1. This lecture was conducted during the Nephrology Unit Grand Ground by a Sub-intern under Nephrology Division, Department of Medicine in King Saud University. Nephrology Division is NOT responsible for the content of the presentation for it is intended for learning and /or education purpose only.

2. presented by FAISAL AL-DAHASH 25-04-2012 Polycystic Kidney Disease

3. Contents 1. Introduction 2. Pathophysiology 3. Clinical presentation 4. Diagnosis 5. Complications and Association 6. Conventional therapy 7. New therapies

4. Introduction Autosomal-dominant most common inherited nephropathy It accounts for 3-10% of all patients commencing regular dialysis

5. 2. Pathophysiology The genes responsible are (PKD1) and (PKD2) The corresponding protiens are polycystin 1 and a calcium ion channel, repectively Polycystin-1 acts as the regulator of PKD2 channel activity ↓ Ca intracellularly → ↓ cAMP → Defective cell signalling → disoriented division of the cells along the nephron → cyst formation

6. 2. Pathophysiology contd. ↓ p21 (kinase inhibitor that mediates cell cycle arrest )* activation of mTOR ( a kinase that regulates cell growth and metabolism)** loss of renal function is due to *Bhunia AK, Piontek K, Boletta A, et al. PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell 2002;109:157–68 **Lieberthal W, Levine JS: The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol 20: 2493–2502, 2009 mechanical compression apoptosis of the healthy tissue reactive fibrosis

7. 3. Clinical presentation Clinical presentation usualy at the 2 nd decade. Presenting symptoms include: acute loin pain and/or haematuria, Symptoms of uraemia and/or anaemia associated with chronic renal failure Complications of associated liver cysts

8. 4. Diagnosis Definitive diagnosis is by ultrasound

9. 5. Complications and associations Cyst infection Renal calculi Intracranial aneurysm formation Mitral valve prolapse

10. 6. Conventional therapy Laparoscopic renal cyst decortication Needle aspiration of cysts

11. Ascofuranone: induces G 1 arrest through p21 activation and c-Myc disruption Rapamycin (Sirolimus): the increase in cyst volume is less than with conventional therapy Perico N, et al: Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol 21: 1031–1040, 2010 Jeong JH, Kang SS, Park KK, Chang HW, Magae J, Chang YC. p53- independent induction of G 1 arrest and p21WAF1/CIP1 expression by ascofuranone, an isoprenoid antibiotic, through downregulation of c- Myc. Mol Cancer Ther 2010;9:2102–13. New therapies

12. Thank you