polycystic kidney disease
DESCRIPTION
Diagnostic Molecular Pathology Approach to the diseaseTRANSCRIPT
Sept. 29, 2014
DIVYA NARAYANAN
POLYCYSTIC KIDNEY DISEASE
OUTLINE• History• Introduction• Pathophysiology• Autosomal Dominant Polycystic Kidney
disease• Autosomal Recessive Polycystic Kidney
disease• Case Study
HISTORY • Illness and death of Polish King Stefan Bathory (1533-1591) -
Possibly the first known case of PKD.• Autopsy report described kidneys as ‘large like those of bull, with
uneven and bumpy surface’ (surgeon Jan Zigulitz & Buccella).
• Lejars in 1888, published in his thesis the term ‘Polycystic Kidney Disease’. He described that PKD is a defined clinical entity with characteristic symptoms and susceptibility to be diagnosed clinically.• Osler in 1902, indicated two cases with clinical symptoms
proving the presence of Polycystic Kidney Disease.
Embalmed Body of King Stefan Bathory
Prof. Franciszek Walter at Krakow Medical School in 1933 concluded that the death of King Bathory is most likely due to PKD and uraemia.
INTRODUCTION
INTRODUCTION• It is characterized by an abnormal proliferation of renal tubular epithelial cells, which manifests as cysts that increase gradually in size and number, leading to massive kidney enlargement and progressive decline of renal function.
• Three types of PKD:• Autosomal Dominant Polycystic Kidney Disease (ADPKD)
• Autosomal Recessive Polycystic Kidney Disease (ARPKD)
• Glomerulocystic Kidney Disease (GCKD)
PATHOPHYSIOLOGY
Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Incidence – 1:400- 1:1000 individuals
Genetics – PKD1(chr 16p13.2;polycystin1;Type I) and PKD2(chr 4q21-q23;polycystin2;Type II) gene mutations. PKD3 (unidentified but predicted to be present)
Somatic second hit hypothesis (Dr. Alfred Knudson)
Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Molecular Mechanism
Disease characteristics• Present in any age: Generally in 40-50 yrs ;
occasionally in fetal/neo-natal period• Cyst formation in Kidney and Liver.• End stage renal failure (ESRD) in >50% of the cases
above age 60.• Arterial hypertension (>50% cases)• Vascular aneurysms• Cardiac valve defects• Colonic diverticula• Affects fertility in males but not in females.
Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Diagnostic Investigations• Urinalysis• Sonography• Renal ultrasound and IVP (Intravenous Pyelogram)• CT scan/ MRI• Renal function tests• Molecular Testing: Direct mutation analysis
Treatment• Narcotic analgesics for pain• Antibiotics for infection• Laparoscopic cyst decortication• Therapeutic intervention• Renal dialysis• Renal transplantation
Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Incidence – 1:20,000
Genetics – PKHD1 (chr6p21.1-p12; fibrocystin )
Disease characteristics• Manifested in infancy and childhood with high mortality rate due to
renal failure.• 30-50% affected neonates die shortly after birth; 67% children who
survive newborn period die at 15yrs of age• Principal manifestations:
•Fusiform dilatation of renal collecting ducts and distal tubuli• Dysgenesis of the hepatic portal triad
• Hypertension, Flank mass, Hepatomegaly and renal insufficiency • Potter Phenotype (Short and snubbed nose, Deep eye creases,
Micrognathia, Low-set flattened ears)• Inverse relative degrees of kidney and liver involvement• Caroli disease
Autosomal Recessive Polycystic Kidney Disease (ARPKD)
Autosomal Recessive Polycystic Kidney Disease (ARPKD)
Potter Phenotype
Flank mass
Autosomal Recessive Polycystic Kidney Disease (ARPKD)
Diagnostic Investigations• Radiography• Ultrasonography• CT scan• Ultrasonography and magnetic resonance cholangiography• MRI (RARE-MR-urography)• Histopathology• Molecular Diagnosis
• Linkage analysis• Direct DNA analysis• 33 different mutations in 57 alleles• frequent truncating mutations: 9689delA (9 alleles)
and 589insA (8 alleles).
Case study
42 years old
Female
Diagnosed hypertension at age 32
& ADPKD at age 36. Hypertension
controlled; abdominal & flank discomfort
treated
Ultrasonography showed renal, liver and
ovarian cysts
Mother underwent unilateral nephrectomy
in childhood.3 pack an yr tobacco
use ceased at 26BP: 124/84 mmHg;
Heart rate: 70 beats/min; 2/6 heart
murmur; Serum creatinine: 0.74mg/dL
MRI result: innumerable cysts in
liver & kidney; Right & left kidneys: 19 & 22.3 cm resp.; Total: Kidney
vol. – 1925 mL, cyst vol. – 1289 mL; cyst fraction: 67%; Liver vol. – 1431 mL, cyst vol. – 174 ml; cyst
fraction: 12.2%
MRI of abdomen
Case Study
Touchdown/Hot-start PCR
Amplification
• Long-range PCR fragments of PKD1(exon 1-33)• PKD1 (exons 34-46) and PKD2(exon 1-15); Splice junctions,
5’ (PKD1) & 3’ untranslated regions• GeneAmp High Fidelity PCR System• PCR fragments: 250-550 bp
Heteroduplex analysis &
SURVEYOR® nuclease digestion
• SURVEYOR™ nuclease cleaves at the 3’ side of any mismatch site (upto 12bp length)
Transgenomic WAVE® Nucleic
Acid High Sensitivity Fragment
Analysis System
Sequenced on ABI 3100 Genetic
Analyzer
LABORATORY TESTS
Case Study
Result: Heterozygous nonsense mutation
References• Ellis Avner, William Harmen, Patrick Niaudet, and Norishige Yoshikawa (2009), Pediatric
Nephrology, Sixth Edition• Abdelaziz Y. Elzouki (ed.) (2012), Textbook of Clinical Pediatrics, Second Edition• Carsten Bergmann(2013), ARPKD and early manifestations of ADPKD:the original polycystic
kidney disease and phenocopies; Pediatr Nephrol DOI 10.1007/s00467-013-2706-2• Florian Lang (2009), Encyclopedia of Molecular Mechanisms of Disease• H. Chen (2014), Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-
9_193• Vincente E. Torres and Michael L. Watson (1998); Polycystic Kidney Disease: antiquity to the
20th century, Nephrol Dial Transplant 13: 2690-2696• William E. Braun (2014); Advances in autosomal dominant polycystic kidney disease—2014
and beyond, CLEVELAND CLINIC JOURNAL OF MEDICINE doi:10.3949/ccjm.81gr.14001• Madhukar S. Patel, Praveen Kandula, DavidWojciechowski, James F.Markmann, and Parsia A.
Vagefi (2014); Trends in the Management and Outcomes of Kidney Transplantation for Autosomal Dominant Polycystic Kidney Disease, Journal of Transplantation, Article ID 675697
• Max Christoph Liebau (2014), An emerging molecular understanding and novel targeted treatment approaches in pediatric kidney diseases, Frontiers in Pediatrics, doi: 10.3389/fped.2014.00068
• Michael R. Eccles and Cherie A. Stayner (2014), Polycystic kidney disease – where gene dosage counts, F1000Prime Reports 2014, 6:24 (doi:10.12703/P6-24)
• Gustavo Blanco and Darren P. Wallace (2013), Novel role of ouabain as a cystogenic factor in autosomal dominant polycystic kidney disease, Am J Physiol Renal Physiol 305: F797–F812
• Vicente E. Torres and Peter C. Harris (2009); Kidney International, doi:10.1038/ki.2009.128• S. Kern et al (1999); RARE-MR- urography: A new diagnostic method in Autosomal Recessive
Polycystic Kidney Disease, Acta Radiol 40(5):543-4