickAlbumin 10 g/LCreatinine 84 umol/L

• Thus far 8 relapses of nephrotic syndrome with severe hypoalbuminaemia in 18 months and dependent on steroids...

What next?

Clinical Practice Guideline for GlomerulonephritisPublished June 2012

“Helping clinicians know and better understand the evidence (or lack of evidence) that determines

current practice.”

Guideline 5.2 for Frequently Relapsing/Steroid Dependent MCD

5.2.1: We suggest oral cyclophosphamide 2–2.5 mg/kg/d for 8 weeks. (2C)

5.2.2: We suggest calcineurin inhibitors (CNIs) for FR/SD MCD patients who have relapsed despite cyclophosphamide, or for people who wish to preserve their fertility. (2C)

5.2.3: We suggest MMF 500–1000 mg twice daily for 1–2 years for patients who are intolerant of corticosteroids, cyclophosphamide, and CNIs. (2D)

Treatment Strategy

• Started on cyclophosphamide 100mg daily– Remission within 3 weeks!

• Overlapping therapy with ciclosporin 75mg bd and then cyclophosphamide stopped– One episode of pyelonephritis requiring hospital admission and

associated with AKI – recovered

• ACR fell to 45 mg/mmol in Nov ‘06

Complications of NS - Infection

Nephrotic patients liable to infection because : Loss of immunoglobulin in urine Oedema fluid acts as a culture medium Use of immunosuppressive agents in management Malnutrition / Negative Nitrogen Balance

Recurrent Upper Airways Infection, peritonitis, cellulitis and UTI may be seen.

Organisms: Encapsulated (Pneumococci, Haemophilus Influenzae)Gram negative (e.g. E.coli)

2007 – ‘Annus Horribilis’

13 grams proteinuria

Treatments tried (and failed)• Prednisolone

– Cushingoid– Osteoporotic Bones– Borderline Blood Sugars

• Ciclosporin• Mycophenolate

– Severe GI symptoms on escalating dose

• Diuretics / ACE inhibitors + Angiotensin Blockers– Recurrent Hypovolaemia on trying to increase dose

• Rituximab – Tried as ‘rescue therapy’ in minimal change disease presenting in children– Some evidence of efficacy in small cohorts of adults– Albumin improved from 5g/L to 11 g/L

From Bad to Worse...

April 2009

• Commenced on haemodialysis for management of AKI episode

– Severe hypoalbuminaemia and heavy proteinuria persisted with no response to all treatments

– Declining GFR possibly secondary to hypovolaemia and medication effects

• but progressive chronic kidney disease is not a feature of MCD)

• and remained dialysis dependent 3 months later

Diagnosis Revisited – August 2009

• ‘The biopsy shows well developed focal segmental glomerulosclerosis with complete sclerosis of 4 out of the 10 glomeruli and segmental sclerosis in a further 5. This is associated with a moderate degree of tubular atrophy and interstitial fibrosis. There is also evidence of acute tubular necrosis. Hypertensive vascular changes are also seen.

Focal Segmental Glomerulosclerosis

• On light microscopy the presence in some but not all glomeruli (hence the name focal) of segmental areas of mesangial collapse and sclerosis

Classifications of FSGS: Aetiology

Primary– ‘Idiopathic’

Secondary– Toxins– Genetic Abnormalities (Slit Diaphragm Proteins)– Infections (HIV Associated Nephropathy, Erythrovirus)– Obesity– Heroin Nephropathy– Drug Toxicity (Pamidronate)

Diagnosis revised

• FSGS can be challenging to diagnose (sampling error i.e. in the renal biopsy none of the glomeruli demonstrate sclerosis)

• FSGS may be primary disorder or can occur as a secondary response to nephron loss (as is reflux nephropathy) or previous glomerular injury.

• Differentiating between primary and secondary FSGS is important for therapy

• Primary FSGS may respond to immunosuppression whereas secondary FSGS does not

• Secondary FSGS is best treated with drugs like ACEi that lower the intraglomerular pressure

Progress on Dialysis

Ongoing– Malnutrition secondary to negative nitrogen balance (albumin

<20g/L despite supplements and intra-dialytic nutrition)– Nephrotic Range Proteinuria (>20g/24hours)

March 2010Admitted from dialysis unit with acute shortness of breath. CTPA notes pulmonary arterial filling defects

Complications of NS - Hypercoagulability

1 ↑concentration of I,II, V,VII,VIII,X and fibrinogen2 Urinary losses of regulatory anticoagulant substances: anti-

thrombin III3 Decreased fibrinolysis4 Higher blood viscosity (overaggressive diuresis)5 Increased platelet aggregation

Classic Recognised Complication – Renal Vein Thrombosis

2010 – The Final Straw

Bilateral Nephrectomy

But there’s more...

10/3/2013Received offer for deceased donor renal transplantDonor

– 15 year old male, COD – Intracranial Haemorrhage– Creatinine at retrieval 82 umol/L– Mismatch 1-1-0

Following negative crossmatch → Proceeded to surgery

Post-Operative Creatinine: D0-D6

‘Mischief, thou art afoot...’

• Day 3 Post Transplant– urinary Albumin/Creatinine Ratio

• 500 mg/mmol (≈ 5 g/24h)

First Transplant clinic– diarrhoea and Nausea from anti-rejection drugs– postural Hypotension on examination– polyuric, ++++ protein on dipstick

Laboratory Results

19/3/2013

Albumin 41 g/L

20/3/2013(and 3 litres IV Fluids later)

Albumin 33 g/LUrine ACR back - 500

133 5.6 16.1108 17 130

135 5.8 15.5107 22 141

Primary FSGS – A soluble factor Involved

1980’s• Injecting serum from a patient with recurrent FSGS induced

proteinuria in rats

Recurrent FSGS after Transplantation

• Proteinuria may herald the development of FSGS even if a

biopsy does not show glomerular abnormalities.

• 20–40% risk of FSGS recurrence

• 40–50% with FSGS recurrence lose their grafts

Factors influencing the risk of recurrence of FSGS

Increased RiskChildhood OnsetRapid progression to

uraemia in original disease

Patients with pre-transplant nephrectomy

Living DonorWhite RaceElderly Donor

Reduced RiskFamilial FSGSNon-nephrotic proteinuria

in original diseaseBlack Race

Ponticelli, NDT 2010

Clinical Course Post-Transplant

• 5 sessions of plasma exchange– Clear ‘soluble factor’

• Maximised ACEi early– Stabilise podocytes

• Given 1 dose rituximabSo far...Complete remission of proteinuria, Creatinine

120 umol/L

Resolution of Recurrent Focal Segmental Glomerulosclerosis after Retransplantation

Gallon et al, NEJM 2012

Learning points from this case

• Nephrotic syndrome (a clinical triad of proteinuria, hypoalbuminaemia and oedema)

• Nephrotic syndrome has potentially life threatening consequences (thromboembolism, malnutrition, infection)

• Management is often challenging with inconsistent response to immunosuppression

• If no response to therapy reconsider the original diagnosis (further renal biopsy)

• Primary FSGS has a high risk of recurrence in renal transplant but may respond to plasmapheresis

• The soluble marker causing FSGS remains to be identified