Transcript Inherited kidney diseases (PPT / 8844.5 KB)

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
Nephrology Department
Curry Cabral Hospital, “CHLC”, Lisbon
Case presentation - 1
• 22 years old caucasian female.
• Serum creatinine – 1.9 mg/dL (routine
analyses).
• Hypertension since 16 years old.
• Hyperuricemia.
Case presentation - 2
• 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 corticomedullar differentiation.
• Bilateral cortico/medular cysts.
Case presentation - 3
• Urinary sediment – irrelevant
• Without :
–Proteinuria
–Hematuria
–Earing loss
Case presentation - 4
Pedigree analysis
?
?
I.1
II.1
III.1
III.2
III.3
KT
IV.1
IV.2
KT
CKD
cysts
IV.3
I.2
II.2
II.3
HD
HD
III.4
III.5
HD
CKD
cysts
IV.4
II.4
III.6
IV.5
CKD
V.1
CKD
cysts
Filled symbols, affected individuals; open symbols, unaffected individuals; slash, deceased; HD, hemodialysis; KT, kidney
transplantation; CKD, chronic kidney disease. Arrow identifies proband.
Case presentation - 5
In short:
• Non proteinuric inherited renal
phenotype, transmitted in an
autosomal dominant pattern.
• Affected individuals displayed
hyperuricemia/gout and/or renal cysts.
Case presentation - 6
Differential diagnosis
•
ADPKD
•
Medullary cystic kidney disease /
Familial juvenile hyperuricemic
nephropathy
Case presentation - 7
A kidney biopsy was performed
Kidney Biopsy
LM:
Striking features in the biopsy were:
• Interstitial nephritis, thickened
tubular basement membranes.
• Cytoplasmatic inclusions in tubular
distal cells.
Kidney Biopsy LM
Kidney Biopsy LM
Kidney Biopsy
EM:
• On EM there is swelling of
endoplasmic reticulum cisternae.
• With discret granular inclusions
inside.
Electron Microscopy
Electron Microscopy
Normal endoplasmatic reticulum
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
• Screening for mutations in the UMOD gene
The coding region of the UMOD gene was
directly sequenced and a heterozygous
missense mutation was found in exon 7.
The c. 1463G>A (p.Gly488Asp) allele is a
novel mutation and found to co-segregate
with the disease in the pedigree.
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.
Uromodulin
Uromodulinassociated
associatedrenal
renaldiseases
diseases
• Mutant uromodulin is retained in the
endoplasmic reticulum and cellular
trafficking is delayed, leading to
reduced uromodulin secretion into
urine.
Uromodulin associated renal diseases
Mutant Uromodulin
TALH (ER) Uromodulin Acumulation
↓ Na+/K+/ 2 Cl-
Tubular atrophy
Interstitial fibrosis
↓ VLEC
↑ Reabs. Na+ e UA
Toxicity ?
+ APOPTOSIS ?
↓ Fr Excr
UA
Hypertension
Hyperuricemia
ø urine
Uromodulin
↓/
Uromodulin
associated
renal
diseases
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 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.