3. Definition
ADPKD is a multisystem disorder characterized by multiple,
bilateral renal cysts associated with cysts in other organs,
such as liver, pancreas, and arachnoid membranes.
It is a genetic disorder mediated primarily by mutations in two
different genes and is expressed in an autosomal dominant
pattern, with variable expression.
4. Typically leads to renal failure mainly due to continued
enlargement of cysts.
ADPKD is the most common life-threatening monogenic
disease, affecting 12 million people worldwide.
Approximately 5% of patients who initiate dialysis annually in
the United States.
5. Etiology and Pathogenesis
The polycystic kidney disease (PKD) proteins now known as
polycystin 1 (PC1) and polycystin 2 (PC2) play a critical role in the
normal function of the primary cilium that is essential to
maintaining the differentiated phenotype of tubular epithelium.
Disordered function of polycystins is the basis for cyst formation
in PKD by permitting a less differentiated tubular epithelial
phenotype.
7. PKD1 PKD2
Located on Chromosome 16
[16p13]
Located on Chromosome 4
[4q21-q23]
Codes for Polycystin 1 protein
(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 in cell-cell adhesions.
Code PC2: non-selective cation
channel, permeable to Calcium.
Located mainly in SER.
8. Mutations in PKD1 and PKD2
Loss of ciliary function of PC1 and PC2
Reduced calcium signaling
Increase of adenylyl cyclase activity + decrease
of phosphodiesterase activity
Increased cellular cyclic AMP (camp)
Promotes protein kinase A activity
Proliferation and fluid secretion of cyst-lining cells through
chloride and aquaporin channels
Cyst growth
Increased cell proliferation and fluid secretion, decreased cell differentiation,
and abnormal extracellular matrix.
9. Cysts only occur in 5% of the tubules
in the kidney
Enormous growth of these cysts
ultimately leads to the loss of normal
surrounding tissues
Loss of renal function
11. Clinical Manifestations
Asymptomatic [until the fourth to fifth decade of life and are
diagnosed by incidental discoveries]
Pain—in the abdomen, flank, or back—is the most common initial
complaint. [may result from renal cyst infection, hemorrhage or
nephrolithiasis]
Gross hematuria [resulting from cyst rupture occurs in ~40% of
patients and many of them will have recurrent episodes.]
12. Physical Examination
Hypertension
Palpable, bilateral flank masses
Nodular hepatomegaly occurs in those with severe polycystic
liver disease
Symptoms related to renal failure (eg, pallor, uremic fetor, dry
skin, edema) are rare upon presentation.
13. Complications
Hypertension 60-100% [Cardiovascular complications are the major
cause of mortality in patients with ADPKD]
Infection [second most common cause of death for patients with
ADPKD]
Gross hematuria 50%
Nephrolithiasis 20-25%
Renal failure 50% by age 60 (PKD1) and 85% in lifetime
Polycystic liver disease
Cerebral aneurysms [occur in 4-10% of patients]
14. Hypertension
Increased activation of the renin-angiotensin-aldosterone
system,
Increased sympathetic nerve activity,
And impaired endothelial cilium function-dependent
relaxation of small resistant blood vessels.
15.
16. Nephrolithiasis
More than half of the stones in patients with ADPKD are composed of uric
acid, with the remainder due to calcium oxalate.
Distal acidification defects,
Abnormal ammonium transport,
Low urine pH and
Hypocitraturia
17. Intracranial aneurysm (ICA)
The disease gene products PC1 and 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. Mitral valve prolapse occurs in up
to 30% of patients with ADPKD.
22. Investigations
Serum electrolytes, including calcium and phosphate
Complete blood cell count [An increased hematocrit may result
from increased erythropoietin secretion from cysts]
Urinalysis
Urine culture
Uric acid determination
parathyroid hormone assay
23. Complete blood cell count :
An increased hematocrit may result from increased
erythropoietin secretion from cysts.
Urinalysis:
Decrease in urine-concentrating ability,
Microalbuminuria occurs in 35% of patients,
Nephrotic-range proteinuria is uncommon]
24. 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
25. 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.
26. At-risk subjects between 15
and 29 years of age
At least two renal cysts
(unilateral or bilateral)
Sensitivity of 96%
And specificity of 100%
Age 30 to 59 years At least two cysts in each
kidney
Sensitivity of 100% and
specificity of 100%
Age 60 years or
Older
At least four cysts in each
kidney
Sensitivity of 100% and
specificity of 100%
27. Computed tomography (CT) scan
CT is 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.
28. Unenhanced axial computed tomography scan of the abdomen in a 45-year-old woman with autosomal
dominant polycystic kidney disease. The scan shows numerous cysts of different sizes involving the kidneys,
liver, and pancreas
29. Magnetic resonance imaging (MRI)
MRI is the best imaging tool to monitor kidney size after treatment to
assess progress.
Mri is more sensitive than either ultrasonography or ct scanning.
It may be more helpful in distinguishing renal cell carcinoma from
simple cysts.
Renal cysts show a homogeneous, low to intermediate signal intensity
on t1-weighted images and a homogeneous, high signal intensity on
t2-weighted images.
30. 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
31. Control blood pressure
Blood pressure control to a target of 140/90 mmhg is recommended
according to the guidelines from JNC VIII 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 angiotensin-converting enzyme
(ace) inhibitors (ie, captopril, enalapril, lisinopril) or angiotensin ii receptor
blockers (arbs) such as telmisartan, losartan, irbesartan, and candesartan.
Calcium channel blockers are not recommended.
32. 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.
33. Hematuria
It usually results from cyst rupture or stone passage.
Drink large amounts of water, rest and pain killer if necessary.
Hematuria is usually self-limited.
34. Abdominal pain from enlarged kidneys
Avoid Non-steroidal anti-inflammatory drugs (NSAIDs), because they can
worsen renal function and potentiate hyperkalemia.
Treatment involves surgical cyst decompression which is effective for pain
relief in 60-80% of patients.
Infected renal or hepatic cysts do not respond to conventional antibiotic
therapy
Very large cyst
Acute pain is from cyst hemorrhage or an obstruction by a clot, stone, or
infection
Nephrectomy is used as a last resort to control the pain and to make room
for a kidney graft.
35. Renal Failure
More than half of ADPKD patients eventually require
peritoneal dialysis, hemodialysis, or kidney transplantation.
Peritoneal dialysis may not be suitable for some patients with
massively enlarged polycystic kidneys due to the small intra-
abdominal space for efficient peritoneal exchange of fluid and
solutes and increased chance of abdominal hernia and back
pain.
36. Specific treatment strategies
No specific medication is available for autosomal dominant polycystic
kidney disease (ADPKD)
Specific treatment strategies for ADPKD have focused on slowing renal
disease progression and lowering cardiovascular risk.
Most approaches target the slowing of renal disease progression by
inhibiting cell proliferation and fluid secretion.
Targeting cell proliferation: sirolimus and everolimus
Inhibitors of the mTOR pathway; OPC31260 and tolvaptan
Reduce camp levels: somatostatin analogues.
A combination of different growth inhibitors may enhance efficacy and
reduce side effects.
37. Vasopressin Receptor Antagonists:
OPC 31260, Tolvaptan
Multicenter, placebo-controlled, double-blinded trial (TEMPO 3:4)
Inclusion: 18 to 50 years, GFR >60ml/min, TKV >750ml.
Dose: 60 to 120mg daily, 2:1 Drug: Placebo
Results after 3 years:
Tolvaptan Placebo
Increase in TKV 2.8% 5.5%
Decline in kidney
function
-2.61 mg/ml -3.81mg/ml
Adverse effects noted with Tolvaptan:
1. Increased liver enzymes (4.9%)
2. Chest pain (0.8%)
3. Headache (0.5%)
Torres VE, Chapman AB, Devuyst O et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. NEJM 2012;
367:407
38. Somatostatin:
RCT on 34 patients with ADPKD with Somatostatin or placebo.
Large multicentric trials required.
Results after one year:
Somatostatin Placebo
Mean kidney
volume
Stable, 0.25%
increase
8.60% increase
GFR Reduced to same
degree
Reduced to same
degree
Hogan et al. Randomized ClinicalTrial of long-acting Somatostatin for ADPKD and liver disese. J Am Soc Nephro 2010; 21: 1052
39. mTOR inhibitors:
*Double blind, two year. 431 patients with PKD (mean GFR 55 ml/min/1.73m2) with
placebo or everolimus.
Increase in protein: creatinine in Everolimus group.
S/e: Leukopenia, thrombocytopenia, hyperlipidemia.
**Trial 2:
Open-label RCT, 18 months. 100 patients with PKD (mean GFR 70 ml/min) with placebo or
sirolimus.
NO CHANGE IN TKV OR GFR after 18 months.
Albumin: creatinine 38% increased in Sirolimus group.
***Novel strategy:
Kidney-targeted folate-conjugated form of rapamycin inhibited mTOR activity in the kidney but not
other organs in a mouse model.
Everolimus Placebo
Increase in TKV 230ml 310ml
Decrease in GFR 8.9ml/min 7.7 ml/min
