Autosomal Dominant Polycystic Kidney Disease (ADPKD):
Pathogenesis,
Clinical Findings,
and Complications
Author:
Yan Yu*
Reviewers:
David Waldner*
Sean Spence*
Andrew Wade*
* MD at time of
publication
Legend: Published April 14, 2019 on www.Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications thecalgaryguide.com
One theory (mechanism unclear): these mutations in the polycystin
gene result in dysfunctional Ca2+ channels on epithelial cells
PKD1 mutation
(~78%)
Abnormal Ca2+ entry disrupts intracellular Ca2+ signaling
In the Kidney: all segments of the nephron develop cysts: sacs of flattened epithelium
filled with proteinaceous fluid, replacing normal parenchyma with dysfunctional tissue
PKD2 mutation
(~15%)
Expansive cell
proliferation
Low urine
Osmolality
(< 500 mmol/kg) Abnormally expandable basement membranes PKD3 mutation (rare) ↑ fluid secretion 95% inherited, autosomal dominant mutations 5% spontaneous mutations In adults, the same pathophysiology occurs in epithelial tissue throughout the body When pH of urine <5.5, uric acid is in its protonated form & is less soluble àprecipitates uric acid stones Nephrolithiasis Urine accumulates within cysts Cyst growth Pyelonephritis Damaged tubules leak proteins into filtrate Proteinuria Flank pain Inability to concentrate urine Low urine specific gravity (<1.010) ¯ NH3 production, ↑ acidity of renal tubule (¯ pH) Activates nociceptors Cyst hemorrhage Urine stasis à precipitation of CaOxalate stones within cysts Multiple Renal Cysts (bilaterally, in cortex and medulla, on Ultrasound) In the Brain: expansion & weakening of cerebral arterial walls “Berry Aneurysms” 9- 12% (ask about this on Family Hx!) In many organs: epithelial tissue expansion & fluid secretion In the Heart: abnormal valve collagen matrix Valve prolapse & regurgitation Liver (90%), spleen/pancreas (5-10%), thyroid (rare) cysts In seminal vesicles: Cyst formation disrupts sperm motility Infertility In GI tract: Cyst formation Herniations, diverticuli Dysfunctional collecting ducts Abdominal mass (enlarged kidneys) (may be palpable) Blood leaks into renal tubules Hematuria (isomorphic) Bacteria accumulate in the static urine Dysfunctional proximal tubules Unknown mechanisms à ¯ urine citrate àmore urine Ca2+ binds to oxalate than to citrate à↑ Ca- Oxalate stones Note: PKD1 mutations have more severe prognosis than PKD2 mutations (earlier disease onset, larger cysts) Vessels tear more easily Stretches renal capsule Cysts compress renal vasculature ¯ Glomerular perfusion To ↑ perfusion à kidneys activate RAAS Hypertension