Cystic kidney dz Flashcards
Autosomal dominant polycystic disease
Most common inherited polycystic dz
Manifests in adulthood: 3rd-5th decade of life
Autosomal dominant, incomplete penetrance
Family history is positive only in 60% of cases
Nearly 50% of ADPKD pt’s reach ESRD before the age of 60
What are the genetics of ADPKD?
Mutations in PKD1 and/or PKD2, which encode membrane proteins called polycystins (PC1 and 2)
Homozygotes are lethal
Heterozygotes are likely affected by a “second hit” somatic mutation, leading to a loss of normal haplotype at tissue level
Trans-heterozygoes have a more severe clinical course- have mutations in both genes
What do PC1 and PC2 do?
Form the polycystin complex in ADPKD: the c-termini of PC1 and 2 bind and they form a complex
They live on motile cilia, in different parts of the body including the renal epithelium
They sense flow (in kidney: urinary flow) –> disrupted planar polarity –> cyst formation
Also you get increased rate of epithelial proliferation & increased fluid secretion
What are the common renal complications of ADPKD?
Hypertension
Flank/abdominal pain
Macroscopic hematuria: cyst hemorrhage, contact sports
Fever and abdominal pain: cyst infection
Kidney stones: stagnant urinary flow
Low-grade proteinuria: tubular dysfunction
Polyuria: decreased renal concentrating ability
Progressive decline in GFR: 50% at ESRD by age 60
What are the extrarenal complications of ADPKD?
Liver: hepatic cysts
Heart: PFO, mitral valve prolaps
GI: colonic diverticula
Subcutaneous, ovarian, testicular, pancreatic, and pulmonary cysts
Cerebral anuerysms: rare but letha; screen for those with positive fam hist for stroke or aneurysm or new onset severe headache; treat with enurysm coiling or clipping
Aortic aneurysms
How do you diagnose ADPKD?
Based on fam hist and imaging studies
Detectible cysts > 1cm in size via MRI and CT- more sensitive
In adults with + fam history, diagnostic criteria include:
Age < 30, at least 2 cysts
Age 30-60: at least 2 cysts in each kidney (bilateral)
Age >60: at least 4 cysts in each kidney
How do you treat renal complications of ADCKD?
Hypertension: salt restriction, ACEI or ARB to preserve renal function
Hematuria: due to intra-parenchymal or cyst hemorrhage; bed rest, analgesics, and hydration to increase the urinary flow to 2-3 L/day
Cyst infections: typically require hospital admission & iv abx; fluooroquinolones have good intra-cyst penetration
Renal stones: treatment similar to pt’s without ADPKD
Flank pain: acute pain - renal infx, cyst hemorrhage, renal stones
chronic pain: distention of kidney capsule or compression of abd structures
What’s the progression of ADPKD?
What’ss predictive of rate of progression?
Start with concentrating defect, htn, proteinurea
Progress to pain, hematuria, stones, infections
PKD2 have milder dz course and longer renal survival
Kidney volume is predictive of subsequent rate of progression
What is autosomal recessive PKD?
Childhood nephropathy
Affected children often present in utero with enlarged echogenic (light) kidneys and oligohydraminos secondary to poor urine output (Potter syndrome)
30% of affected neonates die shortly after birth as a result of severe pulm hydoplasia and resp insufficiency
Those who survive the perinatal period most commonly present with systemic htn, renal insufficiency, and portal htn
Potter syndrome
Renal failure in utero –> oligohydraminos= low volume of amniotic fluid –>
IUGR
Characteristic facial features
Lung hypoplasia (resp failure)
What is the molecular defect in ARPKD?
PKHD1 gene = fibrocystin, which is also on the cilia of the collecting duct
Bilary dysgenesis, portal htn, liver failure
Large echogenic kidneys, renal cysts, renal failure
What is Nephronophthisis?
Most frequent genetic cause of ESRD in children; usually ESRD by age 13
Initial sx are mild, start at approx age 6 yr, consist of polyuria, polydipsia, secondary enuresis & anemia
Renal US is useful only in advanced dz when you can see cysts
Renal histology = traid of corticomedullary cysts, tubular BM disruption, and tubulointerstitial fibrosis
** biopsy required for diagnosis
Most frequent extra-renal involvement includes:
Eye: retinitis pigmentosa
Brain: cerebellar vermis aplasia
Liver: liver fibrosis
What is the genetic mutation for NPHP?
Many different genes- lots of heterogeneity
They are all ciliary proteins
WHat is MCKD?
Medullary cystic kidney dz
Pathologically indistinguishable from NPHP but adult onset and AD mode of inheritance
- biopsy: tubule fibrosis, dilation, and TBM disruption
Renal manifestations are similar to NPHP: impairment of urine concentration ability & polyuria, absent or minimal proteinuria, no hematuria, RUSG with normal/small echogenic kidneys, no visible cysts
Extrarenal manifestations of hyperuricemia & gout (decreased uric acid excretion, low FeUA); no liver manifestations
What is the mutation in MCKD?
MCKD1 or MCKD2 = mucin 1 or muromodulin
Makes Uromodulin = a protein that’s normally produced by tubules, secreted in the urine, and cleared
Mutation –> altered uromodulin folding can’t seceret the protein –> trapping in the ER –> tubular epithelial damage –> interstitial fibrosis, defect in uric acid excretion, defect in urinary concentration
