persistent microscopic haematuria: is it a benign condition?cmft.nhs.uk/media/1400708/persistent...
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Persistent microscopic haematuria:
Is it a benign condition?
Rachel Lennon
Senior Lecturer and Consultant in Paediatric Nephrology
Paediatric Nephrology Study Day
12th June 2015
Overview
• Differential diagnosis
• Familial haematuria
• Alport syndrome
– Wide phenotypic variation
• Thin basement membrane nephropathy
• Prognosis
• Recommendations
Differential Diagnosis
• Glomerular
– IgA disease (HSP)
– Glomerulonephritis: C3 deposition
– Basement membrane glomerulopathy
• Non-glomerular
– Infection, hypercalciuria, renal stone disease, polycystic kidneys, tumours, arteriovenousmalformation, loin-pain-haematuria syndrome, fabricated/induced illness
A specialised capillary wall
Lennon R, Randles MJ, Humphries MJ:
The Importance of Podocyte Adhesion for a Healthy Glomerulus. Frontiers 2014
Barrier breakdown
Lennon R, Randles MJ, Humphries MJ:
The Importance of Podocyte Adhesion for a Healthy Glomerulus. Frontiers 2014
Red cell traversing the barrier
Collar JE, Ladva S, Cairns T and Cattell V:
Red cell traverse through thin glomerular basement membranes Kidney International 2001
Familial haematuria- genetics
• Alport Syndrome – COL4A3,4,5,6
• Thin basement membrane nephropathy– COL4A3,4
• Epstein/Fechtner/Sebastian/May-Hegglin– Macrothrombocytopenia
– MYH9
• Glomerulopathy with fibronectin deposits – FN1
• C3/CFHR5 glomerulonephritis– CFHR5
Overview
• Differential diagnosis
• Familial haematuria
• Alport syndrome
– Wide phenotypic variation
• Thin basement membrane nephropathy
• Prognosis
• Recommendations
• ‘Hereditary nephritis’, hearing loss, lenticonus– Cecil Alport 1927
• Rare: 0.2/10,000, 1-3% of patients on dialysis
• Molecular basis– Karl Tryggvason 1990
• Mutations – COL4A3,A4- autosomal recessive
– COL4A5- X-linked
• Impaired collagen IV assembly– kidney, inner ear and eye
• ESRD: 2nd decade
• Collagen network required to maintain long term GBM integrity
Electron micrograph
Irregular GBM
Basket weave
Lamellation
Alport Syndrome
Collagen IV
Collagen IV: alpha 1,1,2
Collagen IV: alpha 3,4,5: Alport syndrome
Collagen IV: alpha 5,5,6
Case 1
• 2 year old male
• Pyrexia, ‘cola’ coloured urine
• Normal creatinine and immunology
• Familial renal disease
• Microscopic haematuria and proteinuria
• Renal biopsy EM:
– Variable thickness GBM
• Eye examination and audiometry normal
• 2 mutations in COL4A5 (exons 33,35)
Case 2
• 8 year old female with ESRD
• No renal biopsy
• Dialysis and deceased donor transplant aged 9
• Satisfactory graft function at age 17
• 2 mutations in COL4A5 (exons 33,35)
– Heterozygous
• Eye examination and audiometry normal
• Skewed X-inactivation
Case 3
• 5 year old male– Fever, elevated creatinine
– Persistent microscopic haematuria and proteinuria
– No biopsy-family history
– 2 mutations in COL4A5 (exons 33,35)
– Commenced ACE inhibition
• Renin-angiotensin blockade may slow progression of renal disease in XLAS males
• Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol 2013;24(3):364-75.
Case 4
• 6 month old male
• Facial swelling, macroscopic haematuria
• Nephrotic syndrome
• Daily 20% albumin replacement
• 28 day trial of steroids
• Renal biopsy– GBM and podocyte abnormalities
• ACE inhibition
• Commenced peritoneal dialysis aged 3
• 2 mutations in COL4A5 (exons 33,35)
Other family members
• Mother investigated aged 39 (affected children)– Microscopic haematuria, mild proteinuria
– Normotensive
– eGFR 82 ml/min/1.73 m2
– Started ACE inhibition
– Mutant COL4A5 allele
• 2 uncles (maternal) – In Pakistan
– Died in 20’s ERSD
• Grandmother (maternal) ESRD age 58– received dialysis
• Grandfather (paternal ) ESRD
Could there be an additional genetic explanation?
Genetic testing for
steroid resistant
nephrotic syndrome
Bristol
39 genes
£600
4-6 weeks
MYO1E
• MYO1E– Encodes myosin 1E
– A podocyte-expressed non-muscle myosin
– Actin-rich adhesion structures modulating ECM degradation and invasion
• Case 2 and case 4
– biallelic variants in MYO1E
• MYO1E mutations – a subset of children with FSGS and glucocorticoid resistant
proteinuria• Mele et.al., MYO1E mutations and childhood familial focal
segmental glomerulosclerosis. N Engl J Med 2011;365(4):295-306.
Common pathways
Lennon R, Stuart HM, Bierzynska A, Randles MJ, Kerr B, Hillman KA, Batra G, Campbell J, Storey H,
Flinter FA, Koziell A, Welsh GI, Saleem MA, Webb NJ, Woolf AS: Coinheritance of COL4A5 and
MYO1E mutations accentuate the severity of kidney disease. Ped Nephrol 2015
Overview
• Differential diagnosis
• Familial haematuria
• Alport syndrome
– Wide phenotypic variation
• Thin basement membrane nephropathy
• Prognosis
• Recommendations
Benign familial heamaturia
-Thin basement membrane nephropathy
• 1% of the population
• 30% lifetime risk of
renal failure
• Predisposition
– 35– 50% IgAN have GBM
abnormalities
– 40– 50% TBMN have
COL4A3/A4 mutations
– Nephrotic syndrome
mutation (NPHS2)
Lifetime risk of renal failure
Kaplan–Meier analysis of renal survival by
age in 228 thin basement membrane
nephropathy patients (118 females)
CFHR5 nephropathy patients- gender
difference. Greek-Cypriot origin
Deltas C, Pierides A, Voskarides K:
Molecular genetics of familial hematuric diseases Nephrol Dialysis Trans 2013
Intervention
• RAAS blockade:
– ACE inhibition/Angiotensin receptor blockade
• Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter
F. Expert guidelines for the management of Alport
syndrome and thin basement membrane nephropathy. J
Am Soc Nephrol 2013;24(3):364-75.
• Anti-mIR 21: Fibrosis. Phase 1 trial
• Gene therapy
• Recombinant collagen IV protein
Recommendations
Deltas C, Pierides A, Voskarides K:
Molecular genetics of familial hematuric diseases Nephrol Dialysis Trans 2013
Summary
• Familial glomerular MH is not benign
• Genetic testing- 5 genes (more to come)
– Multiple mutations can explain a variable phenotype
• Risk factors for progression: Family history, genetics
• Assessment by nephrology/genetics: Renal RaDaR
• Lifelong BP and urinalysis
• Use of RAAS blockade with persistent proteinuria