RENAL CYSTIC DISEASE

CLASSIFICATION OF
RENAL CYSTIC DISEASE AND ADPKD
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
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Moderators:
Professors:
• Prof. Dr. G. Sivasankar, M.S., M.Ch.,
• Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
• Dr. J. Sivabalan, M.S., M.Ch.,
• Dr. R. Bhargavi, M.S., M.Ch.,
• Dr. S. Raju, M.S., M.Ch.,
• Dr. K. Muthurathinam, M.S., M.Ch.,
• Dr. D. Tamilselvan, M.S., M.Ch.,
• Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

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Dept of Urology, GRH and KMC, Chennai.

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ADPKD
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INTRODUCTION
• ADPKD is the most common inheritable form of renal cystic disease
▪ Incidence of approximately 1 in 400 to 1000 live births
• Important cause of renal failure, accounting for 7% to 15% of patients who
receive hemodialysis.
• The trait has a 100% penetrance.
• Transmitted in an autosomal dominant fashion,
• 50% of an affected individual’s offspring will likewise be affected.
• positive family history is one of the major criteria for
the diagnosis of ADPKD, 10% of cases occur sporadically.
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• Most cases are identified between the fourth and fifth
decades of life, the condition has been reported in
newborns and infants .
• Renal failure is seldom seen before the age of
40 years
• Disease manifests during infancy, in which case it is much
more aggressive.
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• (PKD3) is now accepted as the cause of disease in a
very small percentage of patients who have been
found to have neither a PKD1 nor a PKD2 gene defect
.
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• Every cell of the nephron and collecting duct has the PDK1
orPDK2 mutation;
• only 1% to 2% of these glomerular units are affected by cyst
formation.
• Only those nephrons that undergo a disruption of a second
allele undergo cystic enlargement.
During
the
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➢ This is the “second hit” of the Knudson theory, which has
been proposed to explain the focal nature of the cysts
(Knudson, 1971)
.
• Mutated PKD1 (or PKD2) gene is inherited from one parent,
• wild-type gene is inherited from the unaffected parent.
.
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• During the lifetime of the individual,
• wild-type gene undergoes a somatic mutation and becomes
inactivated.
• Loss of heterozygosity caused by somatic mutations of the
PKD1 and PKD2 genes has been identified in the cells lining
the cysts in both the kidney and liver
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➢ classic ADPKD phenotype is seen in conjunction with tuberous
sclerosis.
• Contiguous gene syndrome - which is a disorder caused by deletion
of multiple gene loci that are adjacent to one another
• PDK1 gene is immediately adjacent to the TSC2 gene on
chromosome 16,
• Large deletions in this area can involve both the PDK1 and TSC2
genes.
• classic features of tuberous sclerosis in addition to the renal cystic
phenotype of ADPKD.
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PATHOGENESIS
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• This process regulates the proliferative state of the renal tubular cells
through a variety of signaling pathways
• e.g., cAMP,
extracellularly regulated kinase [ERK],
mammalian target of rapamycin[mTOR]).
The cilia likely serve as organization centers for this
signal transduction .
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CLINICAL FEATURES
(1) Microscopic and gross hematuria,
(2) Flank pain
(3)Gastrointestinal symptoms (perhaps secondary to renomegaly or
associated colonic diverticula)
(4) Renal colic (secondary either to clots or stones)
(5)Hypertension.
. Microscopic or gross hematuria is seen in 50% of patients, and in 19%to
35% it is the presenting sign .
. Because patients with ADPKD have increased renal mass, erythropoietin
levels are increased, making anemia unusual even when ESRD is present
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➢ Pain MC Symptom, Causes:Mass effect
• Bleeding into the cysts,
• Urinary tract infection(including infected cysts),
• Nephrolithiasis.
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• Uric acid stones and calcium oxalate stones are equally prevalent
.
• The finding of hydronephrosis, which helps make the diagnosis of stones
• not useful in ADPKD patients because of the number of cysts
camouflaging the findings.
• Urinary tract infections are more frequent in female patients
• Cyst aspiration for both diagnostic and therapeutic reasons should be
considered in the setting of suspected cyst infection.
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• Hypertension is present in roughly 50% of patients 20 to 35
years old having ADPKD with normal renal function.
• Virtually 100% of patients with ESRD have hypertension
• .
• hypertension -renin mediated,
secondary to stretching of the intrarenal vessels around
cysts, causing distal ischemia.
• Diagnosis and treatment of this hypertension slow renal
failure, morbidity and mortality from heart disease and
cerebral aneurysm.
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• Renal function is usually maintained,until the fourth to sixth
decade of lif.
• Risk factors for earlier onset of ESRD include
(1) PKD1 gene mutation,
(2)Male gender
(3) First episode of hematuria before age 3 years, onset of
hypertension before age 35 years.
(4) Hyperlipidemia
(5)Sickle cell trait
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• There is a strong relationship between the decline in renal
function and the size of the kidneys and cyst volumes.
• As the cysts, and thus the kidneys become larger,renal
function declines proportionately.
• Hypertension and vascular remodelling secondary to cyst
expansion contribute to progressive renal failure.
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EXTRARENAL MANIFESTATIONS
➢ Hepatic cysts,
• - MC extrarenal manifestation of ADPKD. These cysts are associated with
PKD1 and non-PKD1 genotypes.
• They are present in virtually all ADPKD patients by the age of 50 years.
• Hepatic cysts are more prevalent and their size greater in females .
• Hepatic cysts are usually asymptomatic
• symptoms due to mass effect or from complicating infection or
hemorrhage.
.
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• When secondary portal hypertension appears, differentiating
ADPKD from ARPKD can be difficult.
• ARPKD, portal hypertension is seen much more frequently
and is always secondary to congenital hepatic fibrosis.
• congenital hepatic fibrosis, on very rare occasions
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• ICA—predominately aneurysms of the circle of Willis (berry
aneurysm)— 10% to 30% of patients
• 9% of these patients die because of SAH.
• MC -severe headache, frequently associated with nausea
and vomiting.
• Morbidity and mortality from these aneurysms are strong
family history.
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• Cysts may also occur in the seminal vesicles (40%), arachnoid
membrane (8%), and pancreas (5%).
• Seminal vesicle cysts rarely cause infertility; however, many of
these men may have problems with sperm motility.
• Arachnoid membrane and pancreatic cysts are typically
asymptomatic.
• Other abnormalities associated with ADPKD are mitral valve
prolapse and colonic diverticulosis.
• Patients who have diverticulosis are more likely to have
hepatic cysts and symptomatic berry aneurysms .
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ASSOCIATION WITH RCC
• The incidence of renal adenomas is almost as high in ADPKD
as in ARCD associated with ESRD (i.e., one in four to five
patients).
• ESRD is associated with an increased incidence of RCC,
especially when associated with ARCD (three to six times the
incidence seen in the general population)
✓ The incidence of RCC in patients with ADPKD is no higher than
that in the general population.
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• RCC that are seen more frequently in patients with
ADPKD than in the general population
• RCC in ADPKD is often diagnosed at a younger age,
is more often concurrently bilateral (12% vs. 1% to
5% in the general population), multicentric (28% vs.
6%), and sarcomatoid in type (33% vs. 1% to 5%)
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• The diagnosis of RCC in the context of ADPKD can be quite
difficult,
Tumor may be masked by the complex cystic
appearance of the kidney.
cystic hemorrhage
Degenerating blood clots
Proteinaceous debris.
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HISTOPATHOLOGY
• ADPKD kidneys typically maintain their reniform shape
• Both kidneys are usually equally affected, and the cysts
range from a few millimeters to a few centimeters in diameter
and appear diffusely throughout the cortex and medulla with
communications at various points along the nephron .
• The cysts appear to begin as focal tubular outpouchings, and
as they enlarge they usually become detached from their
tubule of origin.
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The first pathologic finding in fetuses is focal tubular dilation,
• Epithelial hyperplasia or even adenoma formation in the cyst wall is
common, and the basement membrane of the wall is thickened.
• Arteriosclerosis is present in more than 70% of patients with preterminal
or terminal renal failure, and interstitial fibrosis, with or without
infiltrates, is common .
• This fibrosis may be secondary to infection or to an inflammatory reaction
set off by spontaneously rupturing cysts.
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• Up to 90% of adults with ADPKD have cysts of the liver
.
• These cysts are lined by a single layer of epithelium
resembling that of the biliary tract and contain fluid that
resembles the bile salt–independent fraction of the bile.
• The electrolyte composition and osmolality are similar to
those of serum,
• The concentrations of phosphorus, cholesterol, and glucose
are lower.
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• They are derived by progressive proliferation and dilation of
the biliary ductules and peribiliary glands
Hepatic cyst detached as they grow
Macroscopic cyst usually do not communicate with the biliary
system.
Minimal to moderate dilation of the extrahepatic bile ducts.
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EVALUATION
• H/O at least three generations of the patient’s family history.
• H/O- renal disease, hypertension, and strokes.
• Patients and families should be counseled before any imaging
or other testing is undertaken.
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• Genetic testing- imaging results are equivocal and when a
definite diagnosis is required.
• Benefits of testing –
family planning,
early detection and treatment of disease complications,
and selection of genetically unaffected family members for
living donor–related renal transplantation.
• Disadvantages- discrimination in terms of insurability and
employment associated with a positive diagnosis,
psychological stress of impending organ failure.
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CT/MRI
• CT or MRI (or both) may be helpful in some cases and often is
superior to ultrasonography for detecting cysts in organs
other than the kidney .
CT is helpful in making the diagnosis of hemorrhage within a
cyst. More acute hemorrhage has a higher density (50 to 90
Hounsfield units [HU]) than old hemorrhage.
MRI also may be helpful, particularly in patients with
compromised renal function, because no contrast agent is
needed .
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TREATMENT AND PROGNOSIS
• Current therapy is directed toward lessening the
complications of ADPKD and delaying the onset of ESRD.
• There is no known cure at this time
.
• More than 60% of patients with ADPKD have hypertension ,
which can worsen renal function,
cause cardiac disease,
predispose the patient to intracranial hemorrhage.
• The complications of ADPKD can be reduced significantly by
controlling the BP.
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• ACE inhibitors or angiotensin receptor antagonists would
seem to be logical first-line choices.
• Hypertension associated with ADPKD appear to be renin
mediated
• ACE Inhibitor increase renal blood flow, have minimal side
effects, and may have renoprotective properties beyond BP
control.
,
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• Ongoing studies will determine whether a low BP target is
more protective of renal function than a standard BP target
(<130/80)
• combination drug therapy is more advantageous than single-
drug therapy.
•
• Chronic pain must be evaluated and entities such as infection,
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• stone and tumor treated accordingly.
• The use of chronic nephrotoxic analgesics (nonsteroidal
anti-inflammatory drugs [NSAIDs]) must be avoided.
• The use of narcotic analgesics should be limited to acute
pain episodes
• patient dependence on narcotics is a significant risk in this
patient population.
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SURGICAL MANAGEMENT
• Failure of conservative management.
• USG/CT guided cyst aspiration is both diagnostic and
therapeutic.
• Unroofing of multiple cysts /large cyst(Laparoscopic/open)
• Surgical intervention appears only to improve
symptomatology
• Does not appear to either accelerate the decline of renal
function or preserve declining renal function.
• Nephrectomy is indicated for symptomatic patients with
ESRD.
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• Upper urinary tract infections are common in patients with
ADPKD, especially women, and must be treated appropriately.
• patient with suspected pyelonephritis does not respond to an
appropriate antibiotic, one must consider whether the
infection may be present in a noncommunicating cyst .
Actual cyst infections can be quite challenging to treat owing to
poor cystpenetration of many antibiotics.
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• Lipophilic antibiotics, such as trimethoprim-sulfamethoxazole,
chloramphenicol, and fluoroquinolones are the best choices.
• Antibiotic therapy fails, percutaneous or surgical drainage of
infected cysts may be required.
• Urinary tract obstruction, renal or perinephric abscess, or
urolithiasis, must be excluded.
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• Screening for asymptomatic berry aneurysms is not currently
recommended unless
• The patient has a family H/O aneurysm or subarachnoid
hemorrhage
• previous aneurysm rupture
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Need for screening in preparation for major elective surgery
• High-risk occupation (e.g., airline pilot)
• High anxiety level over the possibility of ICA.
CT and magnetic resonance angiography are the imaging
studies of choice, although the former requires intravenous
contrast.
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• Aneurysm rupture occurs most often in people with
larger aneurysms
poorly controlled high BP.
• Screening of low-risk patients is not recommended
because aneurysms are rare in this group
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•
Conservative management is usually recommended
ADPKD patients with small (<7 mm) aneurysms detected by
presymptomatic screening.
Aneurysms that are larger than 7 to 10 mm have a higher risk of
rupture (up to 2% per year for larger aneurysms).
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• Cerebral aneurysms of this size and those that cause
symptoms may be corrected with
• open surgical clipping or with endovascular procedures
• placing a coil within the aneurysm.
➢ Smaller aneurysms that do not cause symptoms are
much less likely to rupture and are not routinely
corrected,except in patients with a history of bleeding
aneurysm.
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EMERGING THERAPEUTICS
➢ HALT PKD study is the largest treatment study ever performed on
patients with PKD,
• Examined the role of BP control versus the impact of specific
medications on the course of the disease
• And assessed whether combination ACE inhibitor (lisinopril) and
angiotensin receptor blocker (ARB; telmisartan) therapy is more
effective in slowing cyst progression than ACE inhibition alone.
• The study was completed in June 2014, and in a recent report by
Schrier and colleagues (2014) showed that in early ADPKD, the
combination of lisinopril and telmisartan did not significantly alter
the rate of increase in total kidney volume.
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➢ As compared with standard blood-pressure control (120-130/70-80),
rigorous blood-pressure control (95-110/60-75) was associated with
• A slower increase in total kidney volume,
• No overall change in the estimated GFR,
• A greater decline in the left-ventricular-mass index,
AND greater reduction in urinary albumin excretion (Schrier et al, 2014).
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❑ Approaches have also been undertaken to reduce the levels of
cAMP in the kidneys of ADPKD patients
.
➢ A recent phase III trial showed that compared with placebo,
tolvaptan, a selective vasopressin V2-receptor antagonist,
• slowed the increase in total kidney volume
• Decline in renal function over a 3-year period in these
patients.
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➢ Somatostatin, known to inhibit vasopressin-induced cAMP,
• Has also been tested in humans and has
• shown substantial retardation of the increase in kidney
volume (Chapman, 2007).
➢ Two studies have evaluated the efficacy of blocking mTOR
with rapamycin
• shown a significant reduction in kidney cyst burden (Tao et al,
2005; Wahl et al, 2006).
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Other drugs Newer drugs
(1) ErbB1 (epidermal growth factor receptor) and ErbB2 tyrosine kinase
inhibitors
(2) Src kinase inhibitors
(3) MEK inhibitors, and
(4) cyclin-dependent kinase inhibitors.
These drugs, which have been developed for the treatment of neoplastic
diseases, may also be considered for the treatment of PKD (Sweeney et
al, 2000; Bukanov
et al, 2006; Omori et al, 2006; Wilson et al, 2006; Brenner, 2008).
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