25th European Congress Pathology August-September 2013 Lisbon

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