AN APPROACH TO CYSTIC KIDNEY

DISEASE

Dr. Abhijit Taraphder

Head, Dept. of Nephrology
Apollo Gleneagles Hospitals
Kolkata
 CYSTIC KIDNEY DISEASES
• Described under “ Ciliopathies”
• By sensing extracellular signals and transferring
them to the interior of the cell, cilia regulate
cellular functions e.g. proliferation,
differentiation, polarity & maintenance
• Include a variety of entities like ADPKD, ARPKD,
nephronophthisis (+ MCKD), Senior-Loken
syndrome, Joubert Syndrome, Meckel-Gruber
syndrome, Bardet-Biedl syndrome, von Hippel-
Lindau syndrome & tuberous sclerosis
 CYST - GENERATION
• A complex array of molecular processes leads
to aberrant proliferation of tubular epithelial
cells and expansion of tubule wall giving rise
to cyst formation
• Cysts eventually separate from the parent
tubules to become isolated sacs filled with
fluid that is secreted into the cyst cavity
through CAMP- dependent transport of
chloride
 CYST - GENERATION
• Cysts formed in uterus grow faster than those
that form in adults
• Once the creatinine starts to rise, GFR falls at a
faster pace
• Cysts form in < 5000 nephrons, but the
function of the whole kidney is affected

[ Bae TK and Grantham JJ. Nat Rev Nephro 2010;6:96-

106]
 ISSUES TO BE DISCUSSED
• Clinical approach to diagnosis
• “ Simple Cysts” : the meaning
• Renal transplantation
Cyst in the recipient
Cyst in the donor
• Extrarenal manifestations
• Take home message
 Points not to be covered
• Pathogenesis & genetics
• Prognosis & follow up
• Treatment and trials
• Metabolic derangements
• Controversies
DIAGNOSTIC APPROACH
• Age of onset/ presentation
• Kidney size
• Localization of cysts
• Renal manifestations
• Extrarenal manifestations
• Genetic testing
[ Kurschat EC et al, Nat Rev Nephrol 2014;10:687-699]
 ADPKD
 Adult patients with enlarged bilateral
polycystic kidney disease: most likely diagnosis
 In families of unknown genotype, 3 or more
unilateral/ bilateral cysts in patients aged
between 15 and 39 years, two or more cysts in
each kidney aged 40-59 years and 4 or more
cysts in each kidney aged 60 and above are
sufficient to make a diagnosis (USG criteria
2009)
 ADPKD
 Cysts are distributed throughout the cortex &
medulla and also in other organs
 Most notable extrarenal monifestation: ICA
 A defect in urine concentrating ability in early
childhood
 Hematuria, hypertension, pain, lump in
adulthood
 Progressive disease: ESRD in 6th to 8th decade
 PKD1 truncating mutations have the worst
outlook
 Height-adjusted TKV> 600ml predicts progression
 ARPKD
 Enlarged echogenic kidneys with cysts
distributed in both cortex and medulla
 Always associated with biliary dysgenesis and
congenital hepatic fibrosis diagnosed in utero
or soon after with
 In adults medical attention is drawn because
of portal hypertension, recurrent cholangitis
or rarely cholangiocarcinoma
 ARPKD
 Nephrocalcinosis is found in 71%
 Parental consanguinity, absent renal cysts in
both parents and a sibling having confirmed
ARPKD are highly suggestive of the diagnosis
 Mortality: 25% in the newborn
 50% of children progress to ESRD by the age of
10 years
 NEPHRONOPHTHISIS
 An autosomal recessive disease characterized
by small kidneys with cysts localized to the
corticomedullary junction
 Polydipsia, polyuria, and enuresis start at 4-6
years
 Growth retardation and anemia develop later
 Hypertension, edema, hematuria absent
 ESRD typically develops in the first 3 decades
 NEPHRONOPHTHISIS
 Common extrarenal manifestations include
retinitis pigmentosa (Senior- Loken syndrome)
sinus inverses, oculomotor apraxia (Cogan
syndrome), cranioectodermal dysplasia, short-
rib dysplasia and occipital encephalocoele
(Meckel- Gruber syndrome)
 Leading genetic cause of ESRD in children,
adolescent and growing adults
 MEDULLARY CYSTIC KIDNEY DISEASE
 Resembles nephronophthisis minus extrarenal
manifestations
 Hyperuricemia and gout are common
 Small kidneys with corticomedullary cysts
 ESRD usually develops after the 4th decade of life
 An autosomal dominant disease
 JOUBERT SYNDROME
 A nephronophthisis like syndrome with liver
fibrosis, retinitis pigmentosa, coloboma of the eye
& altered respiratory pattern in neonatal life
 A classical variant is associated with vermis
aplasia ( molar tooth sign in MRI) characterized
by ataxia, oculomotor apraxia, nystagmus,
hypotonia and respiratory distress
 BARDET- BIEDL SYNDROME
 An autosomal recessive disease characterized by
polydipsia, polyuria, UTI, renal tubular acidosis
(proximal) and Fanconi like syndrome
 At birth the kidneys are enlarged with cortico
medullary cysts
 By the age of 2 years, size becomes normal and
progression resembles nephronophthisis with
secondary FSGS
 Extrarenal manifestations include polydactyly,
juvenile obesity, mental retardation,
hypogonadism and anosmia
 MEDULLARY SPONGE KIDNEY
• Dilated medullary and papillary connecting
ducts give the renal medulla a spongy
appearance
• Typically associated with medullary
nephrocalcinosis, increased risk of UTI,
recurrent calcium nephrolithiasis, hematuria &
bone mineralization defects.
• Symptoms usually start between 4th & 5th
decade
 MEDULLARY SPONGE KIDNEY
• A paintbrush or bouquet of flower appearance
is typical finding in IVU
• However, nowadays CT is preferred
• Hydration and K-Citrate are the mainstay of
treatment
• Hypercalciuria, if present, warrants thiazides
• Coagulase negative staph is an unusual
pathogen in cases of UTI
 ACQUIRED CYSTIC DISEASE
• Renal cysts may be seen in association with
ESRD or hypokalemia
• Tend to be multiple
• Cyst infection is uncommon
• Tumour formation common in ACKD of ESRD
• Nephrolithiasis uncommon
• Extrarenal manifestations uncommon
 RENAL CYSTIC TUMOURS
Tuberous sclerosis
• Autosomal dominant disease
• Renal involvement includes angiomyolipomas,
renal cysts, oncocytomas and renal cell
carcinomas ( clear cell, papillary & chromophobe)
• Extrarenal manifestation are angiofibromas of the
skin, cerebral tubers, subependymal giant cell
astrocytomas and lymphangio-leiomyomatosis of
the lungs
• In the majority, tuberous sclerosis complex
results from sporadic germ line mutations in TSC1
& TSC2
 RENAL CYSTIC TUMOURS
von Hippel- Lindau syndrome
 First hereditary cancer syndrome described
 Mean age at diagnosis 26 years
 Hemangioblastoma may occur in the retina,
spinal cord and brain
 Pheochromocytoma, pancreatic neuroendocrine
tumours, endolymphatic sac tumours of the ear
and cystadenomas of the epididymis may coexist
 Mean age of diagnosis of RCC: 40 years
 Average life expectancy < 50 years
 Nephron- sparing surgery preferred
 AGE DISTRIBUTION OF RENAL CYSTIC DISEASE
NEONATES INFANTS/CHILDREN

ADPKD

ARPKD

NEPHRONOPHTHISIS
MSK
TSC
VHL
SIMPLE CYSTS
 FEATURES OF ADULT RENAL CYSTIC DISEASES
SIMPLE CYSTS ADPKD MSK VHL TSC ACKD

ONSET >40 YRS 30-40 YRS 20-40 YRS 30-40 YRS 10-30 YRS WITH ESRD
CYSTS SINGLE/ MULTIPLE MULTIPLE FEW/ MULTIPLE MULTIPLE
MULTIPLE BILATERAL
CYST UNCOMMON COMMON COMMON UNCOMMON UNCOMMON UNCOMMON
INFECTION
TUMOUR NO RARE NO RCC/ OFTEN RCC/ COMMON
FORMATION BILATERAL ANGIOMYOLIP
OMA

BLOOD NORMAL/ INCREASED NORMAL NORMAL/ NORMAL/ NORMAL/

PRESSURE INCREASED INCREASED INCREASED INCREASED
RENAL NORMAL NORMAL/ NORMAL NORMAL NORMAL/ IMPAIRED
FUNCTION IMPAIRED INCREASED
STONE NO COMMON COMMON NO NO NO
FORMATION
LIVER CYSTS NO COMMON NO RARE NO NO
PANCREAS NO OCCASIONAL NO YES, MULTIPLE NO NO
CYSTS
CNS NO ANEURYSMS NO HEMANGIOBLA SEIZURE/ NO
INVOLVEMENT STOMAS MENTAL
RETARDATION

SKIN LESION NO NO NO NO FACIAL ANGIO NO

FIBROMA
 ROLE OF GENETIC TESTING
• ADPKD
Inconclusive radiology
Positive F/H with no cysts < 30 years of age
Potential LR donors with no cysts
Clinical ADPKD with absent F/H
Family planning/ Insurance decisions
 ROLE OF GENETIC TESTING
• ARPKD
Prenatal diagnosis when one child is affected
In individuals being evaluated as a potential
kidney donor
Indicated in cases of inconclusive radiology
• Nephronophthisis & related disorders
Routine screening not recommended owing to
the low frequency of detected mutations
 FUTURE OF GENETIC TESTING
 A large variety of gene mutations can lead to
cystic kidney diseases
 Mutations in the same gene can cause
different disorders
 Different phonotypes may be manifested as a
result of mutations of one or more genes
 Introduction of next-generation sequencing
(NGS), with a targeted approach, search can
be focussed on specific genes ( a ciliary panel)
 SIMPLE RENAL CYSTS
•Asymptomatic, solitary, unilateral
•Located in the renal cortex
•Smooth wall lined by a single layer
of epithelial cells
•Round/oval in shape
•No internal debris/septa
•Usually less than 3cm in size
 SIGNIFICANCE OF “ SIMPLICITY”
• Chance of malignancy
Simple cysts have a < 1% risk
• Followup:
a) no following indicated in “ simple” cysts
b) CT Scan at 3/6/12 months interval and then
yearly in stage 3F onwards
• Whether fore runners of cystic kidney diseases
 SIMPLE CYSTS Vs CYSTIC KIDNEY
DISEASE
• Age at presentation (? 40 years)
• Family history ( yes/no)
• Number of cysts ( Ravine criteria)
• Kidney size ( Small/ Large)
• Method of investigation ( USG/ CT/ MRI)
• Genetic testing
 AGE & SIMPLE CYSTS
• Detected in fetuses in early pregnancy (14-16
wks) with an incidence of 0.09%
but majority are transient
• Extremely rare between birth & 20 years
• Between 30 & 49 years: 1.7%
• Between 50 & 70 years: 11.5%
• Above 70 years: 22.1%
[ Ravine D et al. Am J Kid Dis 1993; 22: 803-807 ]
 RISK FACTOR/OUTCOME
• Overall consensus is lacking
• Most StⅠ cysts grow slowly
• Most cysts do not become more than double
in 10 years
• Only a handful of case reports describe
evolution into neoplasms
SIMPLE CYST(S) IN DONOR KIDNEY
 No consensus
 Abnormal renal imaging including the presence of
2 or more cysts in each kidney is a
contraindication to kidney donation
[Pham PC, et al. Am J Kid Dis 2007;50:1043-1051]
 The presence of stage 1 renal cysts in a potential
kidney donor is not a barrier to renal
transplantation.
[Simms RJ and Ong ACM. NDT 2014, 29: iv 106 – iv 112]
 EXTRA- RENAL MANIFESTATIONS OF
ADPKD
• LIVER and PANCREAS
Hepatic Cysts
Originate from bile duct epithelium
Female tend to have more cysts
Hepatic dysfunction: Rare
No correlation with malignancy
Cysts infection-PET CT
-↑ CA 19-9
Jaundice/ Ascites/ Cholecystitis
Somatostatin analogues/ Resection/ TX
EXTRA- RENAL MANIFESTATIONS OF
ADPKD
Pancreatic Cysts
Increasing age
Female sex
PKD1 mutation
Benign in nature
Chronic pancreatitis
 EXTRA- RENAL MANIFESTATIONS OF
ADPKD
CENTRAL NERVOUS SYSTEM
CNS Cysts
Arachnoid cysts: benign in nature
Increased risk of chronic SDH
Grow slowly
Spinal meningeal cysts
Rare (< 2%) association
 EXTRA- RENAL MANIFESTATIONS OF
ADPKD
Aneurysms
Without F/H: 6%
With F/H : 20%
ICA rapture : 5 times that in general
population
ICA rapture : clusters in family
ICA rapture : 60% mortality
Small (< 7mm), anterior circulation
Both PKD1 & PKD2 gene- association
Also found in abdominal aorta,
splenic-coronary-popliteal arteries
 SCREENING FOR INTRACRANIAL
ANEURYSMS IN ADPKD
Who should be screened
 Any symptomatic patient ( headache, TIA, cranial
nerve palsy)
 Having a positive family history ( specially rapture)
 Past history of ICA rapture
 High risk occupation (e.g. pilot)
 Prior to renal transplantation
 Who will receive long term anticoagulation (e.g.
prosthetic valve)
 Having anxiety regarding an ICA
 SCREENING FOR INTRACRANIAL
ANEURYSMS IN ADPKD
Method of screening
MR angio without gadolinium
Rescreening
Every 5 years in high risk
After 10 years in low risk
 EXTRA RENAL MANIFESTATIONS OF
ADPKD
CARDIOVASCULAR
Hypertension( upwards of 70%)
Left ventricular hypertrophy
Mitral valve prolapse (15%)
Mitral regurgitation (30%)
Aortic regurgitation (10-20%)
Tricuspid prolapse (5%)
Strategy: Early detection of ↑BP
ABPM if required
Routine echo not recommended
ACEI/ ARB to start early
 EXTRA RENAL MANIFESTATIONS OF
ADPKD
PULMONARY
Prevalence of bronchiectasis: 37%
Lower lobe involvement common
Majority remain asymptomatic
Routine screening not recommended
 EXTRA RENAL MANIFESTATIONS OF
ADPKD
• Diverticular disease
Prevalence 40% ( same as general population)
Some studies show higher incidence of infection and
perforation
Screening colonoscopy not recommended
• Abdominal hernias
Prevalence 45% (25% inguinal)
Increased complications (incarceration/strangulation)
May affect RRT modality selection
Many prefer corrective surgery prior to transplantation
 EXTRA RENAL MANIFESTATIONS OF
ADPKD
Fertility
Male fertility affected
Seminal vesicle cyst/ obstruction
Sperm immotility ( asthenozoospermia)
Preeclampsia more common

[ Luciano RL and Dahl NK. NDT 2014; 29: 247-254]

RENAL TRANSPLANTATION IN ADPKD
Indications for native nephrectomy
Recurrent bleeding/cyst infection
Recurrent symptomatic stones
Severe pain/ early satiety
To create space
Suspected malignancy
 RENAL TRANSPLANTATION IN ADPKD
Indications for screening for intracranial aneurysms
Routine pretransplant workup
Or
In high risk patients
Positive family history
Previous rupture
High risk occupation
Apprehensive patient
 RENAL TRANSPLANTATION IN ADPKD
Assessment of liver involvement
CT/ MRI
Baseline serum CA 19-9 levels
OCP/HRT in women
Combined liver kidney Tx
TRANSPLANTATION FROM LR- DONORS
IN ADPKD
• 50% of the siblings & children likely to develop
the disease
• In donors ≥40 years of age, predictive value of
USG as screening test is excellent
• Finding of normal kidneys in such donors has a
negative predictive value of 100%
• In donors aged between 30 and 39 years, a
negative USG must be confirmed by CT/MRI
• If MRI/CT are equivocal, genetic testing must be
carried out
 POST- TRANSPLANT OUTCOME IN
ADPKD
• No difference in 5 year patient and graft-
survival with other nephropathies
• The volume of native kidneys tends to
decrease after successful transplantation
• Most of such decrease occurs during the first
year
• Hematuria/ Cyst infection/ Pain
• Persistent renal concentration defect
 TAKE HOME MESSAGE
• In adults by far the commonest cystic disease
of the kidneys is ADPKD
• Time of onset, laterality, size of the kidneys
and renal function are the most important
indices at diagnosis
• Hematuria, infection, stone formation and
neoplasia are the common complications
• Regular follow up is necessary
• Many issues still remain unresolved