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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=William J Gibson (reviewed by {{Rim}})
|QuestionAuthor=William J Gibson (Reviewed by {{YD}} and {{Rim}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Genetics
|MainCategory=Genetics
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|MainCategory=Genetics
|MainCategory=Genetics
|SubCategory=Renal
|SubCategory=Renal
|MainCategory=Genetics
|MainCategory=Genetics
|MainCategory=Genetics
|MainCategory=Genetics
|MainCategory=Genetics
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|MainCategory=Genetics
|MainCategory=Genetics
|SubCategory=Renal
|SubCategory=Renal
|Prompt=A 40 year old woman with a history of recurrent urinary tract infections presents to her primary care physician with the gradual onset of increasing fatigue, swelling in her feet, and anorexia. She reports flank pain, and a recent decrease in urine volume. On examination, her vital signs are: blood pressure of 145/110, pulse rate of 76 beats/min, and temperature of 37.2 °C (98.9 F). Physical exam is remarkable for bilateral solid masses that can be palpated during abdominal examination. Tapping the lower back elicits sharp pain. Laboratory studies are significant for a creatinine of 2.3 mg/dL, and BUN of 20 mmol/L. Which of the following is most likely true regarding this patient’s condition?
|Prompt=A 48-year-old woman presents to her primary care physician with the gradual onset of increasing fatigue, swelling in her feet, and anorexia. Recently, she also noticed her urine color was darker and she was having an unusual flank 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 blood pressure is 155/110, heart rate is 76/min, and temperature is 37.2 °C (98.9 °F). Physical examination is remarkable for bilateral solid masses that can be palpated during abdominal examination. Light tapping of the back elicits sharp pain at both sides. Laboratory studies are significant for hemoglobin of 9.8 g/dL, 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?
|Explanation=The onset of symptoms suggesting [[renal failure]] and bilateral abdominal masses strongly suggests the diagnosis of [[autosomal dominant polycystic kidney disease]] in this patient.  Approximately 50% of people with this disease will develop end stage kidney disease and require [[dialysis]] or [[kidney transplantation]]. Progression to end stage kidney disease usually happens in the 4th to 6th decades of life. [[Autosomal dominant polycystic kidney disease]] affects about 1 in 400 to 1 in 1000 people.
|Explanation=The onset of symptoms suggesting [[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% 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. [[Autosomal dominant polycystic kidney disease]] affects about 1 in 400 to 1 in 1000 people. Although ADPKD begins in utero, the morphological appearance of the kidneys remains normal, and patients remain asymptomatic until adulthood. 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 ''PKD1'' than ''PKD2''.


Defects in two genes are thought to be responsible for ADPKD. In 85% of patients, ADPKD is caused by mutations in the gene PKD1 on chromosome 16 (TRPP1); in 15% of patients mutations in PKD2 (TRPP2) are causative. The median age at which patients develop [[renal failure]] is 54 for PKD1 patients and 78 for PKD2 patients. Because PKD1 is more common generally, and this woman is presenting with signs of [[renal failure]] at age 40, it is far more likely that she has PKD1 than PKD2. The defective gene in ADPKD1 is thought to encode a cellular membrane protein involved in assembly of the [[cilium]].
Defects in 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 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. 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. Polycystins also 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. Defect of ciliary flow response is believed to result in formation of abnormal cysts observed in ADPKD.


While there are no FDA approved drugs for PKD, recent studies have showed that the vasopressin antagonist [[tolvaptan]] is able to slow the progression of the disease. Patients are often initiated on [[ACE inhibitors]] to decrease [[hypertension]] resulting from renal dysfunction. Patients who have developed [[renal failure]] must undergo [[hemodialysis]] or [[kidney transplantation]].
ADPKD is also associated with the development of cysts in the liver, pancreas, and other organs. Addtionally, 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.
|AnswerA=Caused by a defect in a calcium channel gene
 
|AnswerAExp=ADPKD2 is caused by defects in a [[calcium channel]] gene. ADPKD2 has a later onset and is rarer than ADPKD1 mutations.
While there are no FDA approved drugs specific 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 signs of volume overload are present, patients should follow a low salt diet and are 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 the volume overload. Ultimately, patients with [[ESRD]] undergo [[hemodialysis]] or [[kidney transplantation]].
|AnswerB=Caused by a defect in the assembly of the cilium
|AnswerA=Caused by a defect in a gene that encodes sodium-permeable ion channel complex
|AnswerBExp=This patient's form of [[autosomal dominant polycystic kidney disease]] is caused by ADPKD1 mutations. ADPKD1 is thought to encode a cellular membrane protein involved in assembly of the [[cilium]].
|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.
|AnswerB=Caused by a defect of cilium flow response
|AnswerBExp=Polycystins, which are the defect proteins among patients with ADPKD, normally function to regulate cell cycle and function of the renal primary (immotile) cilium.
|AnswerC=Caused by autoantibodies against glomerular basement membrane
|AnswerC=Caused by autoantibodies against glomerular basement membrane
|AnswerCExp=[[Goodpasture's disease]] is caused by [[autoantibodies]] against [[glomerular basement membrane]] which would not cause renal masses.
|AnswerCExp=[[Goodpasture's disease]] is caused by [[autoantibodies]] against [[glomerular basement membrane]] which do not usually causerenal masses.
|AnswerD=Transmitted in an autosomal recessive fashion
|AnswerD=Caused by an a mutant gene located on chromosome 18
|AnswerDExp=[[Autosomal dominant polycystic kidney disease]] follows an [[autosomal dominant]] pattern of inheritance. There is an [[autosomal recessive]] variant of polycystic kidney disease, but this variant leads to very severe early presenting disease.  Enlarged kidneys can be detected at birth and 50% of neonates die of [[pulmonary hypoplasia]] due to [[oligohydramnios]] from [[renal failure]]. It is far more likely that the patient in this vignette has ADPKD type I.
|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.
|AnswerE=Associated with abdominal aortic aneurysms
|AnswerE=Associated with hepatic cysts that are more massive in men than in women
|AnswerEExp=While a relationship between ADPKD and [[abdominal aortic aneurysm]]s has been proposed, a study of 139 patients failed to detect any increased risk of [[abdominal aortic aneurysm]]s (Torra et al). Instead, [[ADPKD]] is associated with cerebral [[berry aneurysm]]s.  The incidence of these aneurysms climbs to greater than 20 percent for patients aged 60 years and above.
|AnswerEExp=Although hepatic cysts are associated with ADPKD, women tend to have massive cystic enlargement of the liver due to the role estrogen plays in accentuating the growth of these cysts.
|EducationalObjectives=The most common and more severe form of [[autosomal dominant polycystic kidney disease]] is caused by mutations in a cellular membrane protein involved in assembly of the [[cilium]].
|EducationalObjectives=[[Autosomal dominant polycystic kidney disease]] is caused by mutations of ''PKD1'' (chromosome 16) and ''PKD2'' (chromosome 4) that encode polycystins. Polycystins play a role in the regulation of primary (immotile) ciliary response to flow signals from the renal tubular lumen by forming a calcium-permeable ion channel complex.
|References=First Aid 2014 page 87, Torra R, Nicolau C, Badenas C, et al. Abdominal aortic aneurysms and autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1996; 7:2483; Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407-18.
|References=Torra R, Nicolau C, Badenas C, et al. Abdominal aortic aneurysms and autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1996; 7:2483
 
Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407-18.
 
Grantham JJ. Autosomal dominant polycystic kidney disease. N Engl J Med. 2008; 359:1477-85
 
Yoder BK. Role of primary cilia in the pathogenesis of polycystic kidney disease. J Am Soc Nephrol. 2007; 18:1381-8
 
First Aid 2014 page 87
|RightAnswer=B
|RightAnswer=B
|WBRKeyword=ADPKD, Autosomal dominant, Kidney, Renal, Polycystic kidney disease,
|WBRKeyword=ADPKD, Autosomal dominant polycystic kidney disease, autosomal, dominant, autosomal dominant, Kidney, polycystin, polycystins, cilium, cilia, primary cilium, primary cilia, pathogenesis, renal, Polycystic kidney disease,
|Approved=Yes
|Approved=Yes
}}
}}

Revision as of 16:16, 4 September 2014
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 the gradual onset of increasing fatigue, swelling in her feet, and anorexia. Recently, she also noticed her urine color was darker and she was having an unusual flank 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 blood pressure is 155/110, heart rate is 76/min, and temperature is 37.2 °C (98.9 °F). Physical examination is remarkable for bilateral solid masses that can be palpated during abdominal examination. Light tapping of the back elicits sharp pain at both sides. Laboratory studies are significant for hemoglobin of 9.8 g/dL, 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, normally function to regulate cell cycle and function of the 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 causerenal masses.]]
Answer D AnswerD::Caused by an 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 estrogen plays in accentuating the growth of these cysts.
Right Answer RightAnswer::B
Explanation [[Explanation::The onset of symptoms suggesting 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% 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. Autosomal dominant polycystic kidney disease affects about 1 in 400 to 1 in 1000 people. Although ADPKD begins in utero, the morphological appearance of the kidneys remains normal, and patients remain asymptomatic until adulthood. 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 PKD1 than PKD2.

Defects in 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 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. 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. Polycystins also 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. Defect of ciliary flow response is believed to result in formation of abnormal cysts observed in ADPKD.

ADPKD is also associated with the development of cysts in the liver, pancreas, and other organs. Addtionally, 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 specific 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 signs of volume overload are present, patients should follow a low salt diet and are 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 the volume overload. Ultimately, patients with ESRD undergo hemodialysis or kidney transplantation.
Educational Objective: Autosomal dominant polycystic kidney disease is caused by mutations of PKD1 (chromosome 16) and PKD2 (chromosome 4) that encode polycystins. Polycystins play a role in the regulation of primary (immotile) ciliary response to flow signals from the renal tubular lumen by forming a calcium-permeable ion channel complex.
References: Torra R, Nicolau C, Badenas C, et al. Abdominal aortic aneurysms and autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1996; 7:2483

Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407-18.

Grantham JJ. Autosomal dominant polycystic kidney disease. N Engl J Med. 2008; 359:1477-85

Yoder BK. Role of primary cilia in the pathogenesis of polycystic kidney disease. J Am Soc Nephrol. 2007; 18:1381-8

First Aid 2014 page 87]]

Approved Approved::Yes
Keyword WBRKeyword::ADPKD, WBRKeyword::Autosomal dominant polycystic kidney disease, WBRKeyword::autosomal, WBRKeyword::dominant, WBRKeyword::autosomal dominant, WBRKeyword::Kidney, WBRKeyword::polycystin, WBRKeyword::polycystins, WBRKeyword::cilium, WBRKeyword::cilia, WBRKeyword::primary cilium, WBRKeyword::primary cilia, WBRKeyword::pathogenesis, WBRKeyword::renal, WBRKeyword::Polycystic kidney disease
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