Adult polycystic kidney disease

BY DR.K.PRATHYUSHA

UNIT-M2

PKD : multisystemic; progressive hereditary disorder characterized by cyst formation and enlargement in the kidney & other organs (eg, liver, pancreas, spleen).

Potter classification : type 1- ARPKD; type 2- multicystic dysplastic kidney disease; type 3- ADPKD

ADPKD-Genetic disorder mediated by mutations in 2 different genes

Incidence:

Autosomal dominant 1:500-1000 live births PKD1(85%)>PKD2(15%)

Autosomal recessive 1:6000-40000 live births

Genes : mutation

Gene Protein Chromosome

ADPKD1 polycystin 1 short arm 16

ADPKD2 polycystin 2 long arm 4

ARPKD fibrocystin/polyductin 6

Severity -PKD1 >PKD2 ARPKD>ADPKD

Median age of ESRD

PKD1-50 yrs

PKD2-70yrs

If atleast 1family member developed ESRD <55yrs then highly predictive of PKD1

If ESRD<75yrs then predictive of PKD2

Etiology & Pathogenesis

Disordered function of polycystins-defects in primary cilia- is basis for cyst formation

Polycystin 1 may regulate tubular epithelial cell adhesion and

differentiation; polycystin 2 may function as an ion

channel, with mutations causing fluid secretion into cysts.

Mutations in these proteins may alter the function of renal

cilia, which enable tubular cells to sense flow rates.

Cystogenesis

leading hypothesis -tubular cell proliferation & differentiation

are linked to flow rate & that ciliary dysfunction leads to

cystic transformation.

Early -tubules dilate & slowly fill with glomerular filtrate.

Eventually, the tubules separate from functioning nephron

& fill with secreted rather than filtered fluid, forming cysts.

In general

How cysts develop - is not known

Due to disruption of signalling pathways regulated by primary cilium like intracellular Ca2+ ; cAMP ; planar cell polarity Cysts arise from nephrons & collecting tubules - they communicate ; normal parenchyma exists b/w cysts

cAMP - cyst growth & overall enlargement

transepithelial secretion of Cl through apical CFTR channels - Fluid secretion into cyst

Cystogenesis

Signs & symptoms

1. Most common symp - pain in back & sides

pain can be due to:

Enlargement of one or more cystsBleeding: confined inside the cyst or lead to gross hematuria

with passage of clots or a perinephric hematoma

UTI (eg, acute pyelonephritis, infected cysts, perinephric abscess)

Nephrolithiasis and renal colicRarely, a coincidental hypernephromaDull aching pain due to cysts in liver

abdominal pain in patients with ADPKD may be a diagnostic challenge.

2. Other physical symptoms seen in early-stage ADPKD : fatigue, breathlessness, weakness, and malaise

3.Hematuriafrequently the presenting manifestation and usually is self-

limited, lasting 1 week or less.

Polycystic kidneys are unusually susceptible to traumatic injury, with hemorrhage occurring in approximately 60% of individuals.

Mild trauma can lead to intrarenal hemorrhage or bleeding into the retroperitoneal space accompanied by intense pain that often requires narcotics for relief.

On Examination:

Hypertension: common early manifestation in which increased DBP is the rule; Palpable, bilateral flank masses: In advanced ADPKDNodular hepatomegaly: In severe polycystic liver diseaseRarely, symptoms related to renal failure (eg, pallor, uremic

fetor, dry skin, edema)Clinical course - severe early then little less as renal

insufficiency progresses

Complications

Both renal & extrarenal

Renal include :

1. HTN

2. Hematuria & infection

3. Nephrolithiasis

4. Renal failure

HTN

Extrarenal include :

1. Hepatic & pancreatic cysts

2. Cardiac valve defects - MVP; TR; AR

3. Intracranial aneurysms-saccular “berry”

4. Azotemia - seminal vesicle cysts

5. Hernias

Liver/GI complications

Liver cysts -94% common mostly asymptomatic

Marked hepatomegaly results in heaviness , pain

Hepatic cyst infection more serious than renal cyst

CA 19-9 marker for hepatic cyst infection

Intracranial aneurysms

90% in ant.circulation

10% in post.circulation(great risk of rupture)

Mean age of rupture is less in adpkd compared to general

Diagnosis

1. Routine lab tests

2. Genetic testing

3. Imaging studies(gold standard) : includes

USG

X-RAY

CT & MRI

Ultrasound

Technique of choice

Screening of family members

Exploring extrarenal features like hepatic cysts

Ultrasonographic diagnostic criteria for ADPKD1

At least 2 cysts in 1 kidney or 1 cyst in each kidney in an at-risk patient younger than 30 years

At least 2 cysts in each kidney in an at-risk patient aged 30-59 years

At least 4 cysts in each kidney for an at-risk patient aged 60 years or older

USG diagnostic criteria for ADPKD in patients with a family history but unknown genotype 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

Fewer than 2 renal cysts in the findings provides a negative predictive value of 100% and can be considered sufficient for ruling out disease in at-risk individuals older than 40 years.

X-RAY

Early stages - normal

Enlargement of kidneys -

outline may be lost

Curvilinear and ring like

opacities may be seen

Ct scan

Not routine

Useful in doubtful & complicated cases

MRI

Not routine

Helpful to differentiate b/w rcc from simple cysts

Best tool to monitor kidney size after Rx to assess progress

MRA

Not routine

Preferred for diagnosing intracranial aneurysms

Indications :

1. Family h/o; past h/o of stroke

2. s/s of intracranial aneurysms

Differential diagnosis

1. Multiple simple cysts

2. Infantile PCKD

3. Medullary cystic disease/nephronopthisis

4. Von hippel lindau disease:cerebellar hemangioblastoma+ retinal hemangiomas + occasionally pheochromocytomas

5. Acquired uremic cystic disease

Management : medical

No specific medication

pharmacotherapy is given to for following:

1. Control HTN: ACEIs or ARBs 2. Control abnormalities related to renal failure: Drugs to maintain electrolyte levels (eg, calcium carbonate, calcium acetate, sevelamer, lanthanum carbonate, calcitriol [possibly], diuretics, blood pressure medications)3. Treat UTI: fluoroquinolones,sulfa drugs penetrate cyst

4. Treat cyst infections: Gyrase inhibitors (eg, ciprofloxacin, chloramphenicol, clindamycin, levofloxacin); dihydrofolic acid inhibitors (SMP)5. Treat hematuria: Possibly analgesic plus copious oral hydration6. Reduce abdominal pain produced by enlarged kidney 7. Prevent cardiac valve infection in patients with intrinsic valve disease

Surgical Rx:

includes:

Surgical drainage: Usually in conjunction with usg guided puncture; in cases of infected renal/hepatic cysts not responding to conventional antibiotics

Open-/fiberoptic-guided surgery: For excision/drainage of the outer walls of cysts to ablate symptoms

Nephrectomy: Last resort for pain control in patients with inaccessible cysts in the renal medullae;

bilateral nephrectomy in patients with severe hepatic involvement

Partial hepatectomy: To manage massive hepatomegalyLiver transplantation: In cases of portal hypertension due to

polycystic liver or hepatomegaly with nonresectable areas

Patients with ADPKD who progress to end-stage renal disease may require the following procedures:

HemodialysisPeritoneal dialysisRenal transplantation

New trials : HALT PKD ; TEMPO 3:4

Rx: 1.V2 receptor antagonists (tolvaptan) - slow increase in renal volume & decline in renal fnctn. Due to side effects not yet approved

2.mtor inhibitors(rapamycin) slow increase in renal volume but not decline of function - not routinely used

3.somatostatin

4. Rx of choice in ESRD is transplantation

Key points

Autosomal dominant polycystic kidney disease occurs in about 1/1000 people

About half of patients have no manifestations, but in others symptoms of back

or abdominal pain, hematuria and/or hypertension develop gradually, usually

beginning before age 30; 35 to 45% develop renal failure by age 60.

Extrarenal manifestations are common and include cerebral and coronary artery

aneurysms, cardiac valve disease, and cysts in the liver, pancreas, and

intestines.

Diagnose PKD based on imaging studies and clinical findings, reserving genetic

testing for patients with no family history, with inconclusive results on imaging,

or who are young and in whom the diagnosis will affect management.

Do not routinely screen asymptomatic patients for ADPKD or asymptomatic

patients who have ADPKD for cerebral aneurysms.

Arrange genetic counseling for 1st-degree relatives of patients with ADPKD.

Give ACE inhibitors or angiotensin receptor blockers for hypertension and to help

prevent renal scarring and dysfunction; treat other complications as they

arise, and consider use of tolvaptan.

Thank youReference : CJASN / davidson / harrisons internal medicine / NICE/ NCBI