RENAL CYSTIC DISEASE

RENAL CYSTIC DISEASE

1. CLASSIFICATION OF
RENAL CYSTIC DISEASE AND ADPKD
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
1

2. 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

3. 3Dept of Urology, GRH and KMC, Chennai.

4. 4Dept of Urology, GRH and KMC, Chennai.

5. 5Dept of Urology, GRH and KMC, Chennai.

6. 6Dept of Urology, GRH and KMC, Chennai.

7. 7Dept of Urology, GRH and KMC, Chennai.

8. 8Dept of Urology, GRH and KMC, Chennai.

9. 9Dept of Urology, GRH and KMC, Chennai.

10. ADPKD
10Dept of Urology, GRH and KMC, Chennai.

11. 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.
11Dept of Urology, GRH and KMC, Chennai.

12. •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.
12Dept of Urology, GRH and KMC, Chennai.

13. 13Dept of Urology, GRH and KMC, Chennai.

14. 14Dept of Urology, GRH and KMC, Chennai.

15. 15Dept of Urology, GRH and KMC, Chennai.

16. 16Dept of Urology, GRH and KMC, Chennai.

17. •(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
.
17Dept of Urology, GRH and KMC, Chennai.

18. •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
18Dept of Urology, GRH and KMC, Chennai.

19. ➢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.
.
19Dept of Urology, GRH and KMC, Chennai.

20. •During the lifetime of the individual,
•wild-type gene undergoes a somatic mutation and becomes
inactivated.
•Loss of heterozygositycaused by somatic mutations of the
PKD1 and PKD2 genes has been identified in the cells lining
the cysts in both the kidney and liver
20Dept of Urology, GRH and KMC, Chennai.

21. ➢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.
21Dept of Urology, GRH and KMC, Chennai.

22. PATHOGENESIS
22Dept of Urology, GRH and KMC, Chennai.

23. •This process regulates the proliferative state of the renal tubular cells
through a variety of signalingpathways
•e.g., cAMP,
extracellularlyregulated kinase [ERK],
mammalian target of rapamycin[mTOR]).
The cilia likely serve as organization centersfor this
signal transduction .
23Dept of Urology, GRH and KMC, Chennai.

24. CLINICAL FEATURES
(1) Microscopic and gross hematuria,
(2) Flank pain
(3)Gastrointestinal symptoms (perhaps secondary to renomegalyor
associated colonic diverticula)
(4) Renal colic (secondary either to clots or stones)
(5)Hypertension.
. Microscopic or gross hematuriais 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
24Dept of Urology, GRH and KMC, Chennai.

25. 25Dept of Urology, GRH and KMC, Chennai.

26. 26Dept of Urology, GRH and KMC, Chennai.

27. ➢Pain MC Symptom, Causes:Masseffect
•Bleeding into the cysts,
•Urinary tract infection(including infected cysts),
•Nephrolithiasis.
27Dept of Urology, GRH and KMC, Chennai.

28. •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.
28Dept of Urology, GRH and KMC, Chennai.

29. •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 intrarenalvessels around
cysts, causing distal ischemia.
•Diagnosis and treatment of this hypertension slow renal
failure, morbidity and mortality from heart disease and
cerebral aneurysm.
29Dept of Urology, GRH and KMC, Chennai.

30. 30Dept of Urology, GRH and KMC, Chennai.

31. •Renal function is usually maintained,untilthe 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 hematuriabefore age 3 years, onset of
hypertension before age 35 years.
(4) Hyperlipidemia
(5)Sickle cell trait
31Dept of Urology, GRH and KMC, Chennai.

32. •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.
32Dept of Urology, GRH and KMC, Chennai.

33. EXTRARENAL MANIFESTATIONS
➢Hepatic cysts,
•-MC extrarenalmanifestation 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.
.
33Dept of Urology, GRH and KMC, Chennai.

34. •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
34Dept of Urology, GRH and KMC, Chennai.

35. •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.
35Dept of Urology, GRH and KMC, Chennai.

36. 36Dept of Urology, GRH and KMC, Chennai.

37. •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.
•Arachnoidmembrane and pancreatic cysts are typically
asymptomatic.
•Other abnormalities associated with ADPKD are mitral valve
prolapseand colonic diverticulosis.
•Patients who have diverticulosisare more likely to have
hepatic cysts and symptomatic berry aneurysms .
37Dept of Urology, GRH and KMC, Chennai.

38. 38Dept of Urology, GRH and KMC, Chennai.

39. 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.
39Dept of Urology, GRH and KMC, Chennai.

40. •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 sarcomatoidin type (33% vs. 1% to 5%)
40Dept of Urology, GRH and KMC, Chennai.

41. •The diagnosis of RCC in the context of ADPKD can be quite
difficult,
Tumormay be masked by the complex cystic
appearance of the kidney.
cystic hemorrhage
Degenerating blood clots
Proteinaceousdebris.
41Dept of Urology, GRH and KMC, Chennai.

42. HISTOPATHOLOGY
•ADPKD kidneys typically maintain their reniformshape
•Both kidneys are usually equally affected, and the cysts
range from a few millimetersto a few centimetersin 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.
42Dept of Urology, GRH and KMC, Chennai.

43. 43Dept of Urology, GRH and KMC, Chennai.

44. 44Dept of Urology, GRH and KMC, Chennai.

45. The first pathologic finding in fetusesis 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.
45Dept of Urology, GRH and KMC, Chennai.

46. •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.
46Dept of Urology, GRH and KMC, Chennai.

47. •They are derived by progressive proliferation and dilation of
the biliary ductulesand peribiliaryglands
Hepatic cyst detached as they grow
Macroscopic cyst usually do not communicate with the biliary
system.
Minimal to moderate dilation of the extrahepaticbile ducts.
47Dept of Urology, GRH and KMC, Chennai.

48. 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 counseledbefore any imaging
or other testing is undertaken.
48Dept of Urology, GRH and KMC, Chennai.

49. •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.
49Dept of Urology, GRH and KMC, Chennai.

50. 50Dept of Urology, GRH and KMC, Chennai.

51. 51Dept of Urology, GRH and KMC, Chennai.

52. 52Dept of Urology, GRH and KMC, Chennai.

53. 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 hemorrhagewithin a
cyst. More acute hemorrhagehas 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 .
53Dept of Urology, GRH and KMC, Chennai.

54. 54Dept of Urology, GRH and KMC, Chennai.

55. 55Dept of Urology, GRH and KMC, Chennai.

56. 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.
56Dept of Urology, GRH and KMC, Chennai.

57. •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 renoprotectiveproperties beyond BP
control.
,
57Dept of Urology, GRH and KMC, Chennai.

58. •Ongoingstudies 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,
58Dept of Urology, GRH and KMC, Chennai.

59. •stone and tumortreated 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.
59Dept of Urology, GRH and KMC, Chennai.

60. 60Dept of Urology, GRH and KMC, Chennai.

61. SURGICAL MANAGEMENT
•Failure of conservative management.
•USG/CT guided cyst aspiration is both diagnostic and
therapeutic.
•Unroofingof 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.
61Dept of Urology, GRH and KMC, Chennai.

62. •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 noncommunicatingcyst .
Actual cyst infections can be quite challenging to treat owing to
poor cystpenetrationof many antibiotics.
62Dept of Urology, GRH and KMC, Chennai.

63. •Lipophilicantibiotics, such as trimethoprim-sulfamethoxazole,
chloramphenicol, and fluoroquinolonesare the best choices.
•Antibiotic therapy fails, percutaneous or surgical drainage of
infected cysts may be required.
•Urinary tract obstruction, renal or perinephricabscess, or
urolithiasis, must be excluded.
63Dept of Urology, GRH and KMC, Chennai.

64. •Screening for asymptomatic berry aneurysms is not currently
recommended unless
•The patient has a family H/O aneurysm or subarachnoid
hemorrhage
•previous aneurysm rupture
64Dept of Urology, GRH and KMC, Chennai.

65. 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.
65Dept of Urology, GRH and KMC, Chennai.

66. •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
66Dept of Urology, GRH and KMC, Chennai.

67. •
Conservative management is usually recommended
ADPKD patients with small (<7 mm) aneurysms detected by
presymptomaticscreening.
Aneurysms that are larger than 7 to 10 mm have a higher risk of
rupture (up to 2% per year for larger aneurysms).
67Dept of Urology, GRH and KMC, Chennai.

68. •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,exceptin patients with a history of bleeding
aneurysm.
68Dept of Urology, GRH and KMC, Chennai.

69. 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
Schrierand colleagues (2014) showed that in early ADPKD, the
combination of lisinopriland telmisartandid not significantly alter
the rate of increase in total kidney volume.
69Dept of Urology, GRH and KMC, Chennai.

70. ➢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 (Schrieret al, 2014).
70Dept of Urology, GRH and KMC, Chennai.

71. ❑Approaches have also been undertaken to reduce the levels of
cAMPin 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.
71Dept of Urology, GRH and KMC, Chennai.

72. ➢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).
72Dept of Urology, GRH and KMC, Chennai.

73. Other drugs Newer drugs
(1)ErbB1 (epidermal growth factor receptor) and ErbB2 tyrosine kinase
inhibitors
(2)Srckinase 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).
73Dept of Urology, GRH and KMC, Chennai.

74. 74Dept of Urology, GRH and KMC, Chennai.