Download Inherited Renal Diseases Part II

Inherited Renal Diseases
Part II
Maria Ferris and Deb Gipson
10/23/01
Outline
• Lowe Syndrome
• Fabry disease
• Cystinosis
• Cystinuria
• Hyperoxaluria
• Alports
Fabry Disease
• X-linked recessive disorder (Xq22-24)
• Defect is in the alpha-1 galactosidase A
• Diagnosis by assay of peripheral blood
leukocyte level of alpha-galactosidase
– Hemizygous(M) level is near 0
– Heterozygote (F) level may be in the
low normal range. Check urinary
ceramide digalactoside and trihexoside.
– Fetus: determine level in amniocyte
Fabry Disease
• Males: wide range of clinical
abnormalities
• Females: variable range of clinical
expression, may have lipid storage in cells
and be completely asymptomatic
(lyonization)
• Race: White most common
• Incidence: 1:40,000
• Intracellular accumulation of the
glycosphingolipid galabiosylceramide
Fabry: Deposition
– *Endothelial, perithelial, smooth
muscle of blood vessels
– Kidney: glomerluar and tubular
epithelium
– Corneal epithelium
– Myocardium
– Autonomic NS: ganglion cells
– RES: bone marrow, liver, spleen,
lymph nodes
– Lungs, synovial lining and testes
Fabry: Clinical Manifestations
– angiokeratoma (age 10-20) appearance dark
red macules or papules
– acroparesthesias exacerbated by fever and
exercise (childhood)
– anhidrosis (tears and saliva)
– Nausea, abdominal pain, diarrhea
– ophthalmic abnormalities: corneal opacity,
posterior cataracts,
– ischemic cerebrovascular disease: seizure,
TIA, stroke
– ischemic heart disease: MI, dysrhythmias
Angiokeratoma
Kidney
– mild proteinuria (0.5-2g/d) in the 3rd
decade
– Uremia and hypertension in the 4-5th
decade
– ESRD as early as 2nd decade
– Urine: myelin bodies, mild hematuria
Pathology
• Uniform-size empty
vacuoles (formalin)
– Most striking in visceral
epithelial cells of
glomeruli
– Less in renal arterioles,
tubular epithelium,
mesangium, interstitium
• Birefringence and Maltesecross w/ polarized optics
(fresh or frozen)
• Progressive disease:
segmental and global
glomerulosclerosis
Pathology
• IF is negative
• EM: cellular inclusions in all glomerular cells
– Zebra bodies or myelin figures
– Onion skin appearance
– Located in lysosomes
• Foot process effusion w/ heavy proteinuria
• DDX:
– Pulmonary Scilicosis W/ hematuria and
proteinuria: inclusions in glomeruli
– Clororquine therapy: inclusions in glomeruli
– Aminoglycoside: inclusions in tubules
M&M in Fabry Disease
• Natural Hx: death at mean age of 42 from
uremia
• Treated for ESRD: most common causes of
death are cerebrovascular and cardiovascular
• After transplant, the glycosphingolipid deposits
recur but do not limit renal function
• New Rx: IV alpha-galactosidase q 2 weeks.
Approved in Europe last month. Awaiting FDA
approval in US
Alport Syndrome
• Inheritance
– Classic X-linked dominant
– AR
– AD
• Gene: COL4A5 encodes for the alpha 5
chain of type IV collagen
• Gene frequency 1:10,000
Alport Clinical Features
• Hematuria: microscopic may be persistent, gross
hematuria is intermittent if present. Onset 0-10 yrs
• Proteinuria: absent in the first few years of life and
then becomes gradually progressive.
• Hypertension-progressive
• Renal survival
– Males: nearly all affected progress to ESRD; Age is
variable
– Females: better prognosis (X-linked variety); presence
of gross hematuria in childhood, nephrotic syndrome,
and diffuse GBM thickening are poor prognostic signs
Alport Syndrome
• Sensorineural hearing loss: onset by age 15 in
males. Detect by audiometry. Progressive. In
females progressive hearing loss is a poor
prognostic sign
• Ocular defects: 15-30%
– Anterior lenticonus
– Corneal endothelial vesicles
• Platelet defects: megathrombocytopenia + platelet
dysfunction (AD)
• Diffuse leiomyomatosis: upper GI tract,
tracheobronchial tree, females genital. Posterior
subcapsular cataracts. (AD)
Alport Nephropathology: Light
– < 5 years: nearly nl w/ occasional interstitial foam
cells and fetal glomeruli
– mesangial widening
– focal thickening of Bowman’s capsule
– focal endothelial and mesangial proliferation
– split capillary walls
– progressive glomerular sclerosis
– TBM thickening
– interstitial fibrosis and foam cells; tubular atrophy
– occasional crescents
– capsular tuft synechiae
Nephropathology
• IF
– Typically negative
– Increased deposition w/ sclerosis
• EM
* Variable thickening, thinning, basket
weaving, and lamellation of the GBM
Alport Syndrome
Alport: Prognosis
• Post transplant
– 5% Anti-GBM nephritis
– responds to therapy
– likely to recur in next allograft
• Hearing deficit
– may progress to total deafness
• Treatment
– supportive
Primary Hereditary Hyperoxaluria
• Type I
– hyperoxaluria w/ glycolic aciduria
– alanine: glyoxylate aminotransferase deficiency
(peroxisome)
– autosomal recessive; 1:60,000-120,000
• Type II
– hyperoxaluria w/ L-glyceric aciduria
– D-glycerate dehydrogenase deficiency (cytosol)
– very rare
• Type III
– Intestinal hyperoxaluria (hyperabsorptive)
(1)glycine cleavage enzyme; (2) alanine: glyoxylate aminotransferase; (3) Dglyceric acid dehydrogenase; (4) glycerate kinase; (5) trimethylamine oxidase; (6)
lactate dehydrogenase; (7) glycolate oxidase; (8) NKH* = nonketotic
hyperglycinemia; TH4 =tetrahydrofolate.
Behrman: Nelson Textbook of Pediatrics, 16th ed. 2000
Metabolic Pathway
Defective in PH-I
glyoxalate
Pyridoxine
Alanine:glyoxylate aminotransferase
(liver)
oxalate
glycine
Primary Hyperoxaluria-I: Laboratory
• Elevated urinary sodium, oxalate, glycolic
acid, and glyoxylic acid
• Laboratory Normal Values
– Blood oxalate 10-140 mg/dl
– Urine oxalate 10-40 mg/day
– Oxalate/Creatinine urine
• Infants < 0.3 mg/mg
• 1-5 yo < 0.1 mg/mg
• >5 yo < 0.05 mg/mg
Pathology
• Hyperoxalemia: wide spread deposition of
oxalate = oxalosis
• Renal deposition: nephrolithiasis,
tubulointerstitial nephropathy, renal failure
• Light Microscopy: calcium oxalate
crystalline deposits in tubule, interstitium,
interstitial fibrosis, late focal glomerular
sclerosis. Stone in calyceal system are
birefringent
Extrarenal deposition
• blood vessel walls
• bone
• bone marrow
(myelopthesis)
• joints
• heart
• spleen
• liver
• thymus
•
•
•
•
•
•
•
pituitary
adrenal
pancreas
parathyroids
thyroid
brain
heart (conduction
defects)
Primary Hyperoxaluria
Primary Hyperoxaluria - I
Treatment
• Early diagnosis
• Dietary restriction of glycine and high oxalate
foods (spinach, rhubarb, beet roots, iced tea)
• Pyridoxine
• Hydration to limit stone formation (2.5 L/m2)
• + Mg and phosphate supplementation
• Liver / Kidney transplant