Mitchell Rosner, MD Mark Perazella, MD ADPKD Overview

BRCU 2017 • 4th leading cause of ESRD

Cystic Kidney Diseases A •
•
No race/gender favored
>3,000,000 worldwide
Case‐Based Approach • Cysts
— Kidneys
―Liver
―Pancreas
―Spleen
―Brain
• Begin in utero
• Develop in tubules
• Separate from tubules
• Isolated sacs

Grantham JJ. N Engl J Med. 2008;359:1477-1485.

• In 85%‐90% of cases, ADPKD results from a mutation in the PKD1 gene, and the
other 10%‐15% of cases are accounted for by mutations in PKD2.
•
ADPKD Pathogenesis
PKD1 and PKD2 encode for polycystin‐1 and polycystin‐2 proteins (polycystin Cystic Phenotype
signaling complex) which regulate different signals including 3’,5’‐cyclic
adenosine monophosphate (cAMP), mammalian target of rapamycin (mTOR) and
epidermal growth factor receptor pathways. Wild-type PC1/PC2 Polycystic
• Abnormal activation of these signals causes an increased cell proliferation which
is an important component of this disease.
• Cyst enlargement is thought to result from increased fluid secretion; and
abnormal cell replication by the epithelium lining the cyst.
• The processes underlying the decline in renal function include disruption of
glomerular filtration and urine concentrating mechanisms, coupled with
compression of adjacent nephrons in the cortex, medulla and papilla. Cyst‐
derived chemokines, cytokines and growth factors cause fibrosis that is similar to
development of other progressive ESRD • Well differentiated • De-differentiated
• Polarized • Polarization defects
• Normal cell-cell/matrix interactions • ↑ integrin-α2β1, ↓ E-cadherin
• Low rate of division and apoptosis • High rate of division and
• Branching tubules in collagen gels apoptosis
• Reabsorptive • Cysts in collagen gel
• Planar polarity • Secretory phenotype
• Loss of planar polarity

Torres Nat Clin Neph 2:40, 2006

• A 30 year‐old male is known to have a family history • The patient wants to know whether he has ADPKD.
Case side
of ADPKD on his paternal #1 with multiple family Question
• Which of the following #1
is true?
members with ESRD at ages 59‐ a. Molecular genotyping is required to answer his
72. Recently, a renal ultrasound performed for question
symptoms of flank pain and hematuria revealed 3 b. The number of cysts at this time is too few to make a
cysts on the right kidney and 2 cysts on the left determination
kidney. c. The patient most likely has ADPKD
• The patient is otherwise healthy, takes no d. An MRI is required before conclusively answering his
medications and has a normal physical examination. question
 Increased Detection Rate of Simple Renal Cysts with MR
Current Ultrasound Diagnostic Criteria Imaging
for ADPKD
% of the general population
demonstrating any simple cyst by MRI
Family History No Family History
80
< 40 years: 5 cysts distributed 70
3cysts bilaterally bilaterally with a 60
consistent phenotype 50
40‐60 years: 40 18‐29 years
Revised Pei
4 cysts bilaterally Criteria 2009
30 30‐44 years
20 45‐59 years
 60 years: 10
8 cysts bilaterally 0
0 1 cyst 2 3 ‐4 5‐10 > 10
cysts cysts cysts cysts cysts
High PPV but not effective at excluding diagnosis of ADPKD in
young patients and those with mild disease (PKD2 mutations

• In a 20‐year‐old with no cysts detected by CT or MRI and with PKD1‐like disease

Genotyping for ADPKD
Recommendations:
1.Potential kidney donor
from affected family with
cyst numbers below
diagnostic threshold
2.Young individuals < 25, in
whom no cysts are
detected by US, CT, MRI
and family disease is mild
in the family: ADPKD is unlikely and molecular testing is not necessary
• Genotyping: Examples
In a 20‐year‐old with no cysts detected by ultrasonography and with PKD2‐ like
disease in the family: ADPKD is still a possibility and molecular testing is
appropriate
• In a 30‐year‐old with one cyst detected by CT or MRI and PKD1‐like disease in
Other scenarios: family: ADPKD is not likely but molecular testing may provide reassurance
1.Negative family history • In a 40‐year‐old with three cysts detected by CT or MRI and PKD2‐like disease in
‐Atypical presentation
family: ADPKD is a possibility and molecular testing is appropriate
• In a 40‐year‐old with no renal cysts detected by CT or MRI and PKD2‐like disease
‐Extrarenal manifestations in family: ADPKD is unlikely and molecular testing is not necessary
atypical for ADPKD • In a 60‐year‐old with two renal cysts detected by CT or MRI and PKD1‐like
‐Prognostic information disease in family: ADPKD is unlikely and molecular testing is not necessary
2.Early‐onset ADPKD
‐Identify variants associated with
severe disease
3.For those wanting definitive
diagnosis

Harris PC and Rossetti S. Nat Rev Nephrol 2010

• Linkage analysis: limited utility for those where family

PKD Genes and Transcripts
Genotyping
mutation is known
• Direct sequencing of exonic and intronic regions from 1 5 10 15 20 25 30
3kb
35 40 46

genomic DNA is most commonly used method. 1994 TSC2

50 kb gene, 14 kb transcript
• However:
PPKKDD11gegneene

1
23
4 5 6 7 8910 11
12 14
13 15 16171819202122 23 2425262728 293031 333435363738 394041424344 45 46 >
– High degree of allelic heterogeneity in PKD1 and 2 275 mutations 1
23
4 5 6 7 8910 11
12 14
13 15
32
32

16171819202122 23 2425262728 293031 333435363738 394041424344 45 46

PKD1transcript 1kb Missense: 28%

– No single mutation accounts for more than 2% of
affected families 1
1112 13 14 15
2
3kb
3 4 5 6 7 8 910

– Diagnostic screening of a new family requires sequencing PKPDK2Dg2egneene

1996
70 kb gene, 3 kb transcript
of all PKD1 and 2 exons and is expensive 1
1
101011111212 1313
23 4 5 6 7 8 99
23 4 5 6 7 8 91011121314 15
14 15 PKD2transcript > 75 mutations
1kb

Missense: 11%

Harris PC and Rossetti S. Nat Rev Nephrol 2010

2002
PKHD1 gene 472 kb gene, 13 kb transcript
> 275 mutations
Missense: 60%

PKHD1 transcript

Any mutation that inactivates one of the two alleles is likely pathogenic
Harris PC, Rossetti S. Nat Rev Nephrol. 2010;6:197‐206.
• There are scoring systems used to determine whether a
Types and Numbers of Variants (a) and Mutations
(b) Found in PKD1 (Top) and PKD2 (Bottom) Patients Genotyping
mutation that is identified may be pathogenic
• Approximately 91% of patients with phenotypic ADPKD have
mutations detected
– 65% have truncating mutations and are definitive
– 26% have nondefinitive mutations
• Mutations are collated in a database
• Various mutations are associated with distinct phenotypes
– Such as 3’ deletion of PKD1 may disrupt TSC gene with various
signs of TSC as well as severe PKD

Harris PC and Rossetti S. Nat Rev Nephrol 2010

• 9% of patients with no mutation in PKD1 or 2 • The patient is interested in understanding what features of
ADPKD predict progression to ESRD
Other
• Usually have Pitfalls in Genotyping
milder disease and may have negative Question #2
• Which of the following is true?
family history a. Total kidney volume and its change over time is the best
predictor
• May have uncharacterized intronic or promoter b. Age at which the patient’s relatives developed ESRD is the
mutations best predictor
• May have mutations in the many other genes c. The number of renal complications due to ADPKD is the best
predictor
associated with renal cystogenesis: d. There are no features that reliably predict progression to
– HNF1β, PRKCSH, SEC63, GANAB or PKHD1 ESRD

Harris PC and Rossetti S. Nat Rev Nephrol 2010

• Renal cysts are the first verifiable primary manifestation of • Genotype: > 95% PKD1 individuals demonstrate
Kidney
ADPKD and Cyst Volume are Determinants of Characteristics of ADPKD That Associate
renal cysts by age 30
• Cyst formation
RenalALWAYS
Outcomes precedes:
in ADPKD within ESRD
– flank pain • Hypertension: occurs 60% with intact renal function by
– hypertension age 30
– gross hematuria
– reduced GFR
• Proteinuria: is not a common feature of this disease, but
– nephrolithiasis has important prognostic implications
– kidney infections
• Gross hematuria: > 50% will have had an episode by age
• The inverse correlation between kidney volume and function has
been observed for over 30 years in ADPKD1-6 40
ALL CHARACTERISTICS HAVE NOW BEEN SHOWN TO MEDIATE THEIR
1Thomsen Urol Rad 3:85, 1981; 2Chapman Kid Int 64:1035, 2003; 3Fick-Brosnahan AJKD 39:1127, 2002; 4Lee Nephron Clin Pract
103:c173, 2006; 5Tokiwa Clin Exp Neph March 2011; 6Meijer CJASN 5:1091, 2010; RISK THROUGH KIDNEY VOLUME
 Cumulative Survival of PKD1 vs Increased Kidney Volume is Due to
PKD2 Increased Cyst Volume

Total Kidney Volume Total Cyst Volume

Kidney growth is highly variable and

each individual has their own growth curve
Measurement variability= Inter-observer 2.1% , Intra-observer 2.4% , Day-to-Day 2.4%
Grantham, NEJM CRISP 2006; Chapman Kidney Int 64; 1035–1045, 2003

Patterns of Individual Kidney Growth in 241 Patients With

ADPKD
N Engl J Med. 2008;359:1477-1485.
Grantham JJ.

Lifetime model illustrating dynamic change in TKV from birth and
how TKV can be used to judge prognosis
• This patient is now 45 years of age and has now
developed stageQuestion #3with complaints of
3 CKD. He calls
right flank pain and fevers associated with mild
nausea.
• On examination, he has a temperature of 38 degrees
C and moderate right flank tenderness
• Urinalysis reveals numerous white blood cells
 • Which of the following is the next step in • Estimated that 30‐50% of patients with ADPKD may experience a
kidney infection
management ofQuestion
this patient? #3 Cyst Infections in ADPKD
• Determining that an infection is present vs. other etiologies of flank
pain (hemorrhage, nephrolithiasis, expanding cysts) is challenging
A.PET scan to determine site of infection • Urine cultures may be negative as the cyst are not contiguous with
B. Ultrasound with aspiration and culture of any the tubules
• Criteria for likely diagnosis of infection: fever, flank pain and elevated
dominant cyst CRP
• Fluoroquinolones provide the most favorable treatment outcomes
C. Empirical antibiotics with ciprofloxacin and more prolonged course are needed
D.Empirical antibiotics with cefuroxime • PET scans useful in unclear cases
• Cyst aspiration may be required for cure

Alam A, Perrone RD. Clin J Am Soc Nephrol 2009

By age 30, over 50% have at least one complication

ADPKD Patients Suffer
NIH CRISP Renal Complications
Studies; Rahbari-Oskoui, Prior
ASN Renal Week, 2010. Cyst Burden and Patient
to Loss of Kidney Function Complications in ADPKD
Healthy Tissue

Cyst Development and

Enlargement

Vasculature

Function

Age
Urinary
Concentrating Defects

Signs & Hypertension

Symptoms Dull Pain & Discomfort
Proteinuria

Renal Events in ADPKD Result in Extra‐renal Manifestations of

Significant Pain
ADPKD: Liver Cystic Disease
Cyst Infection Nephrolithiasis
-20 Y Female - 35 Y Male
-Acute left - Acute left
flank pain flank pain
-eGFR 106

Left KV 890 ml Left KV 920 ml

Cyst Hemorrhage Nephrectomy for Pain

- 32 Y male -52 Y Male
- Acute -Chronic pain
onset left -Kidney Weight: 21.5 kg
flank pain
- eGFR 80
Left KV 1170 ml

KV= Single Kidney Volume; Normal Single Kidney Volume ~ 150 ml; Normal W eight of 1 kidney ~ 0.15 kg
 • Most often in women (>90%)
Wide Range of Severity of Hepatic • Massive Polycystic
Familial aggregation is not Liver Disease
apparent
Cysts • Renal involvement is often relatively spared
• Estrogen exposure not clearly a risk factor for this
form of PLD
• Ascites, portal hypertension and varices, hepatic
venous obstruction, liver cyst infection

• The patient has read about the risk of intracranial • More often in the anterior circulation (84%)
aneurysms in those with ADPKD. He has no family history of Features ofPKD1
Intracranial Aneurysms in5’ end
Question #4
ICA but wants to know about screening • Mutations in the gene tend to be closer to the
ADPKDwith
of the gene in families individuals
ICA
• Which of the following would you tell him? • Repeat screening in negative individuals is low (2.4% over 10
years) but tends to occur in those with existing ICA (10%)
A. Screening is not indicated • Change in size of existing ICA is slow and uncommon with
B. Screening should occur in all patients at the time of 8/65 showing an increase in diameter over 243 patient years
diagnosis of less than 0.5 mm
C. Screening should be performed with intracranial
angiography
D. Screening can be performed with magnetic resonance
angiography

• Very controversial and no consensus

Screening for ICA
• Aggressive: Screening all patients with ADPCKD by
noncontrast 3T TOF MRA at the time of initial diagnosis with
follow‐up scans at intervals of, at most, 10 years and as
short as 2 years, depending on patient‐specific risk factors,
including the following: family history of IA or SAH, prior
SAH, neurologic symptoms, hypertension, smoking, alcohol
abuse, high‐risk professions (such as pilots), or those
undergoing major elective surgery.
• Conservative: screening patients with both ADPKD and a
family history of IA or SAH, a prior aneurysm rupture,
high‐risk occupations, undergoing major elective surgery, or
having a “warning headache” or severe anxiety regarding
the issue.
Rozenfeld MN et al. Am J Neurorad 2014
• mTOR inhibitors: smaller TKV but no change in rate • Multicenter RCT in 1445 patients
ofReview
decline in of
GFRTherapies for ADPKD
and high incidence of side effects •Vasopressin 2 Receptor
Age < 50 years; eGFR > 60 ml/minAntagonist
and TKV > 750 ml
• Somatostatin analogues: slower increase in TKV, • Effective in slowing TKV increase and fall in GFR
higher rate of cholelithiasis • Prolongs median age at ESRD onset by 6.5 yrs
• Increases life expectancy by 26 yrs
• Other therapies in development: bosutinib, triptolide
• Cost effectiveness has not been demonstrated
• Significant side effects: polyuria, nocturia, elevated
He Q, et al. Am J Med Sci 2012 Hogan MC et al, J Am Soc Nephrol 2010 LFTs
• Future trials ongoing

Torres VE, et al. N Engl J Med 2012

TEMPO Trial Results Tolvaptan in ADPKD

• The patient is now 45 years old and his blood Study A

pressure on the Question
current visit#5
in 154/90 mmHg. Two Clinical Trials: HALT A and B
• His eGFR is 58 ml/min. 15‐49 years and healthy baseline eGFR > 60
• Which of the following would be the agent of choice mls/min
to treat his hypertension?
a. Amlodipine
b. Hydrochlorothiazide Study B:
c. Lisinopril
d. Carvedilol 18‐65 years
e. Lisinopril and telmisartan baseline eGFR > 25 and < 60 mls/min
Study A: Low (95‐110/60‐75 mmHg) versus standard Primary
Hypotheses
(120‐130/70‐80 mmHg) BP control will reduce the rate Primary
Study and
A: Percent Secondary
change in TKV Endpoints
of disease progression measured by change in TKV. Study B: Time to death, ESRD or 50% reduction in eGFR

Secondary
Study A and B: Dual blockade of the RAAS with ACE‐I • Slope of eGFR
and ARB will reduce the rate of disease progression as • Urine albumin and aldosterone excretion
compared to ACE‐I therapy alone. • LVMI, RBF and RVR (Study A only)
• Frequency of all‐cause and cardiovascular hospitalizations
• QOL, pain, PKD related symptoms

Low slope=5.67%/year Standard slope=6.57%/year

Study A: Annualized % Change in TKV

Diff (95% CI)=-0.96 (-1.55, -0.24) P=0.006 Study A: eGFR Slope
Low
-3.1 ml/min/4 mo Standard
+0.5 ml/min/4 mo p<0.001
NEJM Nov 15, 2014 (online)

Low
-3.1 ml/min/4 mo Standa
+0.5 ml/min/4 mo p<0.001
Ln(TKV) ml

Low long term slope = -2.7 ml/min/yr Standard long term slope = -3.1
ml/min/yr p=0.05

Low overall slope = -2.9 ml/min/yr Standard overall slope = -3.0

ml/min/yr p=0.55

NEJM Nov 15, 2014 (online)

Lisinopril‐Telmisartan vs Lisinopril/Placebo Lisinopril‐Telmisartan vs Lisinopril/Placebo

Primary Endpoints Conclusions
Study A Study B
(annualized % TKV change) (time to death, ESRD or 50% •ACE inhibitor monotherapy is safe and achieves excellent
eGFR decrease) BP control in most patients with ADPKD and CKD stages
1‐3.

•Addition of an ARB, although safe under the conditions of

HALT‐PKD, does not confer additional benefit.
Lisinopril/Telmisartan = 5.9% per year
Lisinopril/Placebo = 6.2% per year op
 Low blood pressure treatment in young healthy • A 24 year‐old woman presents with right flank pain,
Conclusions:
hypertensive HALTwith
ADPKD patients Studies
RAAS blockade is hematuria and anemia. Case #2ultrasound revealed 3
Renal
Well tolerated and Safe cysts in the right kidney and 3 cysts in the left kidney.
CT scan is performed and reveals cysts in both kidneys
And results in a
along with a 5 cm mass with hemorrhage in the right
14.2% slower rate of TKV growth over 5 years kidney.
• On exam, the patient has bilateral facial, erythematous
skin lesions, hypopigmented skin lesions on her legs,
and sub‐ungual fingernail lesions.

• Which of the following is the diagnosis in this patient? • The 5 cm mass seen on CT scan is identified as an
Question
a. Autosomal recessive medullary#1cystic kidney disease angiomyolipoma. Question #2

b. Tuberous sclerosis complex • In addition to packed RBC transfusion, which of the

c. Von Hippel‐Lindau disease following is the best option for therapy?
a. Administer DD‐AVP and observe the patients’ course
d. Bardet‐Biedel syndrome
b. Consult a urologist for partial nephrectomy
c. Consult a urologist for total (radical) nephrectomy
d. Consult interventional radiology for embolization
therapy

• Hereditary tumor syndrome • TSC 1: localized on chromosome 9

Tuberous Sclerosis Complex
• Benign tumors in kidneys and several other organs  brain, • Tuberous Sclerosis Complex
TSC 2: localized on chromosome 16
lungs, skin, and heart
• Respectively code for Hamartin and tuberin
– Neurologic involvement
• Seizures • The H‐T complex inhibits mTOR (mammalian target of
– Kidneys involvement rapamycin) a kinase that regulates protein synthesis, cellular
• Angiomyolipoma (80%), cysts (50%) metabolism, differentiation, growth and proliferation
– Pulmonary involvement • The H‐T complex prevents unregulated cell growth and
• Lymphangioleiomyomatosis proliferation
• Autosomal dominant. Incidence 1: 6000
– 2 genes: TSC1, TSC2 Eckardt et al. KDIGO KI, 2015; Cramer et al. Advances in CKD, 2015; Kim et al. Abdominal Radiology, 2016
– Spontaneous heterozygous mutation reported in up to 80%
Eckardt et al. KDIGO KI, 2015; Cramer et al. Advances in CKD, 2015; Kim et al. Abdominal Radiology, 2016
 Tuberous Sclerosis Complex Tuberous Sclerosis Complex
Suspected diagnosis:
‐ 1 major feature or
‐ 2 minor features

Definite diagnosis:
‐ 2 major features or
‐ 1 major plus > 2 minor
features

Cramer et al. Advances in CKD,

2015

Angiofibromas

Tuberous Sclerosis Complex Tuberous Sclerosis Complex

Kidney manifestations:
‐ Multiple Cysts noted in 47%; Micro‐ or macro‐cysts; more common
with TSC2 mutations (gene is next to PKD1)
Ungual Fibromas ‐ Multiple bilateral angiomyolipomas (vascular/muscle/fat) observed in
49%‐80% of cases. Can behave locally invasive
Ash Leaf Mark

Cramer et al. Advances in CKD, 2015

Diagnosis and Surveillance • Surveillance:

Tuberous Sclerosis Complex
•CT scan demonstrating fat within the mass (Hounsfield units) Tuberous Sclerosis Complex
– CT/MRI every 1‐3 years
- Intra‐ and peri‐renal Angiomyolipoma
hemorrhage may be seen Angiomyolipoma Management
– Annual eGFR measurement
•MRI preferred diagnostic method for fat poor angiomyolipoma
- Difficult to differentiate from malignant disease (oncocytomas, renal cell • Treatment:
carcinoma, etc) – No intervention if asymptomatic (< 3 cm)
– Asymptomatic but growing lesion (> 3 cm)
• 1st treatment option is an mTOR inhibitor
– Hemorrhagic/painful complications
• 1st treatment option is embolization followed by steroids
• 2nd treatment option would be kidney sparing resection
Halpenny D, et al. Clinical Radiology, 2010 Krueger et al. TSC consensus, Pediatrics Neurology, 2013
mTOR inhibitors Embolization for painful, bleeding angiomyolipoma
Tuberous Sclerosis Complex
•Sirolimus: Reduction of angiomyolipoma size sustained up to 12 mo after
Tuberous Sclerosis Complex
Angiomyolipoma
sirolimus was stopped Management
(slight angiomyolipoma regrowth) Angiomyolipoma Management
Kiefer RM, et al. Curr Urol Rep, 2017
•Everolimus: Systematic review showed 50% reduction in angiomyolipoma,
SEGA size, and improvement in skin lesions

Bissler et al. NEJM, 2008; Sasongko et al. Cochrane Review, 2016

• A 33 year‐old woman with known von Hippel‐ Lindau • Which of the following would you tell this patient with
Case imaging
(VHL) syndrome undergoes #3 surveillance for VHL? Question #1
renal cell carcinoma. In addition to surveillance, the
patient wants to know if there are other measures that a. Sirolimus has been used successfully to reduce renal
cell carcinoma development
can be undertaken to prevent the development of
b. VEGF inhibition therapy reduces the development of
renal cell carcinoma. renal cell carcinoma
c. Partial or total nephrectomy are the only options for
renal cell carcinoma
d. Percutaneous ablation with radio‐ or cryotherapy are
options to treat renal cell carcinoma

• Autosomal dominant cystic disease Kim et al, Abdominal Radiology, 2016; Katabathina et al, Radiographics.rsna.org, 2010

•
Von Hippel‐Lindau Syndrome
Incidence 1:35 000 births
Von Hippel‐Lindau Syndrome
• 6000‐7000 affected in the USA
• VHL is a tumor suppressor gene on chromosome 3
• Mutation leads to inactivation of the gene.
• There is upregulation of HIF  promoting activation of
VEGF, PDGF, TGF∝
– Uncontrolled cell growth with neoplastic transformation
– VEGF overexpression in malignant cells results in
neoangiogenesis with hypervascular tumors
Kim et al, Abdominal Radiology, 2016; Katabathina et al, Radiographics.rsna.org, 2010
• Clinical manifestations: Von Hippel‐Lindau Syndrome
Von Hippel‐Lindau Syndrome
– Multiple cystsClinical
in both kidneys and pancreas
Manifestations Clinical Diagnostic Criteria
– Benign and malignant tumors in several organs (retinal Danish VHL Coordination group in 2013
hemangioma, cerebellar hemangioblastoma)
– Neuroendocrine tumors, pheochromocytoma (7‐20%)
– Lifetime risk of RCC is > 70%; occurs at young age (mean
age 35 years old)
• Diagnosis:
– 1 characteristic tumor + positive family history or
identification of mutated gene
– 2 characteristic tumors in the absence of family history
Kim et al, Abdominal Radiology 2016 Katabathina et al, Radiographics.rsna.org, 2010

Danish VHL Coordination group in 2013

Von Hippel‐Lindau Syndrome Von Hippel‐Lindau Syndrome
Clinical Classification Imaging

• Supportive care
Von with standard measures
Hippel‐Lindau Syndrome for CKD
• Gout: allopurinol/febuxostat,
Management dietary modifications
• Blood pressure control
• Yearly imaging studies (CT scan or MRI)
• Medical management
– mTOR therapy?
– VEGF antagonists: ongoing investigation
• Nephrectomy (total vs. partial) for RCC
– Partial preferred when possible to preserve nephron mass

Jilg CA, et al. Familial Cancer, 2012