Transcript Cystic_Kidney_Disease

Nephrology Core Curriculum:
Autosomal Dominant Cystic
Kidney Disease
(ADPKD and others)
Inherited Kidney Diseases
Background
• Dominant inherited
polycystic diseases
– ADPKD
– Tuberous sclerosis
– von Hippel-Lindau disease
• Recessive inherited
polycystic diseases
– ARPKD
• As would be expected
with recessive, onset early
in life with ESRD in youth
• Always associated with
congenital hepatic fibrosis
Tuberous Sclerosis
• Hereditary disease with hamartomas in
multiple organ systems
– Autosomal dominant with high penetrance, but
extreme phenotypic variability
Tuberous Sclerosis
Clinical Features
• Hamartomas
– Benign tumors resulting
from disordered cell
migration
• Skin
– Facial angiofibromas
(adenoma sebaceum)
– Fibrous forehead
plaques
– Ungual fibromas
– Shagreen patcheslumbosacral palpable
lesions
– Hypomelanotic
macules- earliest and
most common skin
lesions, occurring in
90% of cases
Tuberous Sclerosis
Clinical Features
• Hamartomas
– Benign tumors
resulting from
disordered cell
migration
• Skin
• Brain
– Cortical tubers
» Associated with
infantile seizures
and mental
retardation
Tuberous Sclerosis
Clinical Features
• Hamartomas
– Benign tumors
resulting from
disordered cell
migration
• Skin
• Brain
– Subependymal glial
nodules
» Arise in the
ventricles. Cause
increased ICP
Tuberous Sclerosis
Clinical Features
• Hamartomas
– Other organs affected:
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Skin
Brain
Retina
Heart- cardiac rhabdomyomas
Kidneys
Liver
Lungs
Bone
Tuberous Sclerosis
Clinical Features
• Hamartomas
– Benign tumors resulting from disordered cell migration
• Kidneys
– Present in 50% of cases
– #1 lesion is angiomyolipomas
» Benign lesion made of adipose tissue, smooth muscle cells,
and arterial vessels
» Fat content makes them easy to diagnose by CT scan
» Bleeding is a risk if >4cm, esp during pregnancy
– Renal cysts (unrelated to angiomyolipomas) also occur in 30% of
patients
Tuberous Sclerosis
Diagnosis
• No definitive features
• Made by combination of major and minor
features
– Require at least two features
Tuberous Sclerosis
Management
• No specific therapy
• Consensus conference
– Evaluated every 1 to 3 years with renal US, CT
or MRI of the brain
– One chest radiograph in adult women
• Surgical resection for CNS lesions causing
hydrocephalus
Von Hippel-Lindau Disease
• Autosomal dominant disease with high
penetrance
– Development of benign and malignant tumors
in multiple organs
• Type I - NO pheos
• Type II- Pheos (runs in 7-20% of families)
Von-Hippel-Lindau Disease
Clinical Features
• Potential Sites– Central nervous system, eyes,
kidneys, adrenal glands, pancreas,
and epididymis are commonly
affected
• Usual lesions
– CNS hemangioblastomas
• In the cerebellum, spinal
cord and brainstem. No
supratentorial lesions
• Benign, but mass effects
cause difficulties
– Recur after surgery
Von-Hippel-Lindau Disease
Clinical Features
• Usual lesions
– Retinal
hemangioblastomas
• In 50% of cases
• Multiple or bilateral
• Red “dots” on retina
that slowly enlarge
• Regular ophtho eval
important
– Laser tx
Von-Hippel-Lindau Disease
Clinical Features
• Usual lesions
– Renal
• Cysts
– 50-70% of patients
• Carcinoma
– 77% of patients by 60 years
old
– Usually multiple and
bilateral
– #1 cause of death
– Inherited form of renal
cancer due to the loss of a
suppressor gene
Von-Hippel-Lindau Disease
Clinical Features
• Usual lesions
– Pancreas
• Cysts in 30% of patients
• Likely to cause confusion
with ADPKD
Von-Hippel-Lindau Disease
Diagnosis
• Positive family history, plus a single
hemangioblastoma or visceral lesion
• No family history, two or more
hemangioblastomas or one and a
visceral lesion
• Direct mutation analysis is now
possible
• Distinguish from ADPKD
– Both with kidney cysts
– ADPKD with rare panc and freq
hepatic
– VHL with rare hepatic and freq panc
• Suspect in any patient with kidney
and pancreas cysts without liver
cysts
Von-Hippel-Lindau Disease
Management
• Regular screening
program
– Annual physical and
ophtho
– Annual MRI of CNS
– Annual abdominal imaging
• Either US,CT,MRI
– If positive family history,
• Periodic metanephrines
screening for pheo
ADPKD
Epidemiology
• Prevalence approximately
1:400 to 1:1000 in people
of European descent
– 600,000 Americans with the
disease
– More than CF, muscular
dystrophy, hemophilia,
Down’s syndrome and
sickle cell anemia–
COMBINED
– Frequency in NonEuropeans unknown
• 4% of ESRD patients
• Common in cats
ADPKD
Genetics
• Two different
mutations
– ADPKD-1
– ADPKD-2– same as
one, except:
• Milder disease
• Older age at diagnosis
• Later onset of
hypertension
• Later onset of renal
failure
ADPKD
Genetics
• Only 1-2% of tubules affected
– Two-hit hypothesis– genetic abnormality not sufficient,
requires an additional insult to manifest
• (argument for aggressive treatment of ADPKD patients)
• Cysts begin as focal dilatations of tubular segments
• Not just impermeable cul-de-sacs. They collect and store urine
from more proximal nephron segments
– Synthesize and transport proteins, hormones, and cytokines
ADPKD
Diagnosis
• Ultrasound
– Insert Australian ultrasound study
– Age adjusted criteria
• 18-29yo, at least 2 cysts
• 30-59yo, at least 2 cysts in each
kidney
• >60yo, four cysts in each kidney
– For r/o diagnosis of ADPKD in patient
at risk, no age at which 100% of gene
carriers have detectable cysts
• US can only prove ADPKD, it cannot
r/o
• 2 studies in families with gene linkage
analysis showed no false negatives
after age 30 yo (but only two families)
– Can’t just screen parents
• 10% of ADPKD patients are new
mutations
ADPKD
Genetics
• Genetic tests by linkage analysis only
– No direct mutation analysis
– Requires at least two related family members with the
disease.
– Expensive ($1000s)
– Only utility is for donor screening
• Other reported uses include family planning decisions and
prenatal diagnosis
– Athena diagnostics launched a molecular test based on
direct mutation analysis
• Detects only 50% of PKD-1 and 75% of PKD-2 mutations
• (takes 4 weeks and $2600 by credit card)
ADPKD
Signs and Symptoms
Signs and symptoms
Frequency
Back pain and flank pain
60% of adults
Hypertension
80% of adults
Gross Hematuria
50% of adults
Renal Concentrating defect
All adults
Palpable kidneys
Potentially all adults
Hepatomegaly
20-30% of women >50yo
Proteinuria
18-68% of adults
CRI
Age dependent
ADPKD
Signs and Symptoms
• Back pain
– Chronic- Likely the result of stretching of the renal
capsule by the enlarging cysts
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Tylenol
Physical measures- ice massage and heating packs
TENS
Autonomic plexus blockade
Decompression of cysts
– Usually laproscopic. Can drain one or hundreds of cysts
– Immediate pain relief in 90%. Persistent relief at 3 years in 2560% of patients
– Some bp improvement.
ADPKD
Signs and Symptoms
• Hypertension
– Occurs well before renal insufficiency
• 40% by 18-24yo
• 54% by 24-30yo
• 65-80% > 30yo
– Hypertension correlates with renal size
• Mechanism clearly complex– but demonstrated to
have hyperplasia of renin producing cells and
increased renin levels
ADPKD
Signs and Symptoms
• Gross hematuria
– Painless or associated with dull colicky pain
– 40-50% of patients experience at least one
episode
• In 20% of patients it is how ADPKD is discovered
– Last 2-7days and cease spontaneously
– Can be seen on CT with contrast- high density
cyst without enhancement after administration
of contrast
ADPKD
Signs and Symptoms
• Renal concentrating defect
• Palpable kidneys- exam is poor at
estimating size
• Palpable hepatomegaly
– 20-30% of patients older than 50
• UTI
– Must use lipophilic agents to treat
• Cipro, Clindamycin, Emycin, and Bactrim
ADPKD
Manifestations
Not just a renal process, it is a basement membrane
abnormality that affects multiple sites
Manifestation
Frequency
Renal Cysts
100% by 30 yo
Nephromegaly
95% by 30 yo
Decreased concentrating ability
All adults
Hypertension
65-80% of adults
Extra-renal
Liver cysts
75% by age 60yo
Pancreatic cysts
9% after age 30yo
Seminal vesicle and prostate
cysts
60% and 11% at 40yo
Arachnoid cysts
5-8%
MVP
25%
Intracranial Aneurysms
2-3%
Abdominal Wall Hernia
45% with ESRD
ADPKD
Signs and Symptoms
• Nephrolithiasis
– 20-36%
– Stone composition
• Higher uric acid than general population--- 50%
• Remainder CaOx
– Due to metabolic factors and urine stasis associated
with distorted renal architecture
• 50% have hypocitraturia
– Can use lithotripsy
ADPKD
Signs and Symptoms
• Renal Cell Cancer
– No increased risk
– Presence should raise the suspicion of a
misdiagnosis
• Consider Von Hippel Lindau disease, esp. if familial
cancers
ADPKD
Urinary findings
• Microscopic hematuria
• Pyuria
• Dipstick Proteinuria
23%
up to 45%
34-68%
– Nephrotic range proteinuria does not occur with
ADPKD alone
– Only 18% with > 300mg/day proteinuria
ADPKD
Extra-renal manifestations
• Liver cysts
– The most common extrarenal
manifestation
– Arise from bile ducts
– Occur later than renal cysts
– By 60yo, 75% will have liver
cysts
– Women > Men
• Multiple pregnancies puts at
greater risk
– Despite hundreds of cysts- liver
function typically remains
NORMAL
– Can become infected- unlike
renal cysts, requires drainage for
clearance
ADPKD
Extra-renal manifestations
Cystic
• Other cysts
– Pancreas– Ovaries
– Seminal vesicles
9% of patients >30 yo
No increase (12%)
60%
• No signif
– Prostate
– Arachnoid cysts
11%
8%
ADPKD
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Extra-renal manifestations
Non-Cystic
Mitral valve prolapse
25%
LVH
Intracranial Aneurysm
Colonic divertics
– Increased in ADPKD ESRD patients, but not pre-ESRD
• Abdominal wall hernias, up to 45%
– Not associated with renal size or volume
ADPKD
Berry Aneurysm
• 4 large, prospective studies
screening asx subjects (High res
CT,MRI, or Conventional Angiography)
• 5-10% of asymptomatic adults
with ADPKD harbor an
Intracranial aneurysm (vs.
normal--???)
• All aneurysms found by screening were
less than 8mm
• No change during a mean f/u of 2.5 years
• Annual risk of rupture for cysts <10mm
is 1/2000
– If >10mm or prior ruptured
aneurysm 1/100-200
– Risk of elective surgery
» Death 1-4% at one year
» Morbidity rate of 15% at one
year
ADPKD
Berry Aneurysm
• Sawyer’s rule of 20s
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1/20 chance of having an asx aneurysm (5-10%)
1/200 chance of rupture if >10mm
1/2000 chance of rupture if <10mm
20% chance of complications with surgery
• 1-4% death + 15 % morbidity at one year
– 20% of aneurysms multiple
ADPKD
Subarachnoid Hemorrhage
• Familial clustering of
aneurysm rupture
– Occurs in the general
population as well
– 5% of ADPKD, but 22% if
+ fhx
• 20-30% with have
multiple aneurysms
• 10% who have one
aneurysm rupture will
have a second rupture
ADPKD
Berry Aneurysm
• Screening recommendations
– Risk benefit ratio against routine screening of asx patients
– Screen
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Prior rupture
Positive Family history
High risk occupation- Air Line Pilots etc
Prior to a surgery with hemodynamic instability associated with
hypertension (KI, 1994 IC aneurysms in ADPKD)
• Neurologic symptoms suggestive of an aneurysm
• ** Trash indication**
– Patient’s who need screening for peace of mind
ADPKD
Berry Aneurysm
• Questions to answer if you screen anyway
– How often?
• Does a negative screen you will never develop cysts?
• At what age will you develop cysts?
• Are you born with cysts and the remain stable for life, or do they
enlarge?
– Serial MRAs show stability for at least 30 months
– No de novo aneurysms over an 8 year period
– Stable for 2.5 – 5 years, otherwise no data
– General recommendation are q5-10 years
– Note
• ADPKD patients have more CVAs than subarachnoids
• ADPKD patients have more hemorrhagic strokes than
subarachnoids
ADPKD
Pregnancy with normal renal function
235 women with 605 pregnancies
• ADPKD has no impact on fertility
• Rate of live birth unchanged
– 77% vs. 82% of normals
• Fetal complication rate- unchanged
• Maternal complications INCREASED (35% vs 19%)
– New or worsening hypertension
– Pre-eclampsia
– Edema
• No impact on renal function
– Except if FOUR or more pregnancies and hypertensive
ADPKD
ESRD
• 50% at 60 years, 75% at 70 years at ESRD
• Negative prognostic factors:
– HTN
• Reviewed 1215 subjects
• Median renal survival 14 years longer if not hypertensive by age 35
years old
– LVH
– Male
– Younger age at diagnosis• -difference of ten years to ESRD between onset <30 vs >30yo
– 3+ pregnancies, UTIs (in men)
– Episodes of gross hematuria, H/o hypertension in parent
– If you have HTN, hematuria, and diagnosis before age 30
years old– 100% ESRD by 48 yo
ADPKD
Modifier Genes
• ACE sub-type
– 2 studies show impact, 2 don’t
• Sickle cell trait
– Likely accelerates
ADPKD
Treatment
• HTN
– MDRD had 200 patients with ADPKD
• No protective effect over a mean 2.2 years
– ? Disease already too far advanced
– Progression is slowed in animal models
– Use of ACE-I
• No evidence that hemodynamics plays an important role in
progression
– Can perform unilateral nephrectomy without accelerating the disease
process
– Proteinuria always less than nephrotic range
– However ultimate progression of disease is due to fibrosis and ACEIs selectively block
– Use of amiloride
• Shown to block Na entry into cysts and halt cyst enlargement in
animal models
ADPKD
Treatment
• Protein restriction
– MDRD- no protective effect on moderate or severe
restriction
• Cyst decompression
– Pain management tool. No evidence for delayed disease
progression
• Animal models
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Protein restriction beneficial
Soy protein supplementation beneficial
Flaxseed beneficial
Statins beneficial
Alkalinization- helps in rats, but not mice
– Thought is that the 2nd ammonia genesis by the kidney in order to
compensate leads to tubular damage
ADPKD
Counseling and Screening
• Newly diagnosed patients should be informed about
ADPKD, it’s hereditary nature, and that children have
a 50% chance of inheriting the gene
• Before screening, subjects should be “informed of the
consequences of diagnostic screening, particularly
regarding insurability.”
– My practice--Screening offers no benefit
• A negative US doesn’t r/o disease
• A positive US will not lead to a change in therapy, but it will make
the person uninsurable and potentially unemployable
• Gene linkage can be performed if potential donation is considered
-remember it costs approximately $2600
Acquired Cystic Kidney Disease
• Development of multiple, bilateral cysts in
kidneys of patients with chronic renal
disease due to causes other than cystic
kidney disease
– 10-20% of pre-dialysis patients
– Increases with dialysis, 50% of patients on HD
x 3 years with cysts
– Major determinant is the duration of renal
insufficiency
Acquired Cystic Kidney Disease
• Cysts are usually less than 0.5 cm
– Occasionally reach 2-3cm
• Affect both the cortex and medulla
• Result of a failure to clear unknown “mytogenic
and cystogenic” substances due to renal
insufficiency
– Lesions regress with transplantation
• Concern is transition to cancer
– Men 7x more than women
– Some recommend screening starting at 3years with
annual US
– Given shortened lifespan with ESRD, others refute