25th european congress pathology august-september 2013 lisbon
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25th European Congress Pathology August-September 2013 Lisbon. Slide Seminar Electron Microscopy/Nephropathology Electron microscopy in focus: native and transplanted Kidney. Inherited kidney diseases Importance of Electron Microscopy for diagnosis. Fernanda Carvalho - PowerPoint PPT PresentationTRANSCRIPT
25th European Congress PathologyAugust-September 2013
Lisbon
Slide Seminar
Electron Microscopy/Nephropathology
Electron microscopy in focus:
native and transplanted Kidney.
Inherited kidney diseases
Importance of Electron Microscopy for diagnosis
Fernanda Carvalho
Nephrology DepartmentCurry Cabral Hospital, “CHLC”, Lisbon
• 22 years old caucasian female.• Serum creatinine – 1.9 mg/dL (routine
analyses).
• Hypertension since 16 years old.
• Hyperuricemia.
Case presentation - 1
• Several close relatives with CKD autosomal dominant, cysts and/or gout .
• Some of them were in CKD stage 5, hemodialysis or transplanted.
• Renal ultrasound:• Kidney with normal size and cortico-
medullar differentiation.• Bilateral cortico/medular cysts.
Case presentation - 2
• Urinary sediment – irrelevant
• Without :–Proteinuria–Hematuria–Earing loss
Case presentation - 3
Pedigree analysis? ?
I.1 I.2
II.4II.3HD
II.1 II.2HD
III.5CKDcysts
III.4HD
III.3III.1 III.2KT
IV.2CKDcysts
IV.1KT
IV.3 IV.4 IV.5CKD
III.6
V.1CKDcysts
Filled symbols, affected individuals; open symbols, unaffected individuals; slash, deceased; HD, hemodialysis; KT, kidney transplantation; CKD, chronic kidney disease. Arrow identifies proband.
Case presentation - 4
Case presentation - 5
Differential diagnosis
• ADPKD
• Medullary cystic kidney disease / Familial juvenile hyperuricemic nephropathy
Case presentation - 6
A kidney biopsy was performed
Case presentation - 7
LM:
Striking features in the biopsy were:• Interstitial nephritis, thickened tubular
basement membranes.
•Cytoplasmatic inclusions in tubular distal cells.
Kidney Biopsy
Kidney Biopsy LM
Kidney Biopsy LM
EM:
• On EM there is swelling of endoplasmic reticulum cisternae.
• With discret granular inclusions inside.
Kidney Biopsy
Electron Microscopy
Normal endoplasmatic reticulum
Electron Microscopy
Kidney Biopsy IHC
Kidney Biopsy IHC
Diagnosis
• Interstitial nephritis.• Dense citoplasmatic inclusions in tubular
distal cells.• On electron microscopy - swelling of ER, due
to the accumulation of uromodulin.+
• Hyperuricemia.• Autosomal dominant inheritance.
Familial juvenile hyperuricemic nephropathy /Medullary cystic Kidney disease
Familial juvenile hyperuricemic nephropathy
• Uromodulin (UMOD) mutations cause autosomal dominant tubulo-interstitial nephropaties that are included in the group of cystic kidney diseases:
• familial juvenile hyperuricemic nephropathy (FJHN)
• medullary cystic kidney disease nephropathy (MCKD
Familial juvenile hyperuricemic nephropathy
• This complex is clinically characterized by:
• alteration of urine concentration
• hyperuricemia,
• tubulo-interstitial fibrosis,
• cortico-medullar cysts
• renal failure.
• Gout and hyperuricaemia suggests FJHN
• Cysts on ultra-sound favours MCKD.
Familial juvenile hyperuricemic nephropathy
• Mutant uromodulin is retained in the endoplasmic reticulum and cellular trafficking is delayed, leading to reduced uromodulin secretion into urine.
Uromodulin associated renal diseasesUromodulin associated renal diseases
↓ Na+/K+/ 2 Cl-
HyperuricemiaHypertension
↓ Fr Excr UA
TALH (ER) Uromodulin Acumulation
↓ / ø urine Uromodulin
↑ Reabs. Na+ e UA
Tubular atrophyInterstitial fibrosis
Mutant Uromodulin
Toxicity ?+ APOPTOSIS ?
↓ VLEC
Uromodulin associated renal diseases
• It is important that physicians consider the diagnosis of FJHN in patients with a family history of hyperuricemia, hypertension associated with renal dysfunction, even if the patient has only mild renal impairment.
Uromodulin associated renal diseasesUromodulin associated renal diseases
• Equate diagnostic: • AD familial CRD• Interstitial nephritis• Irrelevant urinary sediment• Ø Proteinuria• Early hyperuricemia
• To confirm diagnosis:• Hystology: LM ; EM; IHC• Genetic tests
Uromodulin associated renal diseases
Pathologic findings in patients with UMOD
mutations:• Tubular atrophy and interstitial fibrosis.• Tubular basement membrane thickening and
lamellation.• Tubular or glomerular cysts (rare).• Inclusions in the cells of TALH (appear as ER
inclusions on EM).• Dense intracellular UMOD inclusions in the
cells of TALH ( by IHC).
Uromodulin associated renal diseases
In patients with a poor history, inactive urine sediment and evidence of interstitial nephropathy, it is mandatory to look at the cells of TALH and distal tubules searching for abnormal inclusions by LM and EM.
Its evidence implies that UMOD imunohistochemical staining must be done to confirm the composition.
Uromodulin associated renal diseases