Week 4: inherited and cystic renal diseases

Question 1

Autosomal polycystic kidney disease (ADPKD). What are the genotypes?

Answer 1

• PKD1 on Chrom 16: 90% of disease in white Europeans. product of PKD1 is polycystin 1-invoked in matrix protein interaction
• PKD2 gene on chromosome 4: 10% of ADPKD- polycystin 2 is product
• each child had 50% chance of having the defective gene

Question 2

How do you diagnose ADPKD?

Answer 2

• suspect in those with affected family members
• gene linkage analysis
• Ultrasonography for cysts: up to 20% of patients with PKD1 will have normal study before age 30
• symptoms begin by 20s and 30s
• most common: flank pain, hematuria (50%), symptoms seen in HTN
• 80-100% have inability to concentrate urine

Question 3

How do cysts form in ADPKD? Pathogenesis.

Answer 3

• cyst fomartions begins in urtero w/ local dilatation of renal tubule–>cell proliferation with time–>epithelial secretory activity that pumps fluid into cyst space
• only a minority of nephrons develop cysts: two hit hypothesis-somatic mutation of normal PKD1 allele in one tubular cell provides second hit
• ->monoclonal proliferation leading to cyst formation
• fluid accumulation: transfer of chloride into lumen mediated by basolateral NK2Cl and CFTR in apical side
• abnormal signaling: up regulation of mTOR–>increased cAMP–>increased Cl- through CFTR

Question 4

Physical exam findings in ADPKD

Answer 4

• enlarged irregular kidneys are palpable

- urine: leukocytes, RBCs,

Question 5

Extra-renal manifestations of ADPKD

Answer 5

• hepatic cysts >50% of patients
• congenital hepatic fibrosis- rare
• pancreatic cyts
• colonic diverticuli
• cardiac valvular abnormalities
• intracranial aneurysms
• other organ cysts

Question 6

Renal complications of ADPKD in adults.

Answer 6

• HTN
• hematuria, hmorrhage or both
• acute and chronic pain
• UTI
• nephrolithiasis
• nephromegaly
• renal failure

Question 7

Define Alport’s syndrome.

Answer 7

• inherited kidney disease with proteinuria, hematuria, and deafness
• x linked dominant, mutations in COL4A5 gene that encodes alpha-chain of type IV collagen
• develop ESRD, treated by hemodialysis or transplant

Question 8

Pathogenesis of Alport’s syndrome.

Answer 8

• 6 alpha chains that make type 4 glomerular collagen
• embryo: 1 and 2 chain
• immature state: 3,4,5 and 5,5,6
• mature: 3,4,5 and 1,1,2 and 5,5,6
• in alport’s syndrome, don’t have normal structural organization because of mutation in alpha 3,4, or 5

Question 9

diagnosis of Alport’s syndrome.

Answer 9

• family hx of nephritis, hematuria,
• persistant hematuria without another nephropathy
• bilateral hearing loss of high pitches
• mutation in COL4A(3,4,5)
• lack of Alport epitope in immunohistochemical
• GBM thickening, thinning, and splitting
• ocular lesions: lenticonus, posterior capsular cataract, retinal flecks
• gradual progression to ESRD in at least 2 family members
• diffuse leyomyomatosis

Question 10

Define simple cysts.

Answer 10

• solitary or multiple are most common cystic lesions found in the kidney
• mostly asymptomatic