WBR0104
| Author | [[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D. and Rim Halaby, M.D. [1])]] |
|---|---|
| Exam Type | ExamType::USMLE Step 1 |
| Main Category | MainCategory::Genetics |
| Sub Category | SubCategory::Renal |
| Prompt | [[Prompt::A 48-year-old woman presents to her primary care physician with a gradual onset of increasing fatigue, swelling in her feet, and anorexia. Recently, she has also been noticing her urine color is darker, and she is having an unusual back pain. The patient's past medical history is only significant for appendectomy and cesarean section. She denies smoking, alcohol intake, or use of illicit drugs. Her father is a renal transplant recipient and her paternal uncle is currently on hemodialysis. In the clinic, her temperature is 37.2 °C (98.9 °F), her blood pressure is 155/110 mmHg, and her heart rate is 76/min. Physical examination is remarkable for bilateral solid masses that can be palpated during abdominal examination. Light tapping of the back elicits sharp pain on both sides. Laboratory studies are significant for hemoglobin count of 9.8 g/dL, serum creatinine of 2.3 mg/dL, and BUN of 20 mmol/L. Urinalysis is remarkable for 500+ RBC/hpf. Which of the following is most likely true regarding this patient’s condition?]] |
| Answer A | AnswerA::Caused by a defect in a gene that encodes sodium-permeable ion channel complex |
| Answer A Explanation | AnswerAExp::ADPKD is caused by mutations of ''PKD1'' and ''PKD2'' genes that encode for polycystins. These proteins form a calcium-permeable ion channel complex. There is no role for sodium channels in the early pathophysiology of ADPKD. |
| Answer B | AnswerB::Caused by a defect of cilium flow response |
| Answer B Explanation | AnswerBExp::Polycystins, which are the defect proteins among patients with ADPKD, regulate the cell cycle and the function of renal primary (immotile) cilium. |
| Answer C | AnswerC::Caused by autoantibodies against glomerular basement membrane |
| Answer C Explanation | [[AnswerCExp::Goodpasture's disease is caused by autoantibodies against glomerular basement membrane which do not usually cause renal masses.]] |
| Answer D | AnswerD::Caused by a mutant gene located on chromosome 18 |
| Answer D Explanation | [[AnswerDExp::Autosomal dominant polycystic kidney disease is caused by a defect of PKD1 gene located on chromosome 16. Less commonly, PKD2 gene mutation leads to late-onset ADPKD (median age of 69 years). PKD2 is located on chromosome 4.]] |
| Answer E | AnswerE::Associated with hepatic cysts that are more massive in men than in women |
| Answer E Explanation | AnswerEExp::Although hepatic cysts are associated with ADPKD, women tend to have massive cystic enlargement of the liver due to the role that estrogen plays in accentuating the growth of these cysts. |
| Right Answer | RightAnswer::B |
| Explanation | [[Explanation::The onset of renal failure, bilateral abdominal masses, and positive family history strongly suggest the diagnosis of autosomal dominant polycystic kidney disease (ADPKD) in this patient. ADPKD is characterized by the presence of bilateral renal fluid-filled cysts that are susceptible to blood and pyogenic collections following trauma and infections. Approximately 50% of individuals with ADPKD will develop end stage renal disease (ESRD) and require dialysis or renal transplantation. Progression to ESRD usually occurs in the 4th to 6th decades of life. Although ADPKD begins in utero, the morphological appearance of the kidneys remains normal early in life; and patients are asymptomatic until adulthood.
Defects in at least two genes are thought to be responsible for ADPKD. In 85% of cases, ADPKD is caused by mutations in the gene PKD1 on chromosome 16, which encodes polycystin 1 (TRPP1); while the majority of the remaining patients have mutations in PKD2 on chromosome 4, which encodes polycystin 2 (TRPP2). Polycystin proteins play a role in the regulation and vascular development of several organs, including the kidneys. Polycystins play a crucial role in the function of primary/immotile cilia, which are microtubule-based organelles devoid of ribosomes that sense extracellular environmental stimuli from the lumen of the renal tubules. Both polycystins interact under normal conditions to increase calcium flow through its cation channel; thus when one protein is impaired, the function of the other will also be affected. Defect of ciliary flow response is believed to result in the formation of the abnormal cysts observed in patients with ADPKD. The median age at which patients develop renal failure is 53 for patients with PKD1 mutations and 69 for patients with PKD2 mutations. Because PKD1 is more common in the general population (85% of cases), and this woman is presenting with signs of renal failure at age 48, it is far more likely that she has a mutated PKD1 than PKD2. ADPKD is also associated with the development of cysts in the liver, pancreas, and other organs. Additionally, patients with ADPKD are twice more likely to develop brain aneurysms. Other associated diseases include increased susceptibility to urinary tract infections and uric acid renal stones. While there are no FDA-approved drugs for ADPKD, recent studies have shown that the vasopressin antagonist tolvaptan may be able to slow the progression of the disease. Patients with a normal renal function are often advised to drink water frequently to reduce plasma AVP and decrease urine osmolality. When high blood pressure is present, patients should follow a low salt diet and are often initiated on angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-II receptor blockers (ARBs). Many patients will eventually require other anti-hypertensive therapy, such as diuretics to relieve volume overload. Ultimately, patients with ADPKD who progress to ESRD undergo hemodialysis or kidney transplantation. |
| Approved | Approved::Yes |
| Keyword | WBRKeyword::ADPKD, WBRKeyword::Autosomal dominant polycystic kidney disease, WBRKeyword::Autosomal dominant, WBRKeyword::Polycystin, WBRKeyword::Cilia, WBRKeyword::Polycystic kidney disease, WBRKeyword::Renal failure |
| Linked Question | Linked:: |
| Order in Linked Questions | LinkedOrder:: |