Polycystic kidney disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2], Serge Korjian, Yazan Daaboul

Autosomal dominant polycystic kidney disease (ADPKD), previously known as adult polycystic kidney disease, is a systemic disorder characterized primarily by multiple, bilateral renal cysts, cysts in other organs namely the liver and pancreas, and cardiovascular abnormalities including intracranial aneurysms and mitral valve prolapse. ADPKD is one of the most common inherited disorders worldwide almost 15 times more common than cystic fibrosis in the general population. It accounts for up to 3-5% of ESRD cases yearly. Classically, ADPKD presents with hypertension and varying degrees of renal insufficiency. Around half of the patients diagnosed with ADPKD will reach end-stage renal disease (ESRD) by the age of 60 years. Still, disease manifestation and severity is highly variable among patients even those within the same family.

King Stephen Bathory of Poland died from polycystic kidney disease in 1586. His death began the journey of the discovery of polycystic kidney disease as a disease process. In 1888, Fe´lix Lejars first used the term polycystic kidney. In the late 18th century, Dr. Matthew Baillie noted that these cysts were vesicular and not hydatid, and named them false hydatids of kidney. In 1994, PKD1 gene mutation on chromosome 16, was first implicated in the pathogenesis of ADPKD patients.

There is no established system for the classification of polycystic kidney disease. There are 2 types of polycystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). ADPKD has two major types ADPKD1 due to PDK1 mutation, and ADPKD2 due to PDK2 mutation. A third subtype can be considered in patients without any documented mutation. Autosomal recessive polycystic kidney disease (ARPKD) was previously known as infantile polycystic kidney disease and occurs mainly in children.

The pathogenesis of ADPKD is related to the protein products of the PKD1 and PKD2 genes known collectively as polycystins. These proteins are primarily involved in ciliary function in the renal tubular cells and defects in their function leads to intracellular cAMP accumulation and mTOR overactivity causing cell proliferation, fluid secretion, and abnormal extracellular matrix and intercellular interactions the main processes that lead to cyst formation.

Polycystic kidney disease is a genetic disorder. Autosomal dominant polycystic kidney disease (ADPKD) is an autosomal dominant disorder due to the heterozygous inheritance of PKD1 (chromosome 16) or PKD2 (chromosome 4) gene mutations. Despite the disease being monogenic, phenotype is variable possibly due to a two-hit process, haploinsufficiency, or environmental factors. Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the PKHD1 gene.

Autosomal dominant and autosomal recessive polycystic kidney disease must be differentiated from other diseases that cause renal cysts, such as simple renal cysts, medullary sponge kidney, tuberous sclerosis complex, von hippel-lindau disease.

The prevalence of autosomal dominant polycystic kidney disease (ADPKD) is approximately 100 – 250 per 100,000 individuals in the United States. The prevalence of ADPKD varies in different countries. The prevalence of autosomal recessive polycystic kidney disease (ARPKD) is approximately 5 per 100,000 children in the United States. The incidence increases with age for ADPKD. ARPKD commonly affects infants and children. Males and females are equally affected by ADPKD.

There are no established risk factors for polycystic kidney disease. Since both autosomal dominant and autosomal recessive forms are genetic disorders, to review the genetic causes of polycystic kidney disease click here.

According to the Unified criteria for ultrasonographic diagnosis, screening for polycystic kidney disease by ultrasonography is recommended in at risk patients with family history of polycystic kidney disease. According to the kidney disease improving global outcomes (KDIGO), screening for polycystic kidney disease in children less than 18 years of age is not recommended. Serum creatinine, urinalysis and regular blood pressure measurements can also be implemented to test in these patients.

The earliest clinical signs of disease in patients with ADPKD include impaired renal concentrating capacity and hypertension. Other signs include flank pain, nephrolithiasis and urinary tract infections. In general half of the patients diagnosed with ADPKD will progress to ESRD by age 60. PDK1 mutants usually progress faster than PDK2 mutants. Factors associated with worse renal outcome include early age at diagnosis, male gender, uncontrolled hypertension, left ventricular hypertrophy, and cystic liver. Extra-renal manifestations in ADPKD include hepatic cysts usually more prevalent in women and with advancing age and declining renal function. Cysts can also be seen in the seminal vesicles, pancreas, and arachnoid membrane. Furthermore, the development of intracranial aneurysms can be a lethal complication in ADPKD patients whose risk is closely linked to the family history of aneurysms. Mitral valve prolapse is also a common cardiac manifestation seen in 25% of patients. Most cases of ARPKD present in the neonatal period with some disease findings detected on prenatal ultrasound. Most feared and common complication of ARPKD is pulmonary hypoplasia. Half of ARPKD patients usually progress to ESRD by age of 10. The prognosis of ARPKD improves in patients who survive the first few months of life. Survival at 15 years for patients of ARPKD ranges from 50% – 80%.

The diagnostic study of choice for polycystic kidney disease is ultrasound. Findings on an ultrasound diagnostic of polycystic kidney disease include, atleast three unilateral or bilateral cysts in patients 15 – 39 years old, atleast two cysts in each kidney in patients 40 – 59 years old, atleast four cysts in each kidney in patients 60 years of age or older.

The hallmark of polycystic kidney disease is flank or back pain. A positive family history of renal failure, cystic diseases, intracranial aneurysms is suggestive of polycystic kidney disease. The most common symptoms of polycystic kidney disease include hematuria, polyuria, nocturia and hypertension.

Patients with polycystic kidney disease usually are in discomfort. Physical examination of patients with polycystic kidney disease is usually remarkable for hypertension, jaundice, pallor, icteric sclera, palpable nodular hepatomegaly, palpable flank mass.

Common laboratory findings in polycystic kidney disease are urinary abnormalities including reduction in concentration capacity, hypocitraturia, hematuria, and proteinuria. Hyperuricemia is also a common finding and is a risk factor for disease progression and ESRD.

There are no ECG findings associated with polycystic kidney disease.

An x-ray KUB may be helpful in the diagnosis of polycystic kidney disease. Findings on an x-ray suggestive of polycystic kidney disease include, enlarged kidneys, multiple ring like calcifications arising from the renal cyst, elongated and splayed calyces due to the cyst.

Ultrasound may be helpful in the diagnosis of polycystic kidney disease. Findings on an ultrasound diagnostic of polycystic kidney disease include, atleast three unilateral or bilateral cysts in patients 15 – 39 years old, atleast two cysts in each kidney in patients 40 – 59 years old, atleast four cysts in each kidney in patients 60 years of age or older.

Although ultrasonography is the modality of choice for diagnosing ADPKD mainly due to the low cost and lack of radiation exposure, computed tomography and magnetic resonance imaging have higher resolutions and increased sensitivity for renal cysts less than 1 cm in diameter. Findings on CT scan include, numerous renal cysts of varying size and shape with little intervening parenchyma with water attenuation and very thin wall, reduction in sinus fat due to expansion of the cortex, occasional complex cysts with hyperdense appearance, with possible septations or calcifications, multiple homogeneous and hypoattenuating cystic lesions in the liver in patients with liver involvement.

Magnetic resonance imaging can be used to identify cysts smaller than 1 cm and to differentiate complex from simple cysts without contrast or radiation exposure. Renal MRI may be helpful in the diagnosis of polycystic kidney disease. Findings on MRI diagnostic of polycystic kidney disease include, T2 weighted images show enlarged kidneys with multiple cysts, normal parenchyma is absent, presence of fluid/fluid interface, wall thickening, hypointense signals in T2-weighted and DWI images, and hyperintense signals in T1-weighted images.

There are no other imaging findings associated with polycystic kidney disease.

Other diagnostic studies for polycystic kidney disease include, genetic testing, which demonstrates, frame insertions / deletions, non-canonical splice site alterations, combined missense changes.

Patients with polycystic kidney disease are treated with lisinopril or telmisartan for control of hypertension, tolvaptan for slowing disease progression, hydration, analgesia and bed rest. The treatment is targeted more towards managing symptoms and disease complications rather than slowing cyst formation.

Dialysis is not the first-line treatment option for patients with polycystic kidney disease. Dialysis is usually reserved for patients with either end stage renal disease (ESRD) or renal failure.

Surgery is not the first-line treatment option for patients with polycystic kidney disease. Surgery is usually reserved for patients with either end stage renal disease (ESRD), recurrent UTI, chronic pain, renal cell carcinoma, chronic hematuria requiring transfusions. Surgical options are either nephrectomy or renal transplantation.

Since polycystic kidney disease is a genetic disorder. There are no established measures for the primary prevention of polycystic kidney disease.

There are no established measures for the secondary prevention of polycystic kidney disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

King Stephen Bathory of Poland died from polycystic kidney disease in 1586. His death began the journey of the discovery of polycystic kidney disease as a disease process. In 1888, Fe´lix Lejars first used the term polycystic kidney. In the late 18th century, Dr. Matthew Baillie noted that these cysts were vesicular and not hydatid, and named them false hydatids of kidney. In 1994, PKD1 gene mutation on chromosome 16, was first implicated in the pathogenesis of ADPKD patients.

• In 1888, Fe´lix Lejars first used the term polycystic kidney^[1]
• He also stressed on the fact these cysts are bilateral
• In the late 18th century, Dr. Matthew Baillie noted that these cysts were vesicular and not hydatid, and named them false hydatids of kidney^[2]​
• In 1994, PKD1 gene mutation on chromosome 16, was first implicated in the pathogenesis of ADPKD patients^[3]
• Later PKHD1 gene mutation was found in patients with ARPKD^[4]

The following are a few famous cases of Polycystic kidney disease:

• King Stephen Bathory of Poland died from polycystic kidney disease in 1586^[5]
• His death began the journey of the discovery of polycystic kidney disease as a disease process.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2], Serge Korjian, Yazan Daaboul

There is no established system for the classification of polycystic kidney disease. There are 2 types of polycystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). ADPKD has 2 major types ADPKD1 due to PDK1 mutation, and ADPKD2 due to PDK2 mutation. A third subtype can be considered in patients without any documented mutation. Autosomal recessive polycystic kidney disease (ARPKD) was previously known as infantile polycystic kidney disease and occurs mainly in children.

There is no established system for the classification of polycystic kidney disease. In general, 3 types of autosomal dominant polycystic kidney disease (ADPKD) can be recognized based on the gene mutation identification:

• ADPKD1 (Type 1) seen in almost 85% of patients refers to patients with PDK1 mutations
• ADPKD2 (Type 1) seen in around 10-15% of cases denotes a mutation PDK2^[1]
• A third type that is still to be identified accounts for patients with clinical ADPKD without any documented mutation of either PKD1 or PKD2^[2]
• Autosomal recessive polycystic kidney disease (ARPKD) was previously known as infantile polycystic kidney disease and occurs mainly in children^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2], Serge Korjian, Yazan Daaboul

The pathogenesis of ADPKD is related to the protein products of the PKD1 and PKD2 genes known collectively as polycystins. These proteins are primarily involved in ciliary function in the renal tubular cells and defects in their function leads to intracellular cAMP accumulation and mTOR overactivity causing cell proliferation, fluid secretion, and abnormal extracellular matrix and intercellular interactions the main processes that lead to cyst formation.

• The pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) stems from the mutations of PKD1 and PKD2 genes on chromosomes 16 and 4 respectively.
• Polycystin-1 and polycystin-2, the protein products of PKD1 and PKD2, are transmembrane proteins that have distinct functions but interact to form one functional complex explaining the similar phenotype with both mutations.^[1][2][3]
  • Polycystin-1 is a ligand receptor
  • Polycystin-2 is a non-selective cation channel
  • Both proteins are located in the primary cilium in the renal tubular epithelial cells, which is typical of many other proteins also implicated in cystic diseases of the kidneys
• Despite their location, the primary cilia are usually structurally normal in ADPKD. However, functional abnormalities in mechanosensation have been documented.^[4]
• In wildtype variants, the polycystin protein complex detects changes in tubular flow, with resultant changes in Ca²+ influx via the polycystin-2 channel. This mechanism is defective in patients with ADPKD.^[5]
• Even before polycystins were discovered, cyst formation was considered to be the result of 3 processes:
  • Cell proliferation
  • Fluid secretion
  • Abnormal extracellular matrix and intercellular interactions
• With the relatively recent advances in the pathogenesis of ADPKD, polycystins were found to regulate all these processes. ^[4]
• With the alterations in calcium hemostasis within tubular cells, intracellular cAMP concentration increase causing apical cAMP-dependent Cl channels to increase cyst fluid secretion activate cellular proliferation via extracellular signaling.^[6]
• These findings have made intracellular cAMP concentrations the focal point for targeted therapy in ADPKD. ^[4]
• Another proposed mechanism of pathogenesis involved increased mTOR activity.
• Normally, polycystin-1 is involved in suppressing the activity of mTOR , explaining the abnormally increased activity seen in ADPKD.
• mTOR is heavily in involved cell growth and proliferation with suggested involvement in increased cellular proliferation and apoptosis seen in ADPKD. ^[7]
• Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of the disease and its characteristics include: ^[8][9][10]
  • Primarily a disease affecting infants and children
  • Dilation of collecting ducts
  • Biliary dysgenesis
  • Enlarged kidneys
  • Congenital hepatic fibrosis
  • Renal and hepatic morbidity and mortality
• ARPKD is caused by a mutation in PKHD1 gene that codes for an integral membrane protein fibrocystin ^[9][11]
  • It is suggested that fibrocystin may be involved in regulation of cellular adhesion and proliferation
  • Malfunction in fibrocystin leads to cyst formation by forming an undifferentiated secretory epithelium
  • This defect leads to polarization abnormalities and high rate of proliferation and apoptosis
  • There is a subsequent increase in cAMP signaling, epidermal growth factor receptor axis mediated proliferation and excess fluid secretion
• ARPKD: ^[8][9]
  • Bilateral enlargement of both kidneys
  • Impaired lung formation
  • Pulmonary hypoplasia
  • Expansion and elongation of collecting tubules into multiple small cysts

• ADPKD is transmitted in a dominant pattern.^[12]
• Genes involved in the pathogenesis of ADPKD include PKD1 gene, PKD2 gene ^[13]
• Autosomal dominant polycystic kidney disease (ADPKD) is caused by a mutation in either the PKD1 gene or PKD2 gene ^[14]
• ADPKD is an inherited disorder with 2 possible etiologic mutations
• PKD1 mutations found on short arm of chromosome 16 (16p13.3) accounts for roughly 85% of cases ^[15]
• PKD2 mutations found on the long arm of chromosome 4 (4q21) account for 15% of the remaining cases ^[16]
• All cases of ADPKD are heterozygous for either PKD mutations or both
• Homozygous cases usually die in utero ^[17]
• Generally, PKD1 mutants have more severe renal disease with mean age at onset of ESRD around 50 years compared to 75 years in PKD2 mutants ^[18]
• Patients heterozygous for both mutations have the most severe renal manifestations
• Despite the monogenic nature of the disease, the phenotype and severity of the disease as well as the extrarenal manifestations have been known to vary even within the same family
• Several mechanisms have been proposed to explain this variability including: ^[19]
  • A two-hit hypothesis involving loss of two PKD alleles in both germline and somatic cell lines
  • Haploinsufficiency
  • Environmental factors modifying disease processes
• ARPKD is transmitted in a recessive pattern.
• Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the PKHD1 gene ^[9][8]
  • PKHD1 is a gene that shares structural similarities with the hepatocyte growth factor receptor

Conditions associated with autosomal dominant polycystic kidney disease (ADPKD):

• Berry aneurysms ^[20][21]
• Mitral valve prolapse ^[22][23]
• Benign hepatic cysts ^[24][25]

Conditions associated with autosomal recessive polycystic kidney disease (ARPKD):

• Congenital hepatic fibrosis ^[26][27]
• Hepatosplenomegaly ^[28]
• Pulmonary hypoplasia ^[29][30]
• Respiratory distress ^[29]

• On gross pathology, enlarged kidneys, deformed external surface of kidney, numerous spherical cortical and medullary cysts, cysts containing serous, hemorrhagic, fluid, reduced intervening parenchyma between cysts are characteristic findings of ADPKD.^[31]
• On gross pathology, enlarged kidneys, smooth external surface, sponge like appearance, numerous cysts, dilated nephron tubules, rounded cysts on liver parenchyma are characteristic findings of ARPKD.^[32]

• On microscopic histopathological analysis, interstitial fibrosis, tubular atrophy, thickening and lamellation of tubular basement membranes, microcysts and negative immunofluorescence for complement and immunoglobulin are characteristic findings of ADPKD.^{[33][34][35][36]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2], Serge Korjian, Yazan Daaboul

Polycystic kidney disease is a genetic disorder. Autosomal dominant polycystic kidney disease (ADPKD) is an autosomal dominant disorder due to the heterozygous inheritance of PKD1 (chromosome 16) or PKD2 (chromosome 4) gene mutations. Despite the disease being monogenic, phenotype is variable possibly due to a two-hit process, haploinsufficiency, or environmental factors. Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the PKHD1 gene.

• Autosomal dominant polycystic kidney disease (ADPKD) is caused by a mutation in either the PKD1 gene or PKD2 gene.^[1]
• ADPKD is an inherited disorder with 2 possible etiologic mutations.
• PKD1 mutations found on short arm of chromosome 16 (16p13.3) accounts for roughly 85% of cases.^[2]
• PKD2 mutations found on the long arm of chromosome 4 (4q21) account for 15% of the remaining cases.^[3]
• All cases of ADPKD are heterozygous for either PKD mutations or both.
• Homozygous cases usually die in utero.^[4]
• Generally, PKD1 mutants have more severe renal disease with mean age at onset of ESRD around 50 years compared to 75 years in PKD2 mutants.^[5]
• Patients heterozygous for both mutations have the most severe renal manifestations.
• Despite the monogenic nature of the disease, the phenotype and severity of the disease as well as the extrarenal manifestations have been known to vary even within the same family.
• Several mechanisms have been proposed to explain this variability including:^[6]
  • A two-hit hypothesis involving loss of two PKD alleles in both germline and somatic cell lines
  • Haploinsufficiency
  • Environmental factors modifying disease processes
• Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the PKHD1 gene^[7][8]
  • PKHD1 is a gene that shares structural similarities with the hepatocyte growth-factor receptor.
• Genotype-phenotype correlation studies show that truncated PKD1 variants are associated with more severe disease when compared to PKD1 missense and PKD2 variants.
• Recently several genes have been implicated in rare cases of ADPKD.These include  IFT140, GANAB, NEK8, and DNAJB11 .

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2], Serge Korjian, Yazan Daaboul

The prevalence of autosomal dominant polycystic kidney disease (ADPKD) is approximately 100 – 250 per 100,000 individuals in the United States. The prevalence of ADPKD varies in different countries. The prevalence of autosomal recessive polycystic kidney disease (ARPKD) is approximately 5 per 100,000 children in the United States. The incidence increases with age for ADPKD. ARPKD commonly affects infants and children. Males and females are equally affected by ADPKD.

• The prevalence of autosomal dominant polycystic kidney disease (ADPKD) is approximately 100 – 250 per 100,000 individuals in the United States.^[1][2][3]
• In 2013, the prevalence of autosomal dominant polycystic kidney disease was estimated to be 33 cases per 100,000 individuals in Germany.^[4]
• In 1998, the prevalence of autosomal dominant polycystic kidney disease was estimated to be 25 cases per 100,000 individuals in Japan.^[5]
• In 1996, the prevalence of autosomal dominant polycystic kidney disease was estimated to be 90 cases per 100,000 individuals in France.^[6]
• In 1991, the prevalence of autosomal dominant polycystic kidney disease was estimated to be 41 cases per 100,000 individuals in United Kingdom.^[7]
• In 1957, the prevalence of autosomal dominant polycystic kidney disease was estimated to be 100 cases per 100,000 individuals in Denmark.^[8]
• The prevalence of autosomal recessive polycystic kidney disease (ARPKD) is approximately 5 per 100,000 children in the United States.^[9]

• The incidence of ADPKD increases with age; the average age at diagnosis is 30 – 50 years.^[2]
• ARPKD commonly affects infants and children.^[9]

• There is no racial predilection to autosomal dominant polycystic kidney disease.

• Autosomal dominant polycystic kidney disease affects men and women equally.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

Autosomal dominant and autosomal recessive polycystic kidney disease must be differentiated from other diseases that cause renal cysts, such as simple renal cysts, medullary sponge kidney, tuberous sclerosis complex, von Hippel-Lindau disease.

Autosomal dominant and autosomal recessive polycystic kidney disease must be differentiated from other diseases that may cause renal cysts, such as simple renal cysts, medullary sponge kidney, tuberous sclerosis complex, von Hippel-Lindau disease.

Diseases	Clinical manifestations						Para–clinical findings				Gold standard	Additional findings
	Symptoms			Physical examination
							Lab Findings	Imaging		Histopathology
	Flank/abdominal pain	Polyuria	Hematuria	Hepatomegaly	Bilateral flank masses	Hypertension	Urinalysis	Ultrasound	CT scan
Autosomal dominant polycystic kidney disease (ADPKD)[1]	+	+	+	+	+	+	Microalbuminuria Proteinuria Hypocitraturia Hyperoxaluria Low urine pH Hematuria	Bilateral fluid filled cysts Ultrasonography of parents will show cysts	Numerous renal cysts Scant intervening parenchyma with water attenuation and a very thin wall Multiple homogenous cystic lesions in the liver and pancreas	Segmental sclerosis Vascular sclerosis Interstitial fibrosis Tubular atrophy	Ultrasound	Extrarenal manifestations: Hepatic cysts Pancreatic cysts
Autosomal recessive polycystic kidney disease (ARPKD)[2]	+	+	+	+	+	+	Microalbuminuria Proteinuria Hypocitraturia Hyperoxaluria Low urine pH Hematuria	Bilateral fluid filled cysts Ultrasonography of parents will not show cysts	Numerous renal cysts Scant intervening parenchyma with water attenuation and very thin wall	Segmental sclerosis Vascular sclerosis Interstitial fibrosis Tubular atrophy	Ultrasound	Extrarenal manifestations: Portal fibrosis Portal hypertension Ascending cholangitis Biliary dysgenesis Pulmonary hypoplasia in neonates
Simple renal cyst[3]	–	–	–	–	+	–	–	Normal sized kidneys Smooth contour	–	Thin walled cortical cysts Filled with clear yellow fluid Cuboidal, flattened or atrophic epithelium	–	Negative family history of renal cystic disease Age ≥ 30 yrs
Medullary sponge kidney[4][5]	+	+/–	+	–	+	–	Microalbuminuria Proteinuria Hematuria	Malformation of distal collecting tubules Nephrolithiasis	Nephrolithiasis Renal cortex is spared Medullary nephrocalcinosis	Segmental or diffused papillary malformation Enlarged medullary collecting ducts	–	Tubular acidosis Recurrent urinary tract infections
Tuberous sclerosis complex[6][7]	+/–	+/–	+/–	–	+	–	–	Renal cysts Renal angiomyolipomas	CT kidneys will differentiate cystic and solid lesions, as well as renal angiomyolipomas CT brain shows: Cortical hamartomas White matter lesions	Epithelioid tissue Epithelial cysts Angiomyolipoma	–	Seizures Mental retardation Angiofibroma (face) Shagreen patch
Von Hippel-Lindau disease[8][9]	+	+/–	+	–	+	–	–	Renal cysts	Differentiates simple from complex cysts	Clear cell abnormalities Simple cysts Malignant cysts	CT scan	Retinal hemangioma Clear cell renal cell carcinoma Cerebellar and spinal hemangioblastoma Pheochromocytoma Pancreatic tumor

Disease	Symptoms			Signs		Diagnosis
	Abdominal Pain	Hematuria	Headache	Abdominal mass	Abdominal tenderness	Ultrasonography	CT scan	Histology
Polycystic kidney disease	+	+	+ (from hypertension)	+	–	Ultrasound may be helpful in the diagnosis of polycystic kidney disease. Findings on an ultrasound diagnostic of polycystic kidney disease include:[10][11] At least three unilateral or bilateral cysts in patients 15 – 39 years old Atleast two cysts in each kidney in patients 40 – 59 years old Atleast four cysts in each kidney in patients 60 years of age or older	Renal CT scan may be helpful in the diagnosis of polycystic kidney disease. Findings on CT scan diagnostic of ADPKD include: Numerous renal cysts of varying size and shape with little intervening parenchyma with water attenuation and very thin wall. Reduction in sinus fat due to expansion of the cortex Occasional complex cysts with hyperdense appearance, with possible septations or calcifications Multiple homogeneous and hypoattenuating cystic lesions in the liver in patients with liver involvement	On microscopic histopathological analysis, interstitial fibrosis, tubular atrophy, thickening and lamellation of tubular basement membranes, microcysts and negative immunofluorescence for complement and immunoglobulin are characteristic findings of ADPKD.[12][13][14][15]
Wilms tumor	+	+	–	+	+	Best initial diagnostic study used in cases suspected with Wilms tumor. Ultrasonography can help identify the mass as a kidney mass. It can distinguish tumor mass from other causes of renal swelling like hydronephrosis.[16] Doppler ultrasonography can help to detect invasion of renal vein and IVC by the tumor.[17]	Findings on CT scan which can be suggestive of Wilms tumor include:[18] Heterogeneous soft–tissue density masses These masses have frequent areas of calcification (~10%) and fat–density regions Lymph node metastasis CT scan of the renal mass can further reveal: Invasion of surrounding organs Thrombus in or occlusion of the renal vein and/or the inferior vena cava Abdominal lymph nodes and contralateral involvement	Wilms tumor has a triphasic appearance. It is comprised of 3 types of cells: Stromal Epithelial Blastemal All the 3 types are not required for the diagnosis of Wilms tumor. Primitive tubules and glomeruli are often seen comprised of neoplastic cells. Beckwith and Palmer reported in NWTS the different histopathologic types of Wilms tumor to categorize them based on prognosis.[19] Spindled cell stroma surrounding abortive tubules and glomeruli is characteristic. The stroma may include: Striated muscle cartilage bone Fat tissue Fibrous tissue.
Renal cell carcinoma	+	+	+/–	+	–	Ultrasound (US) may be helpful when CT scan results are equivocal. It is noteworthy to mention that not all renal cell carcinomas are detectable on ultrasound.	Both CT and MRI may be used to detect neoplastic masses that may define renal cell carcinoma or metastasis of the primary cancer. CT scan and use of intravenous (IV) contrast is generally used for work–up and follow–up of patients with renal cell carcinoma.	The histological pattern of renal cell carcinoma depends whether it is papillary, chromophobe or collecting duct renal cell carcinoma.
Rhabdoid kidney disease	+	+	–	+	–	Ultrasound shows a complex cystic mass.	CT scan may be diagnostic of malignant rhabdoid tumor. Findings on CT scan suggestive of malignant rhabdoid tumor include a large, heterogenous, centrally located mass, which is lobulated with individual lobules separated by intervening areas of decreased attenuation, relating to either previous hemorrhage or necrosis. Enhancement is similarly heterogeneous. Calcification is relatively common, observed in 20–50% of cases and is typically linear and tends to outline tumor lobules.	Malignant rhabdoid tumor is characterized by the round blue tumor cells of high cellularity composed of atypical cells with eccentric nuclei, small nucleoli, and abundant amounts of eosinophilic cytoplasm with frequent mitotic figures.
Pheochromocytoma	–	–	+ (as a part of the hypertension paroxysm)	–	–	CT is the preferred imaging modality for the diagnosis of pheochromocytoma.	The following findings may be observed on CT scan:[20] Most common extra–adrenal locations are superior and inferior abdominal paraaortic areas, the urinary bladder, thorax, head, neck and pelvis.[21] In sporadic pheochromocytoma, CT and MRI are good choices. The choice depends on availability and cost.[22] In patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome, CT may miss the tumors.[23]	On microscopic pathology, Pheochromocytoma typically demonstrates a nesting (Zellballen) pattern on microscopy. This pattern is composed of well–defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma.
Burkitt lymphoma	+/– (in non–endemic or sporadic form of the disease)	–	–	–	–	Abdominal ultrasonography may show splenomegaly and ascites.	Chest, abdomen, and pelvis CT scan may be helpful in the diagnosis of Burkitt’s lymphoma but it is not done routinely.[24]	On microscopic histopathological analysis, characteristic findings of Burkitt’s lymphoma include:[25] Medium–sized (~1.5–2x the size of a RBC) with uniform size (“monotonous”) –– key feature (i.e. tumor nuclei size similar to that of histiocytes or endothelial cells) Round nucleus Small nucleoli Relatively abundant cytoplasm (basophilic) Brisk mitotic rate and apoptotic activity Cellular outline usually appears squared off “Starry–sky pattern”: The stars in the pattern are tingible–body macrophages (macrophages containing apoptotic tumor cells. The tumour cells are the sky
Intussusception	+	–	–	+/–	+	Ultrasound is the gold standard imaging modality used to diagnose intussusception[26] Target or doughnut sign[27] Edematous intussuscipien forms an external ring around the centrally located intussusceptum Target sign is usually seen in right lower quadrant Layers of intussusception forms pseudo–kidney appearance on the transverse view	CT scan may be helpful in the diagnosis of intussusception. CT scan maybe used when other image modalities like x–ray and ultrasound have not given positive results but suspicion of intussusception is high.	Intussusception occurs if there is an imbalance between the longitudinal and radial smooth muscle forces of intestine that maintain its normal structure. This imbalance leads to a segment of intestine to invaginate into another segment and cause entero–enteral intussusception. Etiology of intussusception is either idiopathic or pathologic (lead point).
Hydronephrosis	+	+/–	–	–	+ (CVA tenderness in case of pyelonephritis)	Ultrasound allows for visualization of the ureters and kidneys and can be used to assess the presence of hydronephrosis and/or hydroureter.	In the case of renal colic (one sided loin pain usually accompanied by a trace of blood in the urine) the initial investigation is usually an intravenous urogram. This has the advantage of showing whether there is any obstruction of flow of urine causing hydronephrosis as well as demonstrating the function of the other kidney. Many stones are not visible on plain x ray or IVU but 99% of stones are visible on CT and therefore CT is becoming a common choice of initial investigation.	The kidney undergoes extensive dilation with atrophy and thinning of the renal cortex.
Dysplastic kidney	N/A	N/A	N/A	N/A	N/A	MCDK is usually diagnosed by ultrasound examination before birth. Mass of non–communicating cysts of variable size. Unlike severe hydronephrosis, in which the largest cystic structure (the renal pelvis) lies in a central location and is surrounded by dilated calices, in multicystic dysplastic kidney the cyst distribution shows no recognizable pattern. Dysplastic, echogenic parenchyma may be visible between the cysts, but no normal renal parenchyma is seen.	MCKD can be discovered accidentally on CT scan. CT scan shows myltiple cysts with absence of renal parenchyma.	MCKD is the result of abnormal differentiation of the renal parenchyma.
Pediatric Neuroblastoma	+	–	–	+/–	+/–	On ultrasound, neuroblastoma is characterized by a heterogeneous echogenicity due to the vascular, necrotic, and calcified content of the mass.[28]	CT scan is the investigation of choice for the diagnosis of neuroblastoma.[29] On CT scan, neuroblastoma is characterized by:[30] Heterogeneous mass Calcification Necrosis Compression of the surrounding vessels Invasion of the psoas muscle or kidneys Swollen lymph nodes	On microscopic histopathological analysis the presence of round blue cells separated by thin fibrous septa are characteristic findings of neuroblastoma. Other findings of neuroblastoma on light microscopy may include:[31] Homer–Wright rosettes (rosettes with a small meshwork of fibers at the center) Neuropil–like stroma (paucicellular stroma with a cotton candy–like appearance) On electron microscopy neuroblastoma is characterized by: Dendritic processes with longitudinally oriented microtubules Membrane bound electron–dense granules that contain catecholamines Presence of desmosomes Absence of glycogen
Pediatric Rhabdomyosarcoma	+	+/–	+/–	–	+/–		On CT scan, rhabdomyosarocma is characterized by: Soft tissue density Some enhancement with contrast Adjacent bony destruction (over 20% of cases)	Rhadbomyosarcoma has an appearance similar to the other round blue cell tumors such as Ewing sarcoma and small cell osteoblastoma.
Mesoblastic nephroma	+	+	–	+	–	Ultrasound may be helpful in the diagnosis of mesoblastic nephroma. Mesoblastic nephroma may presents as a well–defined mass with low–level homogeneous echoes.[32] The presence of concentric echogenic and hypoechoic rings can be a helpful diagnostic feature of mesoblastic nephroma.	CT scan may be helpful in the diagnosis of mesoblastic nephroma. Findings on CT scan suggestive of mesoblastic nephroma include: Solid hypoattenuating renal lesion Variable contrast enhancement No calcification	Classic mesoblastic nephroma Spindle cells in fascicles Infiltrative border Cellular mesoblastic nephroma Plump cells with vesicular nuclei Well–defined border Mitotically active Mixed mesoblastic nephroma Both classic pattern and cellular pattern areas are present

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

There are no established risk factors for polycystic kidney disease. Since both autosomal dominant and autosomal recessive forms are genetic disorders, to review the genetic causes of polycystic kidney disease click here.

There are no established risk factors for polycystic kidney disease. Since both autosomal dominant and autosomal recessive forms are genetic disorders, to review the genetic causes of polycystic kidney disease click here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2], Aarti Narayan, M.B.B.S [3]

According to the Unified criteria for ultrasonographic diagnosis, screening for polycystic kidney disease by ultrasonography is recommended in at risk patients with family history of polycystic kidney disease. According to the kidney disease improving global outcomes (KDIGO), screening for polycystic kidney disease in children less than 18 years of age is not recommended. Serum creatinine, urinalysis and regular blood pressure measurements can also be implemented to test in these patients.

• According to the Unified criteria for ultrasonographic diagnosis, screening for polycystic kidney disease by ultrasonography is recommended in at risk patients with:^[1]
  • Family history of polycystic kidney disease
  • Mutations in PKD1
  • Families with mutations in PKD2
• According to the kidney disease improving global outcomes (KDIGO), screening for polycystic kidney disease in children less than 18 years of age is not recommended.^[2]
• Ultrasonography has been used to screen those with a family history of polycystic kidney disease
• Serum creatinine, urinalysis and regular blood pressure measurements can also be implemented to test in these patients ^{[3] [4]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2], Serge Korjian, Yazan Daaboul

The earliest clinical signs of disease in patients with ADPKD include impaired renal concentrating capacity and hypertension. Other signs include flank pain, nephrolithiasis and urinary tract infections. In general half of the patients diagnosed with ADPKD will progress to ESRD by age 60. PDK1 mutants usually progress faster than PDK2 mutants. Factors associated with worse renal outcome include early age at diagnosis, male gender, uncontrolled hypertension, left ventricular hypertrophy, and cystic liver. Extra-renal manifestations in ADPKD include hepatic cysts usually more prevalent in women and with advancing age and declining renal function. Cysts can also be seen in the seminal vesicles, pancreas, and arachnoid membrane. Furthermore, the development of intracranial aneurysms can be a lethal complication in ADPKD patients whose risk is closely linked to the family history of aneurysms. Mitral valve prolapse is also a common cardiac manifestation seen in 25% of patients. Most cases of ARPKD present in the neonatal period with some disease findings detected on prenatal ultrasound. Most feared and common complication of ARPKD is pulmonary hypoplasia. Half of ARPKD patients usually progress to ESRD by age of 10. The prognosis of ARPKD improves in patients who survive the first few months of life. Survival at 15 years for patients of ARPKD ranges from 50% – 80%.

Autosomal dominant polycystic kidney disease (ADPKD):

• The earliest detectable functional aberration seen in patients with ADPKD is impaired concentrating capacity with a suboptimal increase in urinary osmolality following water deprivation.^[1]
• The second early manifestation of disease is hypertension. Up to 75% of patients with ADPKD on imaging without any renal insufficiency are hypertensive.^[2]
• Even in young patients, 50% of those aged 20-34 years are hypertensive despite normal renal function.^[3]
• Overt clinical signs and symptoms of renal disease usually appear during the fourth or fifth decade.^[4]

Autosomal recessive polycystic kidney disease (ARPKD):

• Most affected individuals present in the neonatal period with some disease findings detected in prenatal obstetric ultrasounds.^[5]
• The most common initial findings in ARPKD patients involve abnormal renal structure and function.^[6]
• Approximately 30% of patients have no lab abnormalities at presentation.

• Common complications of ADPKD include:^{[7][4][8][9][8][10][11][12][13]}
  • Urinary tract infections
  • Pyelonephritis
  • Cyst infection
  • Nephrolithiasis
  • Hepatic cyst
  • Cyst hemorrhage
  • Cyst torsion
  • Intracranial aneurysms
  • Thoracic aortic aneurysms
  • Coronary artery aneurysms
  • Mitral valve prolapse
  • Diverticulosis
  • End stage renal disease (ESRD)

• Common complications of ARPKD include:^[14][15][16]
  • Congenital hepatic fibrosis
  • Portal hypertension
  • Pulmonary hypoplasia
  • Chronic lung disease
  • Biliary dysgenesis
  • Recurrent ascending cholangitis

Autosomal dominant polycystic kidney disease (ADPKD):

• Approximately 60% of patients suffer from flank pain often requiring cyst decompression surgery. Expanding cysts can often by complicated by hemorrhage that self-resolves but usually causes significant pain.^[4]
• Generally, PKD1 mutants have more severe renal disease with mean age at onset of ESRD around 50 years compared to 75 years in PKD2 mutants. But, regardless of the mutation, 50% of ADPKD patients will reach ESRD by age 60 years.^[17]
• Hematuria can be seen in ADPKD especially in advanced cases; however, overt proteinuria is usually uncommon in the context of ADPKD, and proteinuria > 1 g/day should prompt the consideration of a second disease process.^[18][4]
• Several factors have been linked to a worse renal outcome (renal function for given age) including early age at diagnosis, male gender, uncontrolled hypertension, left ventricular hypertrophy, cystic liver, gross hematuria, larger kidney volume, and urinary tract infections.^[19]
• The aneurysms are usually asymptomatic and the mean age at rupture is at 39 years, 12 years younger than in the general population.^[10]
• Significant diverticulosis can be seen in more than half of ADPKD patients especially those in ESRD on hemodialysis.^[20]

Autosomal recessive polycystic kidney disease (ARPKD):

• Half of ARPKD patients usually progress to ESRD by the age of 10.
• Other morbidities include growth retardation, recurrent UTIs, and portal hypertension due to liver involvement.^[21]
• Mortality is still significantly elevated with around one-fourth of patients dying in the first year of life.
• The first month is usually the most critical period with a mortality rate of approximately 15%..^[22]
• A significant portion of these patients have varying degrees of pulmonary hypoplasia that is incompatible with life related to the massive intra-abdominal size of the kidneys.^[23]
• Patients with mild pulmonary hypoplasia might develop chronic lung disease some of which require ventilation support.
• The prognosis improves in patients that survive the first few months of life.
• Portal hypertension secondary to hepatic fibrosis is often the major cause of mortality in these patients.^[24]
• Survival at 15 years ranges from 50 to 80%. Sixty percent of these patients will not require any renal replacement therapy. ^[25]

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