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They are believedto serve at least four distinct functions: Regulation ofglomerular permselectivity (10); structural support for the glomerularcapillary, cooperating with mesangial cells to resist thedistensive force of intracapillary hydraulic pressure (11); remodelingthe glomerular basement membrane (GBM), in cooperationwith endothelial and mesangial cells (12); and endocytosisof filtered proteins (13).
Failure of the Filtration Barrierin 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+ retentionH2O and Na+ Retention → Aggravates Oedema
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
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
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 treatingProteinuric Renal DiseasePAng IIAng IIAngIIEfferent arteriolarvasoconstrictionPodocyte Injury andCytoskeletonRemodelling
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 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.’
Pathological diagnosis– minimal change disease• No obvious histological features on light microscopy despiteclinical 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 withoutreturn 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 severehypoalbuminaemia in 18 months and dependent on steroids...What next?
Clinical Practice Guideline for GlomerulonephritisPublished June 2012“Helping clinicians know and better understand theevidence (or lack of evidence) that determinescurrent practice.”
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)
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
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)
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
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
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.
Focal Segmental Glomerulosclerosis• On light microscopy the presence in some but not allglomeruli (hence the name focal) of segmental areas ofmesangial collapse and sclerosis
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
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
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
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
‘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
Primary FSGS – A soluble factor Involved1980’s• Injecting serum from a patient with recurrent FSGS inducedproteinuria in rats
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
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
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
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)• 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