Presented at Belfast City Hospital Physician's Meeting. Topic - A case of Focal Segmental Glomerulosclerosis with all the complications of nephrotic syndrome and transplant recurrence of FSGS.

1. Challenging Nephrotic Syndrome
Dr Richard McCrory
ST3 Renal Medicine
BCH Physician’s Meeting

2. 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!)

3. Our Challenging Case - Ms LF
19 year old female
Presented January 2005 to Local Hospital
3 week history of:
– lower limb swelling to mid thigh
– polyuria
GP dipped urine - ++++ protein on dipstick

4. Lab Results at Presentation
Hb 161 g/L
White Cells 8.7
Platelets 419
Total protein 47 g/L, Albumin 12g/L
24 hour Urinary Protein – 5.4 g/24h
Cholesterol 10 mmol/l
140 4.4 7.4
103 28 71

5. Clinical diagnosis – nephrotic syndrome
• Oedema
• Hypoalbuminaemia
• Proteinuria (> 3.5 g/24hr)
• Frequent associations with nephrotic syndrome
– hyperlipidaemia
– thromboembolism

6. Glomerular structure facilitating ultrafiltration

7. The Glomerular Filtration Barrier

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

10. Failure of the Filtration Barrier
in Nephrotic Syndrome

11. 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

12. Classifying Nephrotic Syndrome
Diseases with antibody-mediated mechanisms
e.g., lupus erythematosus, membranous nephropathy
Diseases that are associated with metabolic disorders
e.g., diabetes, plasma cell disorders, amyloidosis
Diseases caused by abnormal glomerular cell function
e.g. minimal change glomerulonephritis

13. 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

14. 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

15. Rationale for ACEi / ARB in treating
Proteinuric Renal Disease
P
Ang II
Ang II
AngII
Efferent arteriolar
vasoconstriction
Podocyte Injury and
Cytoskeleton
Remodelling

16. 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

17. 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.’

18. Pathological diagnosis
– minimal change disease
• No obvious histological features on light microscopy despite
clinical problems associated with nephrotic syndrome

19. 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

20. 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

21. However - August 2006
++++ Protein on Dipstick
Albumin 10 g/L
Creatinine 84 umol/L
• Thus far 8 relapses of nephrotic syndrome with severe
hypoalbuminaemia in 18 months and dependent on steroids...
What next?

22. Clinical Practice Guideline for Glomerulonephritis
Published June 2012
“Helping clinicians know and better understand the
evidence (or lack of evidence) that determines
current practice.”

23. 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)

24. 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

25. 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)

26. 2007 – ‘Annus Horribilis’
13 grams
proteinuria

27. 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

28. From Bad to Worse...

29. 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

30. 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.

32. 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

33. Classifications of FSGS: Aetiology
Primary
– ‘Idiopathic’
Secondary
– Toxins
– Genetic Abnormalities (Slit Diaphragm Proteins)
– Infections (HIV Associated Nephropathy, Erythrovirus)
– Obesity
– Heroin Nephropathy
– Drug Toxicity (Pamidronate)

34. 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

35. 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 2010
Admitted from dialysis unit with acute shortness of breath.
CTPA notes pulmonary arterial filling defects

36. Complications of NS - Hypercoagulability
1 ↑concentration of I,II, V,VII,VIII,X and fibrinogen
2 Urinary losses of regulatory anticoagulant substances: anti-
thrombin III
3 Decreased fibrinolysis
4 Higher blood viscosity (overaggressive diuresis)
5 Increased platelet aggregation
Classic Recognised Complication – Renal Vein Thrombosis

37. 2010 – The Final Straw
Bilateral
Nephrectomy

38. But there’s more...
10/3/2013
Received offer for deceased donor renal transplant
Donor
– 15 year old male, COD – Intracranial Haemorrhage
– Creatinine at retrieval 82 umol/L
– Mismatch 1-1-0
Following negative crossmatch → Proceeded to surgery

39. Post-Operative Creatinine: D0-D6

40. ‘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

41. Laboratory Results
19/3/2013
Albumin 41 g/L
20/3/2013
(and 3 litres IV Fluids later)
Albumin 33 g/L
Urine ACR back - 500
133 5.6 16.1
108 17 130
135 5.8 15.5
107 22 141

42. Primary FSGS – A soluble factor Involved
1980’s
• Injecting serum from a patient with recurrent FSGS induced
proteinuria in rats

45. 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

46. Factors influencing the
risk of recurrence of FSGS
Increased Risk
Childhood Onset
Rapid progression to
uraemia in original
disease
Patients with pre-
transplant nephrectomy
Living Donor
White Race
Elderly Donor
Reduced Risk
Familial FSGS
Non-nephrotic proteinuria
in original disease
Black Race
Ponticelli, NDT 2010

47. Clinical Course Post-Transplant
• 5 sessions of plasma exchange
– Clear ‘soluble factor’
• Maximised ACEi early
– Stabilise podocytes
• Given 1 dose rituximab
So far...
Complete remission of proteinuria, Creatinine
120 umol/L

48. Resolution of Recurrent Focal Segmental
Glomerulosclerosis after Retransplantation
Gallon et al, NEJM 2012

49. 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