1. Renal Cystic Disorders Nadeem A Siddiqui MD

2. Renal cystic disorders Non-genetic Non-genetic A) Developmental: Medullary sponge kidney Renal cystic dysplasia B)Acquired: Simple cysts Hypokalemia related CKD related Renal Lymphangiomatosis Solitary Multilocular cysts

3. Renal cystic disorders Genetic: AD ADPKD Von Hipple-Lindau Tuberous Sclerosis Medullary cystic disease Genetic: AR ARPKD Juvenile nephronophthisis X Linked: Orofacial digital syndrome type 1

4. ADPKD: Epidemiology Incidence 1:400 to 1:1000 Incidence 1:400 to 1:1000 Current number affected:400,000 Current number affected:400,000 Approximately 1800 started on HD each year Approximately 1800 started on HD each year Racial distribution Racial distribution

5. Genetics PKD1…..85 to 90 % PKD1…..85 to 90 % PKD2…..10 to 15 % PKD2…..10 to 15 % PKD1 gene is on 16p and codes for polycystin 1. It has 3 homologous copies and hence mutations are difficult to identify PKD1 gene is on 16p and codes for polycystin 1. It has 3 homologous copies and hence mutations are difficult to identify PKD2 gene is located on 4p and codes for polycystin 2 PKD2 gene is located on 4p and codes for polycystin 2

6. Genetics Both polycystin 1 and 2 are regulatory proteins involved in regulation of ion channels. PKD2 may regulate calcium channel function Both polycystin 1 and 2 are regulatory proteins involved in regulation of ion channels. PKD2 may regulate calcium channel function ADPKD kidneys stain heavily for polycystins ADPKD kidneys stain heavily for polycystins

7. Clinical Features Renal Renal1.Hematuria2.Infection3.Nephrolithiasis4.Hypertension 5.Renal failure 6.Pain 7.Cyst rupture and torsion 8.Functional renal disease Extra Renal Extra Renal 1.Polycystic liver disease 2.Intracranial Aneurysms 3.Valvular heart disease

8. Hypertension Seen in 60 to 100% of patients Seen in 60 to 100% of patients

9. Gross Hematuria Seen in up to 50% of patients Seen in up to 50% of patients Flank pain Flank pain Cyst hemorrhage may occur in the absence of gross hematuria Cyst hemorrhage may occur in the absence of gross hematuria Cyst rupture can cause retro-peritoneal bleeding Cyst rupture can cause retro-peritoneal bleeding

10. Cyst Infection UTI UTI Pyelonephritis Pyelonephritis Perinephric abscess Perinephric abscess

11. Nephrolithiasis Seen in up to 25% of all ADPKD patients Seen in up to 25% of all ADPKD patients Stones contain uric acid and calcium oxalate Stones contain uric acid and calcium oxalate Factors responsible for nephrolithogenesis Factors responsible for nephrolithogenesis include decreased urinary NH4,decreased urinary PH, and decreased urinary citrate include decreased urinary NH4,decreased urinary PH, and decreased urinary citrate

12. Renal functional Impairment Renal concentration defect Renal concentration defect Decreased renal blood flow Decreased renal blood flow Acidification defect ( decreased NH3) Acidification defect ( decreased NH3) Increase in renal Angiotensin activity and matrix synthesis Increase in renal Angiotensin activity and matrix synthesis

13. Renal Failure Seen in 50% of patients by age 60 Seen in 50% of patients by age 60

14. ESRD in ADPKD 16,298 patients were treated for ADPKD (5% of all ESRD) 16,298 patients were treated for ADPKD (5% of all ESRD) 2,144 patients entered ESRD 2,144 patients entered ESRD 50% of all ADPKD patients enter ESRD by age 60 50% of all ADPKD patients enter ESRD by age 60 Total cost of RRT for ADPKD pts exceeded $1 billion Total cost of RRT for ADPKD pts exceeded $1 billion Data from FY 2000 Data from FY 2000

15. Risk factors for rapid loss of renal function Hypertension Hypertension Gross Hematuria Gross Hematuria UTI UTI Multiparity Multiparity Male sex Male sex Black race Black race Dx of ADPKD before age 30 Dx of ADPKD before age 30 Onset of hematuria before age 30 Onset of hematuria before age 30 Dyslipidemia Dyslipidemia DD ACE polymorphism DD ACE polymorphism Sickle cell disease Sickle cell disease

16. Extra-renal disease: PLD Dx: > 4 cysts in the liver Dx: > 4 cysts in the liver May occur independent of PKD May occur independent of PKD Biliary hamartomas, biliary fibroadenomas, dilatation of intra/extra hepatic ducts Biliary hamartomas, biliary fibroadenomas, dilatation of intra/extra hepatic ducts Liver cysts increase with estrogen exposure Liver cysts increase with estrogen exposure Cysts may cause abdominal distension, dyspnea, obstructive jaundice and ascites due to IVC compression Cysts may cause abdominal distension, dyspnea, obstructive jaundice and ascites due to IVC compression

17. Extra-renal disease: ICA Overall incidence 8% of all ADPKD patients Overall incidence 8% of all ADPKD patients Familial clustering ( 22% of those with familial h/o ICA) Familial clustering ( 22% of those with familial h/o ICA) Majority are asymptomatic Majority are asymptomatic Yearly rupture rate is 0.5% for aneurysms 10 mm Yearly rupture rate is 0.5% for aneurysms 10 mm 1/3 of all patients with a ruptured aneurysm are not hypertensive at the time of rupture 1/3 of all patients with a ruptured aneurysm are not hypertensive at the time of rupture

18. Indications for screening for ICA Family h/o ICA/SAH Family h/o ICA/SAH Prior aneurysmal rupture Prior aneurysmal rupture Before high risk surgery Before high risk surgery High risk occupation High risk occupation Anxiety on part of the patient Anxiety on part of the patient

19. Screening for ICA MRA with gadolinium is highly sensitive and does not impose risk of contrast nephropathy MRA with gadolinium is highly sensitive and does not impose risk of contrast nephropathy

20. Extra-renal disease: Valvular heart disease MVP….25% MVP….25% MR,TR, tricuspid valve prolapse, AI. MR,TR, tricuspid valve prolapse, AI. Histopathology: myxoid degeneration Histopathology: myxoid degeneration Screening: if clinically indicated Screening: if clinically indicated

21. Diagnostic testing Ultrasound diagnosis Ultrasound diagnosis Genetic diagnosis Genetic diagnosis Pre-symptomatic diagnosis Pre-symptomatic diagnosis

22. Diagnostic Criteria- Ultrasound Age 15-29 ………..2 cysts in one or both kidneys Age 15-29 ………..2 cysts in one or both kidneys Age 30 to 59 …….2 cysts in each kidney Age 30 to 59 …….2 cysts in each kidney Age >60 ………….4 cysts in each kidney Age >60 ………….4 cysts in each kidney

23. Case # 1 A 32 year old man with known h/o ADPKD comes to your clinic with a two day h/o left flank pain. A 32 year old man with known h/o ADPKD comes to your clinic with a two day h/o left flank pain. BP160/90, temp 98.4. BP160/90, temp 98.4. left kidney is palpable and tender left kidney is palpable and tender Serum creatinine is 1.0 and UA shows microscopic hematuria. Urine gram stain is negative Serum creatinine is 1.0 and UA shows microscopic hematuria. Urine gram stain is negative

24. Case #1 continued Which diagnostic test would be most appropriate: Which diagnostic test would be most appropriate: 1) Excretory Urography 2) USG 3) CT with and without Contrast 4) MRI

25. ADPKD genetic diagnosis PKD2 100% mutations detectable PKD2 100% mutations detectable PKD1 75 to 80% mutations detectable PKD1 75 to 80% mutations detectable

26. Genetic screening Who should be screened: Equivocal sonogram in a young adult who is a potential renal transplant donor Equivocal sonogram in a young adult who is a potential renal transplant donor Issues : Issues : Psychological burden Insurance and employment risk

27. Rx of ADPKD Treatment of Flank pain: Treatment of Flank pain: Analgesics Analgesics Avoid NSAIDS Avoid NSAIDS Risk of narcotic dependence Risk of narcotic dependence Cyst decompression, aspiration, ethanol Cyst decompression, aspiration, ethanol sclerosis and laparoscopic fenestration sclerosis and laparoscopic fenestration

28. Rx of ADPKD Treatment of Cyst hemorrhage Treatment of Cyst hemorrhage Self limited Self limited Segmental artery embolization Segmental artery embolization

29. Rx of ADPKD Cyst Infection Cyst Infection Bactrim Bactrim Quinolones Quinolones Chloremphnicol Chloremphnicol

30. Rx of ADPKD Rx of ADPKD Nephrolithiasis: Nephrolithiasis: Extracorporeal shock wave lithotripsy Extracorporeal shock wave lithotripsy Potassium citrate / Bicitra for prevention of nephrolithiasis if needed Potassium citrate / Bicitra for prevention of nephrolithiasis if needed

31. Rx of ADPKD Hypertension: Hypertension: ACE Inhibitors and ARB are preferred ACE Inhibitors and ARB are preferred

32. Rx of ADPKD Treatment of CKD Treatment of CKD Dietary protein restriction Dietary protein restriction Control of dyslipidemia ( statins) Control of dyslipidemia ( statins) Control of acidosis Control of acidosis Prevention of hyperphosphatemia Prevention of hyperphosphatemia management of hypertension management of hypertension

33. ARPKD Incidence 1:20,000 Incidence 1:20,000 30% effected neonates die 30% effected neonates die Genetic locus: 6p Genetic locus: 6p Clinical features: Clinical features:Oligohydramnios Large echogenic kidneys Pulmonary hypoplasia HematuriaPyuria Systemic hypertension Portal Hypertension

34. Case #2 49 yr old female presents with biliary colic. 49 yr old female presents with biliary colic. H/o petit mal seizures in her son and h/o hypo pigmented macules in her grandson H/o petit mal seizures in her son and h/o hypo pigmented macules in her grandson Physical exam: scattered flesh colored facial papules, two dental enamel pits, and many scattered hypo pigmented macules Physical exam: scattered flesh colored facial papules, two dental enamel pits, and many scattered hypo pigmented macules

35. Case #2 continued Labs: normal chemistries and blood count and normal serum creatinine Labs: normal chemistries and blood count and normal serum creatinine CT of the abdomen: Contrast enhancing masses in both kidneys CT of the abdomen: Contrast enhancing masses in both kidneys

36. Tuberous Sclerosis Complex (TSC) AD AD Prevalence 1:10,000 Prevalence 1:10,000 Genetic loci: Genetic loci: TSC1…9q TSC1…9q TSC2…16p adjacent TSC2…16p adjacent to PKD1 locus to PKD1 locus Gene product is Tuberin (GTP ase) Gene product is Tuberin (GTP ase)

37. TSC: Clinical features Renal cysts and angiomyolipomas Renal cysts and angiomyolipomas Renal cell carcinoma (bilateral) Renal cell carcinoma (bilateral) Cortical tuber Cortical tuber Retinal hamartoma Retinal hamartoma Glioma Glioma Astrocytoma Astrocytoma Facial angiofibroma Facial angiofibroma Ungual fibroma Ungual fibroma Shagreen patch Shagreen patch Cardiac rhabdomyoma Cardiac rhabdomyoma Pulmonary lymphangioleiomyoma Pulmonary lymphangioleiomyoma Thyroid adenoma Thyroid adenoma

38. von Hippel-Lindau (VHL) Prevalence 1:30,000 Prevalence 1:30,000 VHL1 : VHL1 : 1. Retinal Angioma 1. Retinal Angioma 2. Spinal/ cerebellar hemangioblastoma 2. Spinal/ cerebellar hemangioblastoma 3. Pancreatic and renal cysts 3. Pancreatic and renal cysts 4.Renal cell cancer 4.Renal cell cancer VHL2: as in VHL1 +Pheochromocytoma VHL2: as in VHL1 +Pheochromocytoma