1. Nephrology Core Curriculum: Autosomal Dominant Cystic Kidney Disease (ADPKD and others)

2. 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

3. Tuberous Sclerosis
Hereditary disease with hamartomas in multiple organ systems
Autosomal dominant with high penetrance, but extreme phenotypic variability

4. Tuberous Sclerosis Clinical Features
Hamartomas
Benign tumors resulting from disordered cell migration
Skin
Facial angiofibromas (adenoma sebaceum)
Fibrous forehead plaques
Ungual fibromas
Shagreen patches- lumbosacral palpable lesions
Hypomelanotic macules- earliest and most common skin lesions, occurring in 90% of cases

5. Tuberous Sclerosis Clinical Features
Hamartomas
Benign tumors resulting from disordered cell migration
Skin
Brain
Cortical tubers
Associated with infantile seizures and mental retardation

6. Tuberous Sclerosis Clinical Features
Hamartomas
Benign tumors resulting from disordered cell migration
Skin
Brain
Subependymal glial nodules
Arise in the ventricles. Cause increased ICP

7. Tuberous Sclerosis Clinical Features
Hamartomas
Other organs affected:
Skin
Brain
Retina
Heart- cardiac rhabdomyomas
Kidneys
Liver
Lungs
Bone

8. 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

9. Tuberous Sclerosis Diagnosis
No definitive features
Made by combination of major and minor features
Require at least two features

10. 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

11. 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)

12. 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

13. 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

14. 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

15. Von-Hippel-Lindau Disease Clinical Features
Usual lesions
Pancreas
Cysts in 30% of patients
Likely to cause confusion with ADPKD

16. 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

17. 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

18. 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 Non-Europeans unknown
4% of ESRD patients
Common in cats

19. 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

20. 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

21. 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

22. 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)

23. ADPKD 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

24. ADPKD Signs and Symptoms
Back pain
Chronic- Likely the result of stretching of the renal capsule by the enlarging cysts
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 25-60% of patients
Some bp improvement.

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. ADPKD Urinary findings
Microscopic hematuria 23%
Pyuria up to 45%
Dipstick Proteinuria %
Nephrotic range proteinuria does not occur with ADPKD alone
Only 18% with > 300mg/day proteinuria

32. 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

33. ADPKD Extra-renal manifestations Cystic
Other cysts
Pancreas- 9% of patients >30 yo
Ovaries No increase (12%)
Seminal vesicles 60%
No signif
Prostate 11%
Arachnoid cysts 8%

34. ADPKD 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

35. 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/
Risk of elective surgery
Death 1-4% at one year
Morbidity rate of 15% at one year

36. ADPKD Berry Aneurysm Sawyer’s rule of 20s
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

37. 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

38. ADPKD Berry Aneurysm Screening recommendations
Risk benefit ratio against routine screening of asx patients
Screen
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

39. 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

40. 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

41. 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

42. ADPKD Modifier Genes ACE sub-type Sickle cell trait
2 studies show impact, 2 don’t
Sickle cell trait
Likely accelerates

43. 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 ACE-Is selectively block
Use of amiloride
Shown to block Na entry into cysts and halt cyst enlargement in animal models

44. ADPKD Treatment Protein restriction Cyst decompression Animal models
MDRD- no protective effect on moderate or severe restriction
Cyst decompression
Pain management tool. No evidence for delayed disease progression
Animal models
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

45. 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

46. 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

47. 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