Autosomal Dominant Polycystic Kidney Disease

AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

DR. TALHA SAMI UL HAQUERESIDENT MEDICAL OFFICER

DEPT. OF NEPHROLOGYBIRDEM GENERAL HOSPITAL

Markedly enlarged polycystic kidneys from a patient with ADPKD in comparison to a normal kidney in the middle. 

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.

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.

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.

GeneProtein

PKD1Polycystin 1

PKD2Polycystin 2

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 yearsCode 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.

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.

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

Epidemiology

12 million people

All ethnic groups

Estimated prevalence of 1:1000 to 1:400

Only half of the patients withADPKD are clinically diagnosed during their lifetime

ADPKD is responsible for 6-10% of ESRD cases

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.]

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.

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]

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.

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

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.

Liver/GI Complications

1. Liver cysts (94% > 35)asymptomatic up to 80%symptomatic uncommon (W:M 10:1)

2. Pancreatic cysts ~10%3. Intestinal diverticuli ~80% patients with ESRD4. Hernias ~10%

Renal failure

Diagnostic ConsiderationsProblems 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

Diagnosis

Positive family history Multiple kidney cysts bilaterally on renal

ultrasonography.

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

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]

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

UltrasonographyUltrasonography 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.

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 orOlder

At least four cysts in each kidney

Sensitivity of 100% and specificity of 100%

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.

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

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.

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

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.

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.

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.

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.

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.

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.

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 PlaceboIncrease 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

Somatostatin:

RCT on 34 patients with ADPKD with Somatostatin or placebo.

Large multicentric trials required. Results after one year:

Somatostatin PlaceboMean kidney volume

Stable, 0.25% increase

8.60% increase

GFR Reduced to same degree

Reduced to same degree

Hogan et al. Randomized Clinical Trial of long-acting Somatostatin for ADPKD and liver disese. J Am Soc Nephro 2010; 21: 1052

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 in other organs in a mouse model.

Everolimus PlaceboIncrease in TKV 230ml 310mlDecrease in GFR 8.9ml/min 7.7 ml/min

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