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Challenging Nephrotic SyndromeDr Richard McCroryST3 Renal MedicineBCH Physician’s Meeting
Outline• A patient with a challenging case history• Key clinical features of nephrotic syndrome• Some recent research• Som...
Our Challenging Case - Ms LF19 year old femalePresented January 2005 to Local Hospital3 week history of:– lower limb swell...
Lab Results at PresentationHb 161 g/LWhite Cells 8.7Platelets 419Total protein 47 g/L, Albumin 12g/L24 hour Urinary Protei...
Clinical diagnosis – nephrotic syndrome• Oedema• Hypoalbuminaemia• Proteinuria (> 3.5 g/24hr)• Frequent associations with ...
Glomerular structure facilitating ultrafiltration
The Glomerular Filtration Barrier
Ronco P. JCI. 2007 117(8):2079-82.
Failure of the Filtration Barrierin Nephrotic Syndrome
Why is there oedema with nephrotic syndrome?Plasma colloid oncotic pressure↓ Oedema and Intravascular volume↓Intravascula...
Classifying Nephrotic SyndromeDiseases with antibody-mediated mechanismse.g., lupus erythematosus, membranous nephropathyD...
Differential diagnosis of nephrotic syndromein an adult1• Membranous nephropathy• Minimal change disease• Focal segmental ...
Management: Feb-Mar 2005• oral prednisolone 60mg daily• rash with captopril, switched to candesartan.• initial rapid reduc...
Rationale for ACEi / ARB in treatingProteinuric Renal DiseasePAng IIAng IIAngIIEfferent arteriolarvasoconstrictionPodocyte...
May 2005• prednisolone reduced to 60mg alternate days– proteinuria promptly relapsed (>5g/24 hours)– serum albumin fell to...
June 2005 – Biopsy Report• ‘The biopsy shows a mild degree of mesangialproliferation…however, it still falls within the ca...
Pathological diagnosis– minimal change disease• No obvious histological features on light microscopy despiteclinical probl...
Minimal change disease• Usually idiopathic• Associations with NSAID use and lymphoma• Management of oedema and proteinuria...
June 2005 – June 2006• Unable to get below 17.5mg prednisolone / day withoutreturn of hypoalbuminaemia– candesartan increa...
However - August 2006++++ Protein on DipstickAlbumin 10 g/LCreatinine 84 umol/L• Thus far 8 relapses of nephrotic syndrome...
Clinical Practice Guideline for GlomerulonephritisPublished June 2012“Helping clinicians know and better understand theevi...
Guideline 5.2 forFrequently Relapsing/Steroid Dependent MCD5.2.1: We suggest oral cyclophosphamide 2–2.5mg/kg/d for 8 week...
Treatment Strategy• Started on cyclophosphamide 100mg daily– Remission within 3 weeks!• Overlapping therapy with ciclospor...
Complications of NS - InfectionNephrotic patients liable to infection because : Loss of immunoglobulin in urine Oedema f...
2007 – ‘Annus Horribilis’13 gramsproteinuria
Treatments tried (and failed)• Prednisolone– Cushingoid– Osteoporotic Bones– Borderline Blood Sugars• Ciclosporin• Mycophe...
From Bad to Worse...
April 2009• Commenced on haemodialysis for management of AKI episode– Severe hypoalbuminaemia and heavy proteinuria persis...
Diagnosis Revisited – August 2009• ‘The biopsy shows well developed focal segmentalglomerulosclerosis with complete sclero...
Focal Segmental Glomerulosclerosis• On light microscopy the presence in some but not allglomeruli (hence the name focal) o...
Classifications of FSGS: AetiologyPrimary– ‘Idiopathic’Secondary– Toxins– Genetic Abnormalities (Slit Diaphragm Proteins)–...
Diagnosis revised• FSGS can be challenging to diagnose (sampling error i.e. in therenal biopsy none of the glomeruli demon...
Progress on DialysisOngoing– Malnutrition secondary to negative nitrogen balance (albumin<20g/L despite supplements and in...
Complications of NS - Hypercoagulability1 ↑concentration of I,II, V,VII,VIII,X and fibrinogen2 Urinary losses of regulator...
2010 – The Final StrawBilateralNephrectomy
But there’s more...10/3/2013Received offer for deceased donor renal transplantDonor– 15 year old male, COD – Intracranial ...
Post-Operative Creatinine: D0-D6
‘Mischief, thou art afoot...’• Day 3 Post Transplant– urinary Albumin/Creatinine Ratio• 500 mg/mmol (≈ 5 g/24h)First Trans...
Laboratory Results19/3/2013Albumin 41 g/L20/3/2013(and 3 litres IV Fluids later)Albumin 33 g/LUrine ACR back - 500133 5.6 ...
Primary FSGS – A soluble factor Involved1980’s• Injecting serum from a patient with recurrent FSGS inducedproteinuria in r...
Recurrent FSGS after Transplantation• Proteinuria may herald the development of FSGS even if abiopsy does not show glomeru...
Factors influencing therisk of recurrence of FSGSIncreased RiskChildhood OnsetRapid progression touraemia in originaldisea...
Clinical Course Post-Transplant• 5 sessions of plasma exchange– Clear ‘soluble factor’• Maximised ACEi early– Stabilise po...
Resolution of Recurrent Focal SegmentalGlomerulosclerosis after RetransplantationGallon et al, NEJM 2012
Learning points from this case• Nephrotic syndrome (a clinical triad of proteinuria,hypoalbuminaemia and oedema)• Nephroti...
Physician's Meeting 23/4/2013 - Challenging Nephrotic Syndrome
Physician's Meeting 23/4/2013 - Challenging Nephrotic Syndrome
Physician's Meeting 23/4/2013 - Challenging Nephrotic Syndrome
Physician's Meeting 23/4/2013 - Challenging Nephrotic Syndrome
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Physician's Meeting 23/4/2013 - Challenging Nephrotic Syndrome

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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.

Publicada em: Saúde e medicina
  • Improve your Kidney Health Naturally, click here to find out how  http://ishbv.com/empoweredh/pdf
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  • Nice to read and know about the very ambigous disease in children . some time difficult to diagnose if the child is suffering from Kwashworkar and merasmus. Good response to steroids . .
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Physician's Meeting 23/4/2013 - Challenging Nephrotic Syndrome

  1. 1. Challenging Nephrotic SyndromeDr Richard McCroryST3 Renal MedicineBCH Physician’s Meeting
  2. 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. 3. Our Challenging Case - Ms LF19 year old femalePresented January 2005 to Local Hospital3 week history of:– lower limb swelling to mid thigh– polyuriaGP dipped urine - ++++ protein on dipstick
  4. 4. Lab Results at PresentationHb 161 g/LWhite Cells 8.7Platelets 419Total protein 47 g/L, Albumin 12g/L24 hour Urinary Protein – 5.4 g/24hCholesterol 10 mmol/l140 4.4 7.4103 28 71
  5. 5. Clinical diagnosis – nephrotic syndrome• Oedema• Hypoalbuminaemia• Proteinuria (> 3.5 g/24hr)• Frequent associations with nephrotic syndrome– hyperlipidaemia– thromboembolism
  6. 6. Glomerular structure facilitating ultrafiltration
  7. 7. The Glomerular Filtration Barrier
  8. 8. Ronco P. JCI. 2007 117(8):2079-82.
  9. 9. Failure of the Filtration Barrierin Nephrotic Syndrome
  10. 10. 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+ retentionH2O and Na+ Retention → Aggravates Oedema
  11. 11. Classifying Nephrotic SyndromeDiseases with antibody-mediated mechanismse.g., lupus erythematosus, membranous nephropathyDiseases that are associated with metabolic disorderse.g., diabetes, plasma cell disorders, amyloidosisDiseases caused by abnormal glomerular cell functione.g. minimal change glomerulonephritis
  12. 12. Differential diagnosis of nephrotic syndromein 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 toestablish a diagnosis1Rivera F, et al. Spanish Registry of Glomerulonephritis.Kidney Int. 2004;66(3):898
  13. 13. 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
  14. 14. Rationale for ACEi / ARB in treatingProteinuric Renal DiseasePAng IIAng IIAngIIEfferent arteriolarvasoconstrictionPodocyte Injury andCytoskeletonRemodelling
  15. 15. 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
  16. 16. June 2005 – Biopsy Report• ‘The biopsy shows a mild degree of mesangialproliferation…however, it still falls within the category ofminimal change disease.’• ‘There is no evidence of tubular atrophy or acute tubularnecrosis. There is no interstitial inflammation or fibrosis.’
  17. 17. Pathological diagnosis– minimal change disease• No obvious histological features on light microscopy despiteclinical problems associated with nephrotic syndrome
  18. 18. 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
  19. 19. June 2005 – June 2006• Unable to get below 17.5mg prednisolone / day withoutreturn of hypoalbuminaemia– candesartan increased to 16mg– frank nephrotic syndrome in November• Eventually...– urinary Protein <1g/24h– no limb oedema for ~4 months
  20. 20. However - August 2006++++ Protein on DipstickAlbumin 10 g/LCreatinine 84 umol/L• Thus far 8 relapses of nephrotic syndrome with severehypoalbuminaemia in 18 months and dependent on steroids...What next?
  21. 21. Clinical Practice Guideline for GlomerulonephritisPublished June 2012“Helping clinicians know and better understand theevidence (or lack of evidence) that determinescurrent practice.”
  22. 22. Guideline 5.2 forFrequently Relapsing/Steroid Dependent MCD5.2.1: We suggest oral cyclophosphamide 2–2.5mg/kg/d for 8 weeks. (2C)5.2.2: We suggest calcineurin inhibitors (CNIs) forFR/SD MCD patients who have relapsed despitecyclophosphamide, or for people who wish topreserve their fertility. (2C)5.2.3: We suggest MMF 500–1000 mg twice daily for1–2 years for patients who are intolerant ofcorticosteroids, cyclophosphamide, and CNIs. (2D)
  23. 23. Treatment Strategy• Started on cyclophosphamide 100mg daily– Remission within 3 weeks!• Overlapping therapy with ciclosporin 75mg bd and thencyclophosphamide stopped– One episode of pyelonephritis requiring hospital admission andassociated with AKI – recovered• ACR fell to 45 mg/mmol in Nov ‘06
  24. 24. Complications of NS - InfectionNephrotic 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 BalanceRecurrent Upper Airways Infection, peritonitis, cellulitis andUTI may be seen.Organisms:Encapsulated (Pneumococci, Haemophilus Influenzae)Gram negative (e.g. E.coli)
  25. 25. 2007 – ‘Annus Horribilis’13 gramsproteinuria
  26. 26. 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
  27. 27. From Bad to Worse...
  28. 28. April 2009• Commenced on haemodialysis for management of AKI episode– Severe hypoalbuminaemia and heavy proteinuria persistedwith no response to all treatments– Declining GFR possibly secondary to hypovolaemia andmedication effects• but progressive chronic kidney disease is not a feature ofMCD)• and remained dialysis dependent 3 months later
  29. 29. Diagnosis Revisited – August 2009• ‘The biopsy shows well developed focal segmentalglomerulosclerosis with complete sclerosis of 4 outof the 10 glomeruli and segmental sclerosis in afurther 5. This is associated with a moderate degreeof tubular atrophy and interstitial fibrosis. There isalso evidence of acute tubular necrosis. Hypertensivevascular changes are also seen.
  30. 30. Focal Segmental Glomerulosclerosis• On light microscopy the presence in some but not allglomeruli (hence the name focal) of segmental areas ofmesangial collapse and sclerosis
  31. 31. Classifications of FSGS: AetiologyPrimary– ‘Idiopathic’Secondary– Toxins– Genetic Abnormalities (Slit Diaphragm Proteins)– Infections (HIV Associated Nephropathy, Erythrovirus)– Obesity– Heroin Nephropathy– Drug Toxicity (Pamidronate)
  32. 32. Diagnosis revised• FSGS can be challenging to diagnose (sampling error i.e. in therenal biopsy none of the glomeruli demonstrate sclerosis)• FSGS may be primary disorder or can occur as a secondaryresponse to nephron loss (as is reflux nephropathy) orprevious glomerular injury.• Differentiating between primary and secondary FSGS isimportant for therapy• Primary FSGS may respond to immunosuppression whereassecondary FSGS does not• Secondary FSGS is best treated with drugs like ACEi that lowerthe intraglomerular pressure
  33. 33. Progress on DialysisOngoing– 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
  34. 34. Complications of NS - Hypercoagulability1 ↑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 aggregationClassic Recognised Complication – Renal Vein Thrombosis
  35. 35. 2010 – The Final StrawBilateralNephrectomy
  36. 36. 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 1-1-0Following negative crossmatch → Proceeded to surgery
  37. 37. Post-Operative Creatinine: D0-D6
  38. 38. ‘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
  39. 39. Laboratory Results19/3/2013Albumin 41 g/L20/3/2013(and 3 litres IV Fluids later)Albumin 33 g/LUrine ACR back - 500133 5.6 16.1108 17 130135 5.8 15.5107 22 141
  40. 40. Primary FSGS – A soluble factor Involved1980’s• Injecting serum from a patient with recurrent FSGS inducedproteinuria in rats
  41. 41. Recurrent FSGS after Transplantation• Proteinuria may herald the development of FSGS even if abiopsy does not show glomerular abnormalities.• 20–40% risk of FSGS recurrence• 40–50% with FSGS recurrence lose their grafts
  42. 42. Factors influencing therisk of recurrence of FSGSIncreased RiskChildhood OnsetRapid progression touraemia in originaldiseasePatients with pre-transplant nephrectomyLiving DonorWhite RaceElderly DonorReduced RiskFamilial FSGSNon-nephrotic proteinuriain original diseaseBlack RacePonticelli, NDT 2010
  43. 43. 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, Creatinine120 umol/L
  44. 44. Resolution of Recurrent Focal SegmentalGlomerulosclerosis after RetransplantationGallon et al, NEJM 2012
  45. 45. Learning points from this case• Nephrotic syndrome (a clinical triad of proteinuria,hypoalbuminaemia and oedema)• Nephrotic syndrome has potentially life threateningconsequences (thromboembolism, malnutrition, infection)• Management is often challenging with inconsistent responseto immunosuppression• If no response to therapy reconsider the original diagnosis(further renal biopsy)• Primary FSGS has a high risk of recurrence in renal transplantbut may respond to plasmapheresis• The soluble marker causing FSGS remains to be identified

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