Case 5

Helmut HopferInstitute of Pathology, University Hospital Basel

Morphological features

• Intratubular crystals of needle-shaped to rectangular aggregates

• Brownish colour in PAS and HE stains

• Birefringence

• Von Kossa stain negative

• Giant cells

• Interstitial fibrosis and tubular atrophy

Clinical history

• Subacute renal failure, serum creatinine 1250 umol/l (14.1 mg/dl)

• Known autosomal dominant polycystic kidney disease since childhood

• Microhematuria, minimal proteinuria• Hypertension• 2 episodes of renal colics, three and two

years prior to admission, radiolucent stones on X-rays

Differential diagnosis

NephrocalcinosisOxalosisUrate nephropathyCystinosisDrug-induced crystals2,8-Dihydroxyadenine urolithiasis

2,8-DHA urolithiasis

• Autosomal recessive inherited adenine phosphoribosyltransferase deficiency (APRT), homozygosity rate 1:50'000-100'000

• Recurrent urolithiasis

♂ ♀• APRT deficient

(heterozygous)• ADPKD

• APRT deficient (heterozygous)

♂ ♀♂• APRT deficient

(homozygous)• ADPKD

• APRT deficient (heterozygous)

• APRT normal• ADPKD

DNA synthesisRNA synthesisEnergy transfer

2,8-DHA urolithiasis

AdenineAdeninemono-

phosphate

8-Hydroxyadenine

2,8-Dihydroxyadenine

APRT

XO

XO

APRT – Adenine phosphoribosyltransferaseXO – Xanthine oxydase

2,8-DHA urolithiasis

AdenineAdeninemono-

phosphate

8-Hydroxyadenine

2,8-Dihydroxyadenine

APRTmutation

XO

XO

APRT – Adenine phosphoribosyltransferaseXO – Xanthine oxydase

Excretion into the urine Formation of crystals at

physiological pH Urolithiasis

2,8-DHA urolithiasis

AdenineAdeninemono-

phosphate

8-Hydroxyadenine

2,8-Dihydroxyadenine

APRTmutation

XO

XO

APRT – Adenine phosphoribosyltransferaseXO – Xanthine oxydase

Prevention of urolithiasis

Allopurinol

2,8-DHA urolithiasis

• Treatment with allopurinol, low purine diet, high fluid intake

• Clinical DD: urate nephropathy (radiolucent stones, standard chemical test does not differentiate)

• Pathological DD: oxalosis (strong birefringence)

Differential diagnosis

NephrocalcinosisOxalosisUrate nephropathyCystinosisDrug-induced crystals2,8-Dihydroxyadenine urolithiasis

Calcium containing crystalsN

ep

hro

calc

ino

sis

Oxa

losi

s

Oxalate nephropathy

• Shape: round to elongate, mostly rhomboid; clusters or rosette-like

• Location: intraluminal, below the tubular epithelium or interstitium

• Colour: transparent, birefringence in polarized light (H&E stain)

• Special stains: von Kossa black, Alizarin orange/red

Alizarin

Kossa

Urate nephropathy• Shape: needle shaped to

rectangular aggregates within an amorphous matrix

• Location: tophi mostly in the medulla

• Colour: FFPE biopsies – mostly dissolved, alcohol-fixed biopsies – pale to deep blue, birefringence in polarized light

• Special stains: von Kossa negative, Alizarin negative

Cystinosis

• Shape: brick, hexagonal, elongated or flat

• Colour: FFPE biopsies – mostly dissolved, alcohol-fixed biopsies – yellow, brown to sand colour, birefringence under polarized light

• Special stains: von Kossa negative, Alizarin negative

Drug-induced crystals

• Sulfonamides• Acyclovir• Methotrexate• Indinavir• Triamterene• ...

Perazella MA, Am J Med 106:

459-465, 1999

Sulfonamide crystals (1960's)

2,8-DHA urolithiasis

• Brownish intratubular crystals

• Strong birefringence• Giant cells• Von Kossa negative

→ Think of 2,8-DHA urolithiasis in all cases of oxalosis!