Polycystic Kidney Disease

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)


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.


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


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)


Potter Phenotype

Flank mass


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

Science

Polycystic Kidney Disease