Polycystic Kidney Disease

what is the most common inherited form of kidney failure?

autosomal dominant polycystic kidney disease (ADPKD)

what is the incidence of autosomal dominant polycystic kidney disease (ADPKD)?

1 in 400 to 1 in 1000 live births

what is autosomal dominant polycystic kidney disease (ADPKD) cause by?

pathogenic variants in either of two genes PKD1 (77% cases) and PKD2 (15% cases)

what are characteristics of PKD1 and why might this cause challenges of PKD1 sequencing?

-GC rich

-has at least 6 nearly identical pseudogenes (with high sequence homology of PKD1 exons 1-32) also on chromosome 16

what are new gene variants that may present similar to autosomal dominant polycystic kidney disease (ADPKD), with bilateral polycystic kidneys but with a variable kidney disease course?

GANAB, DNAJB11, ALG9, and HNF1B

what is used to distinguish classical autosomal dominant polycystic kidney disease (ADPKD) due to PKD1 or PKD2 from these phenocopy genes?

clinical and radiological assessment

which is more severe: PKD1 or PKD2?

-PKD1 related kidney disease is more severe than that of PKD2 (genetic influence)

-develop end stage kidney disease at an average of 54 years, compared to 74 years for PKD2

-among individuals with altered PKD1 alleles, those with truncating variants tend to have more severe disease than those with missense alterations (allelic influence)

what does PKD1 encode?

polycystin 1, a transmembrane receptor like protein of unknown function

what does PKD2 encode?

polycystin 2, an integral membrane protein with homology to the transient receptor potential (TRP) family of ion channels

what do polycystins 1 and 2 interact as?

interact as part of heteromultimeric complex in the primary cilium, endoplasmic reticulum, exosomes, and the plasma membrane

what is a key consequence of polycystin loss?

metabolic reprogramming

what is one hypothesis of how polycystin loss occurs?

polycystin complex in the primary cilium restrains a proproliferative pathway and that inhibition is released upon loss of polycystin signaling or in the absence of cilia

what does cyst formation in autosomal dominant polycystic kidney disease (ADPKD) appear to follow?

-"two-hit" mechanisms, similar to that observed with tumor suppressor genes and neoplasia

-despite heterozygous inheritance of the pathogenic allele, somatic hits in the alternate allele result in clonal expansion of a renal tubular epithelial cell with consequent cystic transformation of kidney tubules

what does each renal epithelial cell contain as a result of the two-hit mechanism?

contains a unique combination of germ line and somatic variants, resulting in reduced polycystin signaling

how is autosomal dominant polycystic kidney disease (ADPKD) diagnosed?

family history and renal ultrasound examination

what is detected by age 20 in individuals with autosomal dominant polycystic kidney disease (ADPKD)?

80-90% of individuals have detectable cysts and by 30 nearly 100% have them

for what variant is ultrasound-based imaging most validated for in patients with autosomal dominant polycystic kidney disease (ADPKD)?

most validated for PKD1 and less reliable with PKD2-associated milder phenotype

what can ADPKD be confirmed by during prenatal diagnosis or identification?

can be confirmed by sequencing in most families

what does the management of autosomal dominant polycystic kidney disease (ADPKD) focus on?

slowing the progression of renal disease and minimizing its symptoms

what symptoms are treated aggressively in autosomal dominant polycystic kidney disease (ADPKD) to preserve renal function?

hypertension and UTI

how might pain from the mass effect of the enlarged kidney sometime be managed by?

drainage and sclerosis of the cysts

what might individuals with large kidney at risk for?

more rapid decline in renal function

what is a useful predictive marker of kidney disease progression?

total kidney volume

what medication is used in select patients 18+ at risk for rapid ADPKD progression?

Tolvaptan (a vasopressin V2-receptor antagonist)

when might molecular genetic confirmation be consdiered?

1. atypical clinical presentation, especially in the absence of family history

2. preconception and prenatal genetic counseling

3. assessing treatment candidacy with specific therapies or clinical trials

4. screening for a living related kidney donor

what is the risk (%) does each offspring of an individual with ADPKD?

50% risk of being affected

what percentage is sporadic mutation cases in autosomal dominant polycystic kidney disease (ADPKD)?

10-15% of cases

what does severity of ADPKD in individuals with de novo mutations depend on?

-de novo variants can be a mosaic of normal and variant cells

-contribution of variant cells correlated with disease severity

~1% of cases

what is the risk for parents of a child with disease onset in utero having a subsequent child that will be severely affected?

approximately 25%

what kind of mutation can result in very early onset ADPKD?

-biallelic inheritance of partially functional PKD1 pathogenic alleles

-usually manifests in homozygotes or compound heterozygotes as large kidneys with multiple cysts, or as diffusely ecogenic kidneys, mimicking the autosomal recessive form of polycystic kidney disease

what is histopathology of this very early onset ADPKD consistent with?

glomerulocytic kidney disease

what is digenic inheritance in autosomal dominant polycystic kidney disease (ADPKD)?

-the combination of heterozygous variants in two genes, such as PKD1 or 2 and HBF1B or PKHD1 (the gene causing an autoosmal recessive form of polycystic kidney diseaase

-may also lead to very early onset of the disease

what preculed prediction of the severity of autosomal dominant polycystic kidney disease (ADPKD)?

variable expressivity