Autosomal Dominant Polycystic kidney disease

1. AUTOSOMAL DOMINANT POLYCYSTIC
KIDNEY DISEASE

2. Definition
 ADPKDis amultisystem disorder characterized by multiple, bilateral renal
cystsassociated with cystsin other organs, such asliver, pancreas, and
arachnoid membranes.
 It is agenetic disorder mediated primarily by mutations in two different
genes and is expressed in an autosomal dominant pattern, with variable
expression.

3. Etiology and Pathogenesis
 PKDproteins - Polycystin 1 (PC1) and polycystin 2 (PC2) play acritical role in the normal
function of the primary cilium that is essential to maintaining the differentiated
phenotype of tubular epithelium.
• Disordered function of polycystins isthe basisfor cystformation in PKD by permitting aless
differentiated tubular epithelial phenotype.
• In ADPKD, the focal cyst development in the kidneys seems to be associated with a somatic
second hit brought on by either loss of heterozygosity or other mutations in renal cyst lining
epithelial cells

4. PKD1 PKD2
Located on Chromosome 16
[16p13]
Located on Chromosome 4
[4q21-q23]
Codes for Polycystin 1protein
(PC1)
Codes for Polycystin 2 protein
(PC2)
Associated with more severe
phenotype
Less severe phenotype
Incidence: 85% Incidence: 15%
Median age of ESRD 53 years Median age of ESRD 73 years
Code PC1: Cilia, Basolateral
membranes,inter-membrane
junctions.
Helps incell-cell adhesions.
Code PC2: non-selectivecation
channel, permeable to Calcium.
Located mainly inSER.

5. PATHOGENESIS
 The polycystins regulate tubular and vascular development and interact to
increase the flow of calcium through a cation channel formed in plasma
membranes by polycystin 2.
 A mutation of either polycystin can disrupt the function of the other, resulting
in similar clinical presentations.
 Reduction in one of the polycystins below a critical threshold results in inability
to maintain planar polarity, increased rates of pro-liferation and apoptosis,
expression of a secretory phenotype, and remodeling of the extracellular
matrix.

6. Structure of Polycystin receptor
complex

7. Pathogenesis-Role of
Calcium
 PC2 functions as a nonselective cation channel that transports calcium, and
shows significant homology with transient receptor potential (TRP) channels
 Polycystin complex – Influence intra cellular calcium level by acting at the
level of plasma membrane ,TRPC1 and TRPV4,ER.

8. PATHOGENESIS
Mutations in PKD1and PKD2
Lossof ciliary function of PC1and PC2
Reduced intracellular Calcium
Increase of adenylyl cyclase
activity + decrease of
phosphodiesterase activity
Increased cellular cyclic AMP (camp)
 Promotes protein kinase A activity
 CFTR-driven chloride and
fluid secretion and cell
proliferation
 Increased cell proliferation and fluid
secretion, decreased cell differentiation,
and abnormal extracellular matrix.
 Cyst growth

9. Pathogenesis
 Enormous growth of these cysts ultimately leads to the loss of normal
surrounding tissue and causes Loss of renal function
 Cysts occur only in 5% of the tubules in the kidney tion c

11. Liver Cyst Development
 Liver cysts arise by excessive proliferation and dilation of biliary ductules and
peribiliary glands.
 Estrogen receptors, insulin-like growth factor 1 (IGF-1), IGF-1 receptors, and
growth hormone receptor are expressed in the epithelium lining the hepatic
cysts, and estrogens and IGF-1 stimulate hepatic cyst–derived cell
proliferation.

12. Hypertension
 RAAS activation
 Enhanced vascular smooth muscle contractility and impaired endothelium-
dependent vasorelaxation.
 Increased sympathetic nerve activity
 Increased Plasma endothelin-1 levels and insulin resistance.

14. Epidemiology
 Prevalence of geneti-cally affected individuals at birth estimated at 1 in
400 to 1 in 1000
 Only half of the patientswith clinically diagnosed during their lifetime
 ADPKDis responsible for 6-10% of ESRD cases

15. PHENOTYPIC VARIABILITY
 Genic, allelic, and gene-modifier effects contribute to the high pheno-typic
variability of ADPKD.
 PKD1-associated disease is more severe than PKD2-associated disease (age at
ESRD, 58 years vs. 79 years for PKD1 and PKD2, respectively)
 Type of PKD mutation is important.The median age at onset of ESRD was 55
years for carriers of a truncating muta-tion and 67 years for carriers of a
nontruncating mutation.

16. Clinical Manifestations
• Asymptomatic [until the fourth to fifth decade of life andare
diagnosed by incidental discoveries]
• Pain—in the abdomen, flank, or back—is the most common initial
complaint. [may result from renal cyst infection,
hemorrhage,nephrolithiasis,Tumor]
• Visible Hematuria ~40% of patients in the course of disease.Causes are cyst
hemorrhage, stone, infection, and tumor.Retro peritoneal hemorrhage.

18. Renal size
 The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease
(CRISP), has shown that total kidney volume and cyst volumes increased
exponentially.Rates of growth were relatively constant, averaging 5.3% per
year

19. Urinary Tract Infection and Cyst Infection
 UTI presents as cystitis, acute pyelonephritis, cyst infection, and
perinephric abscesses.
 CT scanning/PET CT/Nuclear scanning

20. ESRD
 Up to 77% of patients are alive with preserved renal function at age 50 years,
and 52% at age 73
 Risk factors for renal failure include Male gender,Black race, diagnosis of
ADPKD before age 30, first episode of hematuria before age 30, onset of
hypertension before age 35, hyperlipidemia, low level of high-density
lipoprotein cholesterol, sickle cell trait, and PKD1 truncating mutations.

21. Nephrolithiasis
Renal stone disease occurs in about 20% of patients with ADPKD More
than half of the stones in patients with ADPKDare composed of
uricacid, with the remainder due to calcium oxalate.
Distal acidification defects,
Abnormal ammonium transport,
Low urine pH and
Hypocitraturia
Diagnosis – IVU,CT Urogram

22. GI Manifestations
1.Liver cysts (94% )
asymptomatic up to 80%
symptomatic uncommon (F:M 10:1)
2. Pancreatic cysts ~10%
3. Intestinal diverticuli ~80% pts with ESRD
4. Hernias ~10%

23. Polycystic Liver Disease
 PLD is associated with both PKD1 and PKD2 genotypes
 ADPKD genotype is not associated with the sever-ity or growth rate of PLD in
patients with ADKPD.
 PLD should be suspected when four or more cysts are present in the hepatic
paren-chyma.
 Liver function is preserved
 prevalence by MRI in the CRISP study was 58%, 85%, and 94%, respectively, in
participants age 15 to 24, 25 to 34, and 35 to 44 years

25. Polycystic Liver
Disease
 Symptoms include dyspnea, orthopnea, early satiety, gastroesophageal
reflux, mechanical low back pain, uterine prolapse, and even rib fracture.
 Directly by mass effect causes hepatic venous outflow obstruction, IVC
compression, portal vein compression, and bile duct compression
presenting as obstructive jaundice
 Hemorrhage/infection/torsion of cyst

26. Intracranial aneurysm (ICA)
The disease gene products PC1and PC2
may be directly responsible for defects in
arterial smooth muscle cells and
myofibroblasts.
Other vascular abnormalities in ADPKD
patients include diffuse arterial
dolichoectasias of the anterior and
posterior cerebral circulation, which can
predispose to arterial dissection and
stroke.

28. Intracranial Aneurysms
 8% overall…6% without a family history and 16% with family history
 Yearly rupture rates increase with size, ranging from less than 0.5% for aneurysms smaller than 5 mm
in diameter to 4% for aneurysms larger than 10 mm.
 The mean age at rupture in ADPKD is 39 years
 Screening - Family history of intracranial aneurysm or subarachnoid hemorrhage, previous aneurysmal
rupture, preparation for elective surgery with potential hemo-dynamic instability, high-risk occupations
(e.g., airline pilots), and significant patient anxiety despite adequate information about the risks.
 Repeat screening every 5-10 years

29. Risk Factors for ICA Rupture
1. Most aneurysms have a very low risk of rupture and occurs
without a family history
2. With 2 PKD relatives with SAH the RR= 2.15
3. F>M and ICA>8mm
4. Pack years of smoking
5. HTN > 10 years

31. Other vascular abnormalities
 Thoracic aortic and cervicocephalic arterial dissections, coronary
artery aneurysms, and retinal artery and vein occlusions

32. Cardiac manifestations
 MVP-25%
 TVP,TR,AR,Aortic root dilatation
 Hemodynamically insignificant pericardial effusion can be detected by
CT scanning in up to 35% of patients with ADPKD.

33. Diagnostic Considerations
Problems to be considered in the differential diagnosis of autosomal dominant
polycystic kidney disease include the following:
Acquired renal cystic disease
Autosomal recessive polycystic kidney disease
Medullary cystic disease
Renal dysplasia
Simple renal cysts
Tuberous sclerosis
von Hippel-Lindau Disease

34. Diagnosis
Positive family history
Multiple kidney cysts bilaterally on renal ultrasonography.

35. Investigations
An increased hematocrit may result from increased EPO secretion
from cysts.
Urinalysis:
 Decrease in urine-concentrating ability
 Microalbuminuria occurs in 35% of patients
 Nephrotic-range proteinuria is uncommon.

36. Imaging
Ultrasonography [is the procedure of choice]
Computed tomography (CT) scan
Magnetic resonance imaging (MRI)
Genetic testing
Genetic testing by linkage analyses and mutational analyses

37. Ultrasonography
Ultrasonography is the most widely used imaging technique to help diagnose ADPKD. It can
detect cysts from 1-1.5 cm. This study avoids the use of radiation or contrast material, is
widely available, and is inexpensive.

39. Ultrasonography
 Ultrasonographic diagnostic criteria for ADPKD in patients with a family
history but unknown genotype were established by Pei et al in 2009 and
are as follows :
 Three or more (unilateral or bilateral) renal cysts in patients aged 15-39
years
 Two or more cysts in each kidney in patients aged 30-59 years

40. Ultrasonography
 An ultrasound finding of normal kidneys or one renal cyst in an individual age
40 or older has an NPV of 100%.
 The absence of any renal cysts provides near certainty that ADPKD is absent
in at-risk individuals age 30 to 39, with a false-negative rate of 0.7% and NPV
of 98.7%.
 A normal or indeterminate ultrasound scan does not exclude ADPKD with
cer-tainty in an at-risk individual younger than 30 years.

41. Computed tomography (CT) scan
CTis more sensitive than ultrasonography and can detect cysts as small as 0.5
cm.
Useful in doubtful cases in children or in complicated cases
(eg, kidney stone, suspected tumor).
It exposes the patient to radiation and is more expensive.

43. Magnetic resonance imaging (MRI)
MRI is the best imaging tool to monitor kidney size and diagnose cysts
MRI is more sensitive than either USG or CT scanning .It may be more
helpful in distinguishing RCC from simple cysts.
 Renal cysts show ahomogeneous, low to intermediate signal intensity on
T1WI and ahomogeneous, high signal intensity on T2WI.
 The finding of fewer than five renal cysts by magnetic resonance imaging
(MRI) is sufficient for disease exclusion

44. PROGNOSTIC CALCULATORS
 MAYO classification
 PRO-PKD Calculator

45. Stepwise method to calculate TKV in the clinician’s office using the
Mayo Clinic ADPKD classification online tool.

48. PRO-PKD prognostic scoring

49. PATHOGENESIS OF CYST FORMATION

50.  Ciliary axoneme-
microtubulesBasal body-
centromere derivative
 Nephrocystin 1 –transition
zone
 Transition zone-filtartaion
barrier
 Complex A,B-Axonemal and
membrane components are
transported
 Kinesin 2-Anterograde
transport

51.  Planar cell polarity,
which is mediated
partially through
orientation of
centrosomes and the
mitotic spindle poles
 Cilia-dependent
mechanisms of planar
cell polarity seem to be
central to the
pathogenesis of

52. Pathways for cellular signalling
 WNT Pathway –
Canonical – Beta catenin
Non canonical – maintains cell polarity(planar cell polarity
pathway)
Calcium pathway
 Sonar hedge hog pathway

53. NPHP2/Inversin Implicates Cilia and Planar Cell Polarity
in Cystogenesis
 Inversin/NPHP2 mediates a
switch from the canonical the
noncanonical Wntsignaling
pathway
 In the absence of urinary flow-
WNT pathyway(Beta catenin) is
activated
 Urinary flow increases
expression of inversin -
>reduced DVL(disheveled)
>reduced B-catenin

55. TREATMENT

56. Treatment
Approach considerations
Control blood pressure
Control abnormalities related to renal failure
Treat urinary tract infections
Treat hematuria
Reduce abdominal pain produced by enlarged kidneys

57. Control blood pressure
 Blood pressure control to atarget of 140/90 mmhg is recommended
according to the guidelines from JNCVIII report
 If more than 1 g/day of urinary protein is present, the target blood
pressure is less than 125/75 mm hg.
The drugs of choice for this condition are RAAS blockers

58. Blood pressure control
 Arterial hypertension beforethe age of 35 years has been shown to be a
strong clinical indicator of rapid progression of ADPKD
 HALT-PKD—which compared strict blood pressure control (<110/75
mmHg)with a standard regimen (<130/80 mmHg) in early ADPKD (age<50
years, eGFR>60 mL/min/1.73 m2

60. Fluid intake
 Vasopressin-receptor signalling is central to disease progression due to its
impact on increasing cAMP levels—a key driver of cyst growth
 Daily fluid intake leading to an increase of the urine volume to 3.1 L has
been shown to be sufficient to decrease urine osmolality to levels below the
serum osmolality that indicates suppression of vasopressin secretion

61. Sodium chloride consumption
 Limiting sodium chloride intake (e.g. to a range of 3-4 g/day) .
 Urinary sodium excretion was significantly associated with kidney
growth and decrease in eGFR.

62. Healthy Diet
 Maintaining a normal weight is clearly beneficial in ADPKD
 Overweight/obesity : A greater eGFR decline and a greater annual percent
change in TKV
 Studies in rodent models of ADPKD using calorie restriction yielded interesting
results with a significant impact on both TKV increase and eGFR loss

63. Role of Caffeine
 Caffeine inhibits phosphodies-terases (PDEs), which could lead to an
increase of cAMP in epithelial cells of the renal tubules
 Caffeine can increase BP but influence on TKV and Egfr are negligible as Caffeine
is a weak PDE inhibitor
 ADPKD patients can consume coffee, but should—as the general population—
refrain from excessive amounts (e.g.>3–4 cups or 400 mg caffeine per day)

64. Role of Smoking
 Smoking is associated with more rapid disease progression and risk of ESRD in
ADPKD
 Smoking also increases vasopressin secretion, which may be one
mechanism that leads to more rapid disease progression in ADPKD and
increases the risk of ICA rupture

65. Physical activity
 World Health Organization recom-mends 150 min of moderate-intensity or
75 min of vigorous-intensity activity per week
 Beneficial affect on Hypertension and body weight

66. cAMP as a central player in ADPKD
 In Cyst epithelium : A marked increase in cAMP levels that drives primarily
secretion and to a lesser extent proliferation - the hallmarks of cyst expansion.
 Adenyl cyclase converts ATP to cAMP
 Calcium inhibits Adenyl cyclase
 PDEs are involved in reducing cellular cAMP levels and attenuating
cystogenesis

67. Rationale of V2 receptor antagonists
 Controlling cAMP generation in tubular cells can alleviate cyst growth.
 V2 receptor signalling driven by vasopressin (AVP) was found to be the most
potent inductor of cAMP in isolated cells of the collecting duct
 The predominance of expression of the V2 receptor in the sites of
cystogenesis-collecting ducts, connecting tubules and thick ascending limbs
of Henle - makes this receptor an attractive pharmacological target

68. TEMPO 3:4 Trial
 ADPKD 750 ml Age 15-50 years > 60ml/min 2:1 Tolvaptan/Placebo
 Dose 45/15……….90/30 per day
Conclusions
 Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and
the decline in kidney function over a 3-year period in patients with ADPKD but was
associated with a higher discontinuation rate, owing to adverse events.
 Patients taking tolvaptan experienced a significantly lower rate of kidney growth by
close to 50% and even more importantly eGFR loss was attenuated by 26% (3.7
versus 2.7 mL/min/1.73 m2)

70. Somatostatin analogues in ADPKD
 Regarding the modulation of intracellular cAMP levels in tubular cells, the
second important pathway is somatostatin signalling with the activation of its
Gi-protein coupled receptor reducing Camp

72. SOMATOSTATIN ANLOGUES
 At the current stage somatostatin analogues will not become an agent to be
used to slow down disease progres-sion in ADPKD.
 Somatostatin analogues continue to play a role in the off-label treatment of
patients with severe polycystic liver involvement due to their effects on
hepatic growth

73. AMPK Regulators
 Both the cystic fibrosis transmembrane conductance regulator and the mTOR
pathway are central to cyst formation in ADPKD. AMPK is one of the key
negative regulators of both of these central players and can be activated by
metformin.
 Metformin, a widely used diabetes medication and a known AMPK
activator, was shown to inhibit disease progression in animal models and is
currently being tested in a Phase II clinical trial in ADPKD patients .

74. Metabolic targets in ADPKD

75. Metabolic targets in ADPKD
 Cyst cells - High rate of Glycolysis,low rate of mitochondrial oxd
phosphorylation
 2DG-potent inhibitor of Glycolysis
 BPTES(Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl
sulfide) inhibits Glutamine lysis leading to decreased krebs cycle
 PPAR-Alfa promotes fatty oxidation and inhibits glycolysis
 PPAR-Gamma inhibits fibrosis
 AMPK – Inhibits mTOR and CFTR

76. Role of mTOR inhibitors

77. Role of statins
 Pravastatin : Significantly slower TKV growth; no benefit regarding UAE
and LVMI (a composite endpoint)

78. Correction of Metabolic acidosis
 Acidosis has been linked to CKD progression and bicarbonate supplementation
(600 mg thrice daily, increased as necessary to maintain a bicarbonate level of 23
mmol/L)reduced eGFR decline in a small trial of patients with CKD stage 4 with
plasma bicarbonate of 16–20 mmol/L.
 Maintain a plasma bicarbonate level of 22mmol/L

79. Role of kinases
src/bcr-abl tyrosine kinase inhibitor BOSUTINIB

80. Drugs under trial
 Tesevatinib : A multi-tyrosine kinase inhibitor targeting epidermal
growth factor receptor and vascular endothelial growth factor
receptor is currently examined in a phase 2 trial for the treatment of
ADPKD (NCT03203642).
 GZ/SAR402671, a glucosyl ceramide synthase inhibitor that was
primarily developed for the treatmentof storage disease such as Gaucher’s
and Fabry’s disease

81.  Tissue
targeting
approaches

83. Urinary tract infections
Gram-negative bacteria are the most common pathogens.
Treating infected cysts requires antibiotics that penetrate into the cyst.
 Useful agents are ciprofloxacin, trimethoprim - sulfamethoxazole, clindamycin, and
chloramphenicol.

84. Flank pain
 Analgesics
 Tricyclic antidepressants
 Splanchnic nerve blockade
 Cyst decompression-aspiration f/b sclerosing therapy
 Laporoscopic/surgical cyst fenestration
 Renal denervation
 Nephrectomy/arterial embolisation

85. Cyst Hemorrhage
 Usually self limited
 Extensive subcapsular/retro peritoneal hematoma-blood transfusion
 Segmental arterial embolisation..rarely nephrectomy

86. Nephrolithiasis
 Potassium citrate
 ESWL/PCNL/Ureteroscopy with lase fragmentation

87. Renal transplantation
 No difference in patient/graft survival
 No increased risk of cyst infection/malignant transformation in native kidney
post transplantation
 Indications for pre transplant nephrectomy - History of infected cysts,frequent
bleeding,severe hypertension,massive size of the kidney
 To exclude PKD in donors if they are from within the family.

88. THANK YOU