Polycystic Kidney Disease, Adult


Article Author:
Nancy Finnigan


Article Editor:
Stephen Leslie


Editors In Chief:
Jon Parham
Jon Sivoravong


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
2/3/2019 2:37:15 PM

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder of the kidneys characterized by markedly enlarged kidneys with extensive cyst formation throughout. [1] These cysts progressively enlarge with age, as kidney function gradually declines. The diagnosis of ADPKD is based on family history and ultrasonographic evaluation. In as many as 25% of patients with ADPKD, no family history is identified, which may be related to subclinical disease or a new genetic mutation in about 5% of cases. Patients with ADPKD typically progress to end-stage renal disease (ESRD) by the fifth or sixth decade of life. The rate of progression of ADPKD is related directly to kidney volume.  Therapies aim to slow the decline in renal volume to delay progression.[2][3][4]

Screening family members for ADPKD has been controversial in the past. Prior to 2017, due to the lack of therapy to prevent progression to ESRD, screening of asymptomatic family members has not been routinely performed. With the addition of tolvaptan as a treatment option, early screening of young adults at risk for the disease would provide the opportunity for early treatment.

Etiology

ADPKD is due to an abnormality on chromosome 16 (PKD1 locus) or chromosome 4 (PKD2 locus). PKD1 mutations comprise about 78% of ADPKD cases, while PKD2 mutations comprise about 14% of cases. The remaining cases have no identifiable mutations. PKD1 patients tend to progress to ESRD at an earlier age than PKD2 patients (mean age 54.3 versus 74.0).

Epidemiology

ADPKD occurs in approximately 1 in every 1000 births, with a global prevalence of 10 per 10,000. As many cases have a benign prognosis, it is likely that less than half of these patients are ever diagnosed.

Pathophysiology

The PKD1 and PKD2 genes encode the proteins polycystin-1 and polycystin-2, respectively. These polycystins are integral membrane proteins and are found in renal tubular epithelia. It is postulated that abnormalities in polycystin-1 impair cell-cell and cell-matrix interactions in the renal tubular epithelia, while abnormalities in polycystin-2 impair calcium signaling in the cells.[5][6][7]

The resultant changes in renal pathophysiology include hematuria (often gross), a concentrating defect (resulting in polyuria and increased thirst), mild proteinuria, nephrolithiasis (in about 25% of ADPKD patients), flank pain, and abdominal pain. Cyst rupture, hemorrhage, and infection are common complications. Progressive renal decline often results in end-stage renal disease.

Histopathology

The diagnosis of ADPKD is based on ultrasonographic criteria in patients with a positive family history. Routine biopsies for microscopic examinations are not performed.

History and Physical

Patients with ADPKD may present with a variety of medical conditions, including hypertension, flank pain, abdominal masses, urinary tract infections, renal failure, nephrolithiasis, and cerebrovascular accidents. Hypertension is the most prevalent initial clinical presentation, occurring in 50% to 70% of cases, and is the most common feature directly associated with the rate of decline to ESRD and cardiovascular complications.

Multiple extra-renal manifestations are often present. Cerebral aneurysms occur in about 5% of young adults, and as many as 20% of patients over the age of 60. The risk of a cerebral aneurysm or subarachnoid hemorrhage is highest in patients with a family history of the same.

Extrarenal cysts are common in ADPKD. Hepatic cysts are often noted in these patients, and the prevalence increases with age. As many as 94% of patients over the age of 35 have been reported to have hepatic cysts. Total cyst prevalence and volume is higher in women versus men. Hepatic cysts in ADPKD patients rarely cause liver dysfunction. Rarely, patients develop pain from an acute cyst infection or hemorrhage.  In addition, about 7% to 36% of ADPKD patients develop pancreatic cysts, with a higher prevalence in ADPKD patients with PKD2 mutations.

Cardiac valvular disease has been noted in 25% to 30% of ADPKD patients. Cardiovascular complications, particularly cardiac hypertrophy and coronary artery disease, are the leading causes of death in patients with ADPKD.

Additional complications include colonic diverticula, which are noted in ADPKD patients requiring maintenance dialysis. Abdominal wall hernias are noted in as many as 45% of ADPKD patients, likely related to additional abdominal girth related to increased kidney size.

Evaluation

The diagnosis of ADPKD is made based on ultrasonographic criteria. The criteria for ultrasonographic diagnosis of individuals with a positive family history with unknown genotype (as is usually the case) is as follows:

  • In patients ages 15 to 39 years, at least three unilateral or bilateral renal cysts
  • In patients ages 40 to 59 years, at least two cysts in each kidney
  • In patients age 60 years or older, at least four cysts in each kidney

While ultrasound is the only study required to make a definitive diagnosis, patients are routinely evaluated with a basic metabolic profile and urinalysis to determine the extent of any renal insufficiency.

Treatment / Management

Early management of hypertension is pivotal in reducing cardiovascular mortality, the incidence of left ventricular hypertrophy, mitral regurgitation, and to slow the progression of renal failure. While the target blood pressure in ADPKD patients has yet to be established, the HALT-PKD Study A noted that in early stages of ADPKD with preserved renal function, blood pressure management with systolic blood pressure less than 110 mmHg was strongly associated with significant reductions in the rate of total kidney volume growth, albuminuria, and left ventricular mass index. ACE inhibitors and ARBs are the mainstays of therapy, with beta-blockade and calcium-channel blockers as second-line therapy. As third-line therapy, thiazides are preferred in patients with normal renal function, while loop diuretics are preferred in patients with impaired renal function.[8][9][10][11]

Screening for a cerebral aneurysm is recommended at the time of ADPKD diagnosis in patients that are high risk (those with a family history of an aneurysm or intracranial hemorrhage in a first-degree relative).

Smoking cessation and hypertension management are most prudent, as smoking and high blood pressure increase the risk of a cerebral aneurysm. Of note, RAS blockade and statin use decrease the cerebral aneurysm rate.

Tolvaptan has demonstrated a slower decline than placebo in the eGFR over a one year period in patients with late-stage chronic kidney disease but is associated with elevations of bilirubin and alanine aminotransferase levels.

Multiple additional therapies have been studied in the effort to prevent progression of ADPKD. Dietary sodium restriction, which was part of the HALT-PKD trial, was shown to possibly reduce renal progression, as sodium excretion was associated with an increased risk of kidney growth and eGFR decline.

Statins have shown some benefit in all-cause chronic kidney disease and have suggested benefit in ADPKD patients.  Statins are deployed in chronic kidney disease patients as progressive renal failure is a coronary heart disease equivalent.

Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been studied but have not shown any benefit on renal outcomes.  Diuretics, such as amiloride, have also been tried to decrease cyst volume without measurable improvement in renal function. Protein restriction has provided variable results.  

Octreotide has also been studied in ADPKD and has shown a non-significant slowing of renal function decline with possible attenuation of the effect after 2 years.[12][13]

Differential Diagnosis

The differential diagnosis of renal cysts in adults includes several conditions, including simple renal cysts, complex renal cysts, localized cystic disease, malignancy, and acquired cystic disease of the kidney. It is important to distinguish disorders that may have a malignant potential, such as complex cysts, acquired the cystic disease, and underlying malignancy. A defining feature of ADPKD is marked bilateral, renal enlargement.

Prognosis

ADPKD patients reach ESRD, on average, in the fifth or sixth decade of life. ADPKD accounts for about 10% of all ESRD cases. Patients with hypertension and larger kidney size tend to have a worse prognosis. A family history of the disease may be predictive of the specific mutation and predictive of the patient's course.

Pearls and Other Issues

Autosomal dominant polycystic kidney disease often presents in young adults and is responsible for about 10% of all ESRD cases. Early intervention with optimal blood pressure management along with emerging medical therapies such as tolvaptan are the mainstays of treatment. 

Enhancing Healthcare Team Outcomes

The management of patients with ADPKD is with a multidisciplinary team. The key to management is the control of blood pressure and slow down the progression towards end stage renal disease. Healthcare workers who follow these patients should closely monitor the blood pressure and renal function at regular intervals. 

ACE inhibitors and ARBs are the mainstays of therapy, with beta-blockade and calcium-channel blockers as second-line therapy. As third-line therapy, thiazides are preferred in patients with normal renal function, while loop diuretics are preferred in patients with impaired renal function.

These patients also need to be screened for a cerebral aneurysm. Patients should be urged to quit smoking and remain compliant with their antihypertensive medications.

Multiple additional therapies have been studied in the effort to prevent the progression of ADPKD. Dietary sodium restriction, which was part of the HALT-PKD trial, was shown to possibly reduce renal progression, as sodium excretion was associated with an increased risk of kidney growth and eGFR decline.

Statins have shown some benefit in all-cause chronic kidney disease and have suggested benefit in ADPKD patients.  Statins are deployed in chronic kidney disease patients as progressive renal failure is a coronary heart disease equivalent.

For patients who fail to control their blood pressure, the prognosis is poor. (Level V)

 


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Polycystic Kidney Disease, Adult - Questions

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A 44-year-old African American male with a family history of kidney disease presents with leg swelling. He has a blood pressure of 174/99 mmHg, a laterally displaced point of maximal impulse, peripheral edema, and palpable flank masses bilaterally. Blood work reveals a creatinine of 2.8 mg/dL. A urinalysis shows 22 to 28 red blood cells/high power field and trace protein. What is the most likely diagnosis?



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A patient has adult polycystic kidney disease but no family history of stroke or intracranial aneurysms. The patient works as a secretary. What screening should be done?



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Which of the following statements about adult polycystic kidney disease is incorrect?



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A 40-year-old woman with chronic headaches is found to have an asymptomatic aneurysm of the middle cerebral artery. It is successfully clipped. Her family history is remarkable in that her mother died suddenly at age 48 and her younger sister had a subarachnoid hemorrhage secondary to an aneurysm. What study should be done on this patient?



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Which of the following statements is true about adult polycystic kidney disease?



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A 38-year-old male presents with severe flank pain and vomiting. On exam, he is clearly uncomfortable, pacing about the room and retching. Vital signs are blood pressure 140/85 mmHg, heart rate 120 beats/min, temperature 98.8 F. The physical exam reveals no abdominal tenderness but significant flank tenderness. Urine dipstick analysis for blood is "large." What is seen on the ultrasound below?

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Attributed To: Contributed by Dr. Michael Lambert



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Which of the following are not associated with autosomal dominant polycystic kidney disease?



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A 26-year old presents with vague abdominal and back pain of several month duration. Last week he also had an episode of hematuria which resolved in a day. His physical exam is unremarkable. He was seen in the emergency department a few days ago, and a CT scan was ordered which is shown below. What is the likely diagnosis?

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A 26-year old presents with vague abdominal and back pain of several months in duration. Last week he also had an episode of hematuria which resolved in a day. His physical exam is unremarkable. He was seen in the emergency department a few days ago and a CT scan was ordered which is shown below. Which of the following findings would be unusual in this patient?

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A young patient presents with long-standing pain in his flank and buttocks area. He recently had an episode of hematuria and had a CT scan of the abdomen which is shown. He was adopted and thus is not able to provide any details about his family history. His past history reveals he has had mild hypertension for about 3 months, which has been controlled with enalapril. After review of the CT scan of the abdomen, what other study may be of value in this patient?

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A 45-year-old man presents with abnormal renal function. Ultrasound imaging shows bilaterally enlarged kidneys with multiple cysts of varying size with the largest measuring 3.5 cm. Few of cysts showed calcified stone and sludge. What is the most likely diagnosis?



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Polycystic Kidney Disease, Adult - References

References

Cho Y,Sautenet B,Gutman T,Rangan G,Craig JC,Ong AC,Chapman A,Ahn C,Coolican H,Kao JT,Gansevoort R,Perrone RD,Harris T,Torres V,Pei Y,Kerr PG,Ryan J,Johnson DW,Viecelli AK,Geneste C,Kim H,Kim Y,Oh YK,Teixeira-Pinto A,Logeman C,Howell M,Ju A,Manera KE,Tong A, Identifying patient-important outcomes in polycystic kidney disease: an international nominal group technique study. Nephrology (Carlton, Vic.). 2019 Jan 20;     [PubMed]
Zhang M,Srichai MB,Zhao M,Chen J,Davis LS,Wu G,Breyer MD,Hao CM, Nonselective Cyclooxygenase Inhibition Retards Cyst Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease. International journal of medical sciences. 2019;     [PubMed]
AlNuaimi D,AlKetbi R,AlFalahi A,AlBastaki U,Pierre-Jerome C, Ruptured Berry Aneurysm as the initial presentation of Polycystic Kidney Disease: A case report and review of literature. Journal of radiology case reports. 2018 Sep;     [PubMed]
Pandita S,Khullar D,Saxena R,Verma IC, Autosomal Dominant Polycystic Kidney Disease: Presence of Hypomorphic Alleles in {i}PKD1{/i} Gene. Indian journal of nephrology. 2018 Nov-Dec;     [PubMed]
Malekshahabi T,Khoshdel Rad N,Serra AL,Moghadasali R, Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions. Journal of cellular physiology. 2019 Jan 15;     [PubMed]
Lee JJ,Cheng SJ,Huang CY,Chen CY,Feng L,Hwang DY,Kamp TJ,Chen HC,Hsieh PCH, Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytes. EBioMedicine. 2019 Jan 11;     [PubMed]
Lanke S,Shoaf SE, Population Pharmacokinetic Analyses and Model Validation of Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease. Journal of clinical pharmacology. 2019 Jan 7;     [PubMed]
Arogundade FA,Akinbodewa AA,Sanusi AA,Okunola O,Hassan MO,Akinsola A, Clinical presentation and outcome of autosomal dominant polycystic kidney disease in Nigeria. African health sciences. 2018 Sep;     [PubMed]
Müller RU,Benzing T, Management of autosomal-dominant polycystic kidney disease-state-of-the-art. Clinical kidney journal. 2018 Dec;     [PubMed]
Smith KA,Thompson AM,Baron DA,Broadbent ST,Lundstrom GH,Perrone RD, Addressing the Need for Clinical Trial End Points in Autosomal Dominant Polycystic Kidney Disease: A Report From the Polycystic Kidney Disease Outcomes Consortium (PKDOC). American journal of kidney diseases : the official journal of the National Kidney Foundation. 2018 Dec 29;     [PubMed]
Weimbs T,Shillingford JM,Torres J,Kruger SL,Bourgeois BC, Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease. Clinical kidney journal. 2018 Dec;     [PubMed]
Messchendorp AL,Spithoven EM,Casteleijn NF,Dam WA,van den Born J,Tonnis WF,Gaillard CAJM,Meijer E, Association of plasma somatostatin with disease severity and progression in patients with autosomal dominant polycystic kidney disease. BMC nephrology. 2018 Dec 19;     [PubMed]
Bergmann C,Guay-Woodford LM,Harris PC,Horie S,Peters DJM,Torres VE, Polycystic kidney disease. Nature reviews. Disease primers. 2018 Dec 6;     [PubMed]

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