AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

One third of people older than 50 years develop renal cysts. Although most are simple cysts, renal cystic disease has multiple etiologies. Broad categories of cystic disease include the following:

• Developmental - Multicystic dysplastic kidney (MCDK)
• Genetic - Autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant polycystic kidney disease (ADPKD), juvenile nephronophthisis (JNPHP), medullary cystic kidney disease (MCKD), glomerulocystic kidney disease (GCKD)
• Cysts associated with systemic disease - Von Hippel-Lindau syndrome (VHLS), tuberous sclerosis (TS)
• Acquired - Simple cysts, acquired cystic renal disease, medullary sponge kidney (MSK)
• Malignancy - Cystic renal cell carcinoma (RCC)

Pathophysiology

Cysts develop from renal tubule segments and most detach from the parent tubule after they grow to a few millimeters in size. Cyst development is generally attributed to increased proliferation of tubular epithelium, abnormalities in tubular cilia, and excessive fluid secretion.

Developmental cystic renal disease

Inherited cystic renal disease

Systemic disease with associated renal cysts

Acquired cystic renal disease

Frequency

United States

• MCDK has an incidence of 1 per 1000-4000 live births.²
• ADPKD has an incidence of 1 per 400-1000 persons among whites and accounts for 8-10% of all cases of end-stage renal disease (ESRD).
• ARPKD has an incidence of 1 per 6000-55,000 live births, with a heterozygous carrier frequency of 1 per 70.
• JNPHP affects 1 per 5000 persons.³
• JNPHP and MCKD account for 10-20% of children with chronic renal failure and for 1-5% of all patients undergoing dialysis or transplantation.
• TS has an incidence of 1 per 10,000-50,000 persons, and 20-25% of these patients have renal cysts.⁴
• VHLS has an incidence of approximately 1 per 39,000 persons, and two thirds of these individuals develop renal cysts.
• In acquired cystic renal disease, cysts are present in 8-13% of patients with chronic renal failure prior to dialysis. Following initiation of therapy, 10-20% of patients have acquired cystic renal disease after 3 years of dialysis, 40-60% after 5 years, and more than 90% after 10 years.⁵
• MSK has an estimated incidence of 1 per 5000 persons and is found in approximately 20% of patients with nephrolithiasis.
• Simple cysts are the most common cystic renal lesions. They are present in 5% of the general population, increasing in frequency to 25-33% of patients older than 50 years, and account for 65-70% of renal masses.
• Cystic RCC accounts for less than 1% of RCC cases.

Mortality/Morbidity

• Cystic renal disease accounts for approximately 10% of all ESRD cases.
• ADPKD is 1 of the top 4 causes of ESRD and is the etiology of renal failure in 5-10% of patients undergoing dialysis. ARPKD accounts for 5% of ESRD in children.
• Neonatal mortality secondary to ARPKD approaches 25-35% and is usually related to respiratory compromise.⁶
• More than 50% of patients with ARPKD require kidney transplant before age 20 years. ⁷
• JNPHP is the most common cause of genetic ESRD in children.⁸
• TSC is associated with a high frequency of angiomyolipoma.
• Patients with acquired cystic disease are more likely to develop RCC (5-25%). Additionally, tumors are commonly bilateral, and 15% are metastatic.⁵

Race

• ADPKD is found throughout the world in all racial and ethnic groups.
• Acquired cystic renal disease is most common in white men and African Americans.

Sex

• Multicystic dysplastic kidney is more common in males than in females.
• Symptomatic progression of ADPKD appears to be more rapid in men.
• VHLS affects men and women with equal frequency.
• Acquired cystic renal disease is more common in men.
• MSK has a male-to-female ratio of 2:1.

Age

• ADPKD has a bimodal distribution of onset, with some cases presenting in infancy or childhood.³
• ARPKD presents in infancy, childhood, or adolescence.
• VHLS typically presents in the third or fourth decade of life with visual or central nervous system symptoms.
• MSK typically presents between the third and fifth decades of life.
• Simple cysts are very rare in children but increase in frequency with age.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Developmental cystic renal disease: Multicystic dysplastic kidney (MCDK) is almost uniformly identified during prenatal sonographic examination. The involved kidney partially or completely improves with age in 40-90% of patients.⁹ Bilateral renal involvement is not compatible with life. MCDK can exist independently or as part of syndromes such as the vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial and renal anomalies (VATER) association; Zellweger syndrome; or BOR syndrome.¹⁰
• Inherited cystic renal disease
  
  
  • Autosomal dominant polycystic kidney disease
    
    
    • Patients present in the fourth decade of life with flank pain or intermittent hematuria. Patients may also experience cyst hemorrhage, renal infection, or nephrolithiasis. Hypertension and chronic renal failure are noted in the fifth decade of life, and patients progress to end-stage renal disease (ESRD) in the sixth decade of life.
    • The disease course varies considerably among affected individuals. While all gene carriers are believed to exhibit symptoms by the end of their eighth decade of life, only 50% of carriers actually progress to renal failure.
    • Kidney size (a direct reflection of cyst volume) increases exponentially over time and appears symmetric in a given individual, with an equal growth rate in both kidneys.¹¹
    • All aspects of the disease appear to develop more rapidly in patients with the PKD1 genotype. The kidneys grow more rapidly in these patients, and hypertension and ESRD occur at a younger age; the onset of ESRD in persons with the PKD1 genotype occurs at a mean age of 53 years, while the onset of ESRD in persons with the PKD2 genotype occurs at a mean age of 69 years.¹²
    • Hepatic cysts are the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). These increase in number with age (20% in the third decade of life, 75% after the sixth decade of life) and may cause chronic pain. However, even with extensive cystic involvement, liver function is not compromised. Other clinical associations include cardiac valve disease (particularly mitral valve prolapse [25%]), diverticulosis, cerebral aneurysms (5-10%), pancreatic cysts, and seminal vesicle cysts. ⁶
  • Autosomal recessive polycystic kidney disease
    
    
    • Autosomal recessive polycystic kidney disease (ARPKD) affects renal and hepatic development (dysgenesis of the portal triad), but the degree of organ involvement varies in relation to the age of onset.
    • In the neonatal period, pulmonary disease, resulting from nephromegaly and oligohydramnios, dominates the presentation. Typically, the neonate has profound respiratory compromise, often exacerbated by pneumothorax. This presentation may result in neonatal death.
    • Symptoms in an infant include hypertension (80%), diminished urine concentrating ability, and renal insufficiency. Most affected children develop hypertension within the first few years of life. Growth retardation has been reported in one fourth of children. Fifty percent of affected individuals develop ESRD in the first decade of life, requiring dialysis or transplantation.
    • In older children (4-8 y), the kidneys often are less severely affected, while hepatic disease may predominate. Hepatic involvement usually presents with symptoms secondary to portal hypertension, particularly varices and splenomegaly. Twenty-three percent of children with ARPKD experience variceal bleeding by a mean age of 12.5 years. Hepatic disease may also result in acute bacterial cholangitis or thrombocytopenia secondary to hypersplenism.
  • Glomerulocystic kidney disease (GCKD): This occurs in early (neonatal) and late (adult) forms. Neonates present with hypertension, abdominal masses, and variable degrees of renal failure. Adults typically present with flank pain, hematuria, and hypertension. Hepatic cysts may also develop.¹³
  • Juvenile nephronophthisis (JNPHP): This has several different phenotypic expressions depending on the gene involved. Infantile (NPHP2), juvenile (NPHP1, NPHP4) and adolescent (NPHP3) forms of the disease exist, but most symptoms appear during the first decade of life. These include growth retardation, urine concentrating defects, skeletal dysplasia, and progressive renal failure. Additionally, some degree of hepatic fibrosis and biliary duct enlargement is usually present.¹
  • Medullary cystic kidney disease: This is clinically milder than JNPHP, occurs later in life (third to fourth decades), and has limited extrarenal manifestations. Individuals with this disease due to mutations in the MCKD2 gene present with uremia sooner than those with disease due to MCKD1 mutations and are more likely to develop hyperuricemia and gout.¹
• Systemic disease with associated renal cysts
  
  
  • Tuberous sclerosis (TS): Clinical features of TS include facial nevi, cardiac rhabdomyomas, epilepsy, angiofibromas, and mental retardation. Approximately one half of patients have multiple renal angiomyolipomas. Twenty to 25% of patients have renal cysts, although diffuse renal cystic disease, which may result in chronic renal failure, is rare.
  • Von Hippel-Lindau syndrome (VHLS): Clinical features of VHLS include retinal and cerebellar hemangioblastomas, pheochromocytomas, and cystic disease of the kidneys, pancreas, and epididymis. Renal cysts are very common, occurring in two thirds of patients. Renal cell carcinoma (RCC) develops in as many as 40% of patients.
• Acquired cystic renal disease
  
  
  • Acquired renal cystic disease (ARCD): Acquired cystic disease may be found in patients with all etiologies of ESRD, particularly in patients who are dialysis-dependent. The incidence, number, and size of cysts all increase in proportion to the duration of dialysis. Most patients are asymptomatic, but symptoms may include gross hematuria, flank pain, renal colic, or a palpable renal mass. Hemorrhagic cysts occur in 50% of patients.⁴
  • Medullary sponge kidney (MSK) is usually detected on radiographic evaluation of adults with nephrolithiasis. Fifteen to 20% of patients with calcium oxalate and calcium phosphate renal calculi have MSK. Patients may also have a history of hematuria or urinary tract infection (UTI). Most patients with MSK, however, are asymptomatic. Approximately 10% of patients develop recurrent nephrolithiasis, bacteriuria, and pyelonephritis. Involvement is usually bilateral.
  • Simple cysts usually are clinically silent, although they occasionally hemorrhage and cause acute pain.

Physical

• Developmental cystic renal disease: MCDK may be palpable as a flank mass in an otherwise healthy infant and is the most common cause of a renal mass and the second most common cause of a palpable abdominal mass in neonates.^{14, 2}
• Inherited cystic renal disease
  
  
  • ARPKD: Bilateral flank masses are palpable in 30% of neonates and infants with this disease. Older children may demonstrate signs of portal hypertension.
  • ADPKD: The enlarged kidneys and liver may be palpable.
• Acquired cystic renal disease: Simple cysts rarely become large enough to be palpable.

Causes

• Developmental cystic renal disease: MCDK is thought to arise from abnormal development of the metanephros. This may be a genetic effect or may reflect a defect in the ampullary bud (inducer tissue) or the blastema (responder tissue), with resultant poor nephron induction.² Additionally, in utero obstruction has been identified as a possible cause, leading to urinary stasis and cyst formation. Many patients, however, have normal renal development despite obstruction.
• Inherited cystic renal disease: Currently, the exact mechanism of genetically induced cyst formation has not been fully defined. Similarities between cystic diseases, however, reveal common pathologic pathways. The vast majority of mutations affect the primary cilia of the tubular epithelium, indicating that disruption of this structure relates to disease development.⁶ Additionally, dedifferentiation and increased proliferation of tubular epithelium, along with abnormal fluid secretion, appear to be common elements in cystic disease.
  
  
  • ADPKD: Inheritance is autosomal dominant, with close to 100% penetrance. PKD1 (chromosome 16) encodes for the transmembrane protein polycystin-1 (PC1), which is responsible for cell-to-cell and cell–to–extracellular matrix binding.⁶ Mutations in this gene are responsible for 85-90% of cases. Mutations in polycystin-2 (PKD2, chromosome 4), a calcium channel important for PC1 localization and function, account for the remaining 10-15%.¹² Interestingly, while this is a genetic disease that affects every cell in the kidney, cysts involve only 1-2% of the nephrons or collecting ducts, supporting the hypothesis that a "second hit," or mutation of the abnormal allele, must occur.¹ Five to 8% of cases do not involve a family history and are the result of spontaneous mutations.
  • ARPKD: Inheritance is autosomal recessive. All cases are caused by mutations in PKHD1, a large gene that encodes fibrocystin/polyductin, which appears to be related to the polycystin complex and controls epithelial proliferation, secretion, and structure and development of the renal tubules and biliary ducts.⁷ The genetic defect is located on chromosome 6p21.1-p12.
  • In both ADPKD and ARPKD, epidermal growth factor (EGF) has been identified as an important stimulus for proliferation of cystic epithelium.¹²
  • GCKD is a rare disease that is transmitted in an autosomal dominant manner. The involved gene has not been identified, and both familial and sporadic forms exist. ¹³
  • JNPHP is inherited in an autosomal recessive manner and is due to mutations in the NPHP genes (NPHP1-NPHP5) which are located on multiple different chromosomes and encode nephrocystins and inversin. All of the gene products are found in the primary cilium.^{3, 12, 8} Ten to 20% of cases are associated with retinal disease and are termed Senior-Loken syndrome.
    
    
    • NPHP1 is located on chromosome 2q12-13 and encodes nephrocystin.
    • NPHP2 is found on chromosome 9q22-31 and encodes inversin.
    • NPHP3 is found on chromosome 3q21-22 and encodes nephrocystin-3.
    • NPHP4 is located at chromosome 1q36 and encodes nephrocystin-4.
    • NPHP5 (chromosome 3q13.33-21.2) encodes nephrocystin-5 and is found only in cases associated with Senior-Loken syndrome.
  • Medullary cystic kidney disease (MCKD) is due to mutations in the MCKD1 (chromosome 1q21) and MCKD2 (chromosome 16p12) genes and is inherited in an autosomal dominant manner.¹²
• Systemic disease with associated renal cysts
  
  
  • TS: Inheritance is autosomal dominant, with variable penetrance. Sixty to 70% of cases are due to sporadic mutations. Genetic markers have been identified at chromosome band 9q34 (TSC1, which encodes hamartin) and chromosome band 16p13 (TSC2, which encodes tuberin). TSC2 accounts for two thirds of TS cases.^{6, 1} While the functions of these genes are not understood, TSC2 is adjacent to the PKD1 gene, which is involved in the most common form of ADPKD. In some cases, a contiguous gene syndrome has been described, involving large deletions that affect both TSC2 and PKD1.
  • VHLS: Inheritance is autosomal dominant, with variable penetrance. The genetic defect has been localized to chromosome band 3p25.
• Recent biochemical analyses^{15, 16} have identified a protein (mTOR) that may be the common pathway between several of the genetic forms of cystic disease. mTOR activity is related to cell growth, proliferation, apoptosis, and differentiation. Levels of mTOR have been demonstrated to be increased in cyst epithelium. Under normal conditions, PC1 (mutated in ADPKD) and TSC2 (mutated in TS) suppress or inactivate mTOR. When these genes, as well as others that relate to the primary cilia, mutate, mTOR activity becomes dysregulated, possibly allowing cyst formation. If mTOR is ultimately confirmed as a common pathway to cyst development, it will be an important drug target.
• Acquired cystic renal disease: The exact cause of cyst formation has not been identified. One theory suggests that the development of cysts in acquired renal cystic disease (ARCD) is secondary to obstruction of the tubules by fibrosis or oxalate crystals. Another hypothesis invokes the accumulation of growth factors and stimulatory chemicals (uremia), including EGF, which leads to the development of cysts.¹ The disease occurs in patients on all types of dialysis and appears to regress after transplantation.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Angiomyolipomas
Cysts of the renal sinus (including peripelvic cysts, parapelvic cysts, parapelvic lymphatic cysts, and parapelvic lymphangiectasia)
Hemangioma
Multilocular cystic nephroma

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Developmental cystic disease (MCDK): In MCDK, because of the associated ureteral obstruction, the patient may have pyelonephritis in spite of an unremarkable urine specimen. However, blood cultures and clinical examination should readily suggest this diagnosis.
• Inherited cystic renal disease
  
  
  • Autosomal dominant polycystic kidney disease (ADPKD): Diagnosis is primarily clinical, but, in presymptomatic patients with a family history, gene linkage analysis can be used in combination with sonography for screening.⁶ The combination of these 2 modalities can achieve a detection sensitivity of 88.5% in patients younger than 30 years and 100% in patients older than 30 years.
  • Autosomal recessive polycystic kidney disease (ARPKD): Genetic testing for mutations at PKHD1 is currently available, with 80-85% detection rates.⁷ A neonate may have hyponatremia during the first few weeks of life. The infant subsequently may demonstrate diminished urine osmolality (ie, <500 mOsm/kg) secondary to reduced concentrating ability and metabolic acidosis secondary to decreased urinary acidification capacity. The patient may also have recurrent pyuria. Bilirubin and hepatic enzyme values may also be elevated.
  • Juvenile nephronophthisis (JNPHP) and medullary cystic kidney disease (MCKD): The urine has elevated sodium levels and low specific gravity with minimal proteinuria and normal sediment. Renal tubular acidosis may result in alkalotic urine and systemic acidosis. Genetic linkage analysis may be used to establish the diagnosis.
• Systemic disease with associated renal cysts: Prenatal screening is available for tuberous sclerosis (TS) if the diseased allele can be identified in an affected family member. In the absence of this, no reliable genetic marker for TS is known. Genetic screening techniques can be used to identify likely disease-causing mutations in 58-68% of cases.

Imaging Studies

• Developmental cystic renal disease (MCDK)
  
  
  • Prenatal sonography is the diagnostic tool of choice and can be used to identify MCDK as early as 15 menstrual weeks.⁴ It demonstrates multiple variably sized, noncommunicating cysts outlined by hyperechoic intervening renal parenchyma.¹⁷ The corresponding ureter and renal pelvis are typically not visualized.
  • After birth, serial (one within days of life and another one month later) high-quality sonography should be performed to confirm the diagnosis and to evaluate the contralateral kidney and the rest of the urinary tract.¹⁰
  • Intravenous pyelography (IVP) may show a nonfunctioning kidney or a deformed mass with faint specks of contrast corresponding to small areas of functioning renal tissue. No collecting system or ureter is identified. Shell-like calcifications outlining some of the cysts may be noted.
  • Ureteral obstruction with collecting system dilatation may be difficult to differentiate from MCDK. In these cases, nuclear medicine functional studies can be helpful and demonstrate a rim of functional tissue in the obstructive cases.⁴
  • An association with contralateral ureteropelvic junction obstruction, as well as with renal ectopia, exists. Previously, voiding cystourethrography (VCUG) was routinely performed to rule out reflux into the contralateral kidney. Recent data suggest, however, that VCUG is of little value if serial high-quality ultrasonography findings are consistent with MCDK and demonstrate a normal bladder and contralateral kidney.¹⁰
• Inherited cystic renal disease
  
  
  • Autosomal dominant polycystic kidney disease
    
    
    • Typically, cysts first are observed radiographically in the second to third decades of life. With progression, the kidneys become enlarged with multiple spherical fluid-filled cysts (1-3 cm) that are appreciated readily with CT scanning, ultrasonography, or MRI. Sonographic criteria for ADPKD depend on patient age. Patients younger than 30 years probably have at least 2 cysts in 1 of the kidneys, patients aged 30-60 years probably have at least 2 cysts in each kidney, and patients older than 60 years generally have at least 4 cysts per kidney.
    • Debris may produce heterogeneous cyst attenuation, and cysts may have fluid-fluid levels from hemorrhage. Hemorrhagic cysts demonstrate unenhanced CT attenuation values of 40-100 Hounsfield units (HU). Calcification may be observed in the cyst walls or in the parenchyma between cysts, and nephrocalcinosis or nephrolithiasis is observed in as many as 50% of patients. Calcification likelihood increases with age and is fairly common in patients older than 50 years. Contrast enhancement of the renal parenchyma provides an indication of the amount of functioning renal parenchyma that remains. The likelihood of hepatic cysts increases with age; 40% of patients demonstrate liver cysts by the fourth decade of life, and nearly 90% of patients have them by the sixth decade of life.
    • When ADPKD presents in childhood, ultrasonography may reveal hyperechoic enlarged cystic kidneys, a pattern that may be difficult to differentiate from ARPKD. In this situation, family history and possible ultrasonography of the parents' or grandparents' kidneys is recommended.
    • When malignancy or infected cysts are a concern, a contrast-enhanced CT scan can be performed.
    • Patients should be screened for intracranial aneurysms. This can be readily accomplished noninvasively with magnetic resonance angiography (MRA).
  • Autosomal recessive polycystic kidney disease
    
    
    • Severe cases of this disease can be are detected with sonography in utero, with most cases detected in the third trimester of gestation. Features include enlarged kidneys that maintain their reniform shape and have increased echogenicity. With severe renal disease, urine may be absent in the bladder, and oligohydramnios, pulmonary hypoplasia, and a small thorax may be observed. At birth, neonates require assisted ventilation, and pneumothorax is common.
    • In children, kidney size is typically at least 2 standard deviations greater than normal and diffusely hyperechogenic. Loss of corticomedullary differentiation may be observed, and small cysts oriented in a radial pattern in the distribution of the collecting ducts may be evident. The cysts tend to enlarge over time.
    • Precontrast CT scan images show enlarged smooth kidneys with low attenuation (likely representing the large volume of fluid in the collecting tubules). Renal calcifications are frequently noted. With contrast, poor opacification of the kidneys may be observed (with severe renal failure), and the physician may appreciate radial streaks of contrast extending from the cortical surface to the inner medulla. The classic radial streak pattern is best appreciated with IVP.
    • Liver disease: Ultrasonography demonstrates hepatomegaly with echogenic parenchyma (secondary to fibrosis), hepatic cysts, and dilatation of the peripheral hepatic ducts with fibrous bridging.⁴ Magnetic resonance cholangiography is more sensitive in detecting dilated biliary ducts.
  • Glomerulocystic kidney disease
    
    
    • The kidneys appear either hypoplastic or normal in size on sonography and maintain their reniform shape. Cysts are small (<1 cm) and are observed in an echogenic cortex; the medulla is spared. Corticomedullary differentiation is lost.¹³
    • On CT and MRI, glomerulocystic kidney disease (GCKD) appears as numerous small cortical cysts. These do not enhance with gadolinium during MRI. ¹⁸
  • JNPHP and MCKD: Sonography and CT scan reveal bilaterally shrunken kidneys. On sonography, cysts are observed at the corticomedullary junction in a background of diffusely echogenic renal parenchyma.⁴
• Acquired cystic renal disease
  
  
  • Acquired renal cystic disease (ARCD): Diagnosis can be made if involvement is bilateral, with at least 4 cysts per kidney. Once cysts are observed sonographically, further evaluation with contrast-enhanced CT scan is indicated to rule out carcinoma. Contrast-enhanced helical CT scanning has 96% sensitivity and 95% specificity in detecting carcinoma. In patients who cannot tolerate ionic contrast, MRI may be useful to evaluate for neoplasms.
  • Medullary sponge kidney (MSK): Findings on plain radiographs may be normal, or they may exhibit medullary nephrocalcinosis (represented by multiple discrete calculi clustered in the renal pyramids). At least one renal calculus (typically <5 mm) is often observed. IVP demonstrates a "bouquet of flowers" or "paintbrush" pattern. Ectatic tubules are observed as dense streaks of contrast material radiating from the calyces, while papillary cysts are observed as round opacifications in the papillae. The "brush" pattern of the ectatic tubules must be differentiated from a dense papillary blush, which may be observed in healthy patients; with low-osmolar contrast, papillary blush is observed in as many as 13% of routine IVPs. A greater than 0.3-mm cylinder or streak diameter has been recommended to help differentiate between pathologic tubular ectasia and normal variant physiology. CT scan may show calcifications at the corticomedullary junction.
  • Simple cyst: The most clinically significant aspect of a simple cyst is differentiating it from carcinoma. Simple-cyst walls occasionally calcify and, thus, radiographically mimic malignancy. Sonographic features that support the diagnosis of simple cyst include an anechoic round mass with a smooth and sharply demarcated wall and through-transmission with strong posterior wall echo. If the ultrasonography findings are suspicious or equivocal, a CT scan is warranted. CT scan criteria for a benign cyst include (1) sharp demarcation cyst with a smooth thin wall, (2) homogenous fluid within the cyst (typically with density <20 HU, although higher measurements may be found with a benign proteinaceous cyst or if hemorrhage is present in a benign cyst), and (3) no contrast enhancement. Enlargement of the cyst can raise the concern of malignancy, although the natural history of benign renal cysts does show progressive slow enlargement.
  • Bosniak classification: Bosniak has described a classification scheme for renal cysts based on CT scan findings.¹⁹
    
    
    • Category I (simple cyst) - Thin wall without septa, calcifications, or solid components; measures water density (<20 HU) and does not enhance (<2% chance of malignancy)
    • Category II (minimally complex cyst) - Thin wall (<1 mm) and no enhancement; may contain 1 or 2 hairline-thin septa, fine calcification, or short segment of slightly thickened calcification; includes high-attenuation lesions that are smaller than 3 cm (Malignancy rates in series range from 0-14%. Series with higher malignancy rates include IIF lesions.)
    • Category IIF (indeterminate) - Minimal enhancement and/or thickening of a hairline-thin smooth septum or wall; mildly thickened or nodular calcification; no enhancing soft-tissue components; includes nonenhancing high-attenuation lesions that are 3 cm or larger (approximately 20% likelihood of malignancy)
    • Category III (suspicious indeterminate) - Multilocular lesion with multiple enhancing septae, uniform wall thickening, nodularity, or thick or irregular calcification (30-60% likelihood of malignancy)
    • Category IV (malignant) - Contains enhancing (>10 HU) large nodules or clearly solid components (>90% likelihood of malignancy)
  • MRI may be used to help evaluate renal lesions in patients with either renal impairment or allergy to iodinated contrast material. Contrast-enhanced MRI and CT scan reveal similar findings in most cystic renal lesions. However, MRI suggests a higher classification for some lesions by identifying more septae, areas of wall thickening, or enhancement. Additionally, calcification may not be appreciated with MRI.

Procedures

• Aspiration: In the evaluation of an intermediate renal cyst, fine-needle aspiration has a limited role. Some centers report a sensitivity of more than 70% for core biopsy and cyst aspiration with cytology. The role of ultrasonography or CT-guided biopsy also remains open to debate.

Histologic Findings

Developmental cystic renal disease

• Multicystic dysplastic kidney: Cystic dysplasia is a subset of renal dysplasia. In this form, typical renal configuration is lost. The disease is usually a unilateral process, but it ranges from involving a portion of one kidney to completely involving both kidneys. Grossly, the kidney appears to be an enlarged mass of cysts among immature primitive tissue, often with surrounding fibrosis and an atretic collecting system.¹⁰ The ureter is often stenotic or hypoplastic, and the renal artery is often small or absent.⁴ Microscopy reveals small areas of otherwise normal-appearing glomeruli and tubules interspersed with cysts lined with cuboidal epithelium and surrounded by collars of spindle cells. The cysts are filled with proteinaceous or sanguinous fluid. In addition, immature-appearing cartilage is often present in the tissue.

• Autosomal dominant polycystic kidney disease
  
  
  • The kidneys are enlarged and distorted by multiple renal cysts. Cystic kidneys can exceed 40 cm in length and weigh as much as 5 kg. Cysts range in size from a few millimeters to several centimeters and are distributed relatively uniformly through the medulla and cortex. Cyst fluid ranges from clear to hemorrhagic.
  • Microscopic evaluation shows cystic dilatations in all segments of the nephron, with loss of connection to the tubule. While all segments are involved, the cysts derived from the collecting duct are the largest and most numerous.²⁰ The cysts are lined by a single layer of flattened-to-cuboidal epithelium. The intervening parenchyma demonstrates interstitial fibrosis, tubular atrophy, chronic inflammation, and vascular sclerosis.
• Autosomal recessive polycystic kidney disease
  
  
  • The kidneys are enlarged bilaterally, but a reniform shape is preserved. With neonatal presentation, the kidneys may be 10-20 times normal size. Radial cysts are typically smaller than 3 mm in diameter and extend perpendicularly from the papillary tips to the surface of the cortex. Microscopically, the cysts are lined by flattened (undifferentiated) epithelium and represent fusiform dilation of collecting tubules that retain their connection to the afferent and efferent tubules. The parenchyma adjacent to the cysts progressively develops interstitial fibrosis and glomerulosclerosis.
  • The liver is grossly enlarged, and microscopic evaluation demonstrates bile duct dilatation and periportal fibrosis. This histologic pattern is known as congenital hepatic fibrosis (CHF) and is always present in ARPKD. However, CHF is not specific to this disease.
• GCKD is characterized by dilatation of Bowman space without involvement of the related tubule. The dilated Bowman spaces are lined by a flattened epithelium and contain rudimentary glomerular tufts.¹³
• Juvenile nephronophthisis and medullary cystic kidney disease: These diseases are characterized by thickening and wrinkling of the tubular basement membrane, tubular atrophy, and interstitial fibrosis, leading to bilaterally small kidneys with a pitted surface.³ The renal cortex is uniformly thinned, and cysts are located at the corticomedullary junction and are derived from the collecting ducts and distal tubules.¹² The number of cysts varies (5-50), and cysts measure from several millimeters to 1 cm. However, 25% of cases do not involve grossly visible cysts. Microscopic evaluation demonstrates that the cysts are lined by single layers of cuboidal epithelium.

• TS: Renal cysts are uncommon and usually not extensive, but diffuse cystic renal disease that involves both the cortex and the medulla is occasionally noted, particularly in children. Cysts vary in size from several millimeters to 3 cm. Diffuse renal cystic disease grossly resembles kidneys affected by ADPKD. Microscopically, the cysts are lined by large eosinophilic cells with enlarged hyperchromatic nuclei.¹
• Von Hippel-Lindau syndrome (VHLS): Multiple renal cysts develop bilaterally. Renal cysts are lined with glycogen-rich, clear-appearing cells (similar to those observed with grade I clear-cell renal cell carcinoma [RCC]). Atypia and epithelial hyperplasia are common in the cysts.

• Acquired renal cystic disease
  
  
  • Gross evaluation of early disease reveals cortical cysts filled with clear fluid. Cysts are usually smaller than 0.5 cm in diameter but may be as large as 3 cm in diameter. With more advanced disease, medullary cysts are observed. The disease may progress to numerous diffusely distributed cysts and resemble a small kidney affected by ADPKD.
  • Microscopy reveals a flattened, hyperplastic tubular epithelial lining. Foci of epithelial hyperplasia or renal adenomas are common. The remaining renal tissue exhibits sclerotic glomeruli, atrophic tubules, and interstitial fibrosis. Oxalate crystals are common in the walls of cysts.
• MSK: Gross evaluation reveals normal-sized kidneys, which may be unremarkable with the exception of at least one enlarged and pale renal pyramid. The disease is bilateral in 70% of cases. Microscopic evaluation reveals dilated collecting ducts lined by cuboidal or flattened epithelium. The cystlike cavities range in size from 1-7.5 mm (usually 1-3 mm) and are present in the papillary portions of the pyramids. Roughly half of the dilated channels contain calcifications. Inflammatory infiltrate is found adjacent to the dilated tubules.
• Simple cysts: Cysts measure 1-5 cm in diameter and are filled with clear fluid. The cysts are usually lined by a flattened layer of epithelium, although they may lack an epithelial lining.

TREATMENT

Section 6 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Effective means of prevention or modulation of disease have not yet been identified. Current treatment is aimed at symptom control. In general, therapy is reserved for pain, hypertension, infection, renal salt wasting, and nephrolithiasis.

• Inherited cystic renal disease
• • Autosomal dominant polycystic kidney disease
  • • Patients have decreased ability to concentrate urine and should be encouraged to drink 1-2 L of water daily.
    • Generally, 130/80 is considered the treatment goal for hypertension in this population. Moderate hypertension may be treated with sodium restriction (ie, <100 mEq/d), exercise, and weight control. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are effective in controlling hypertension in autosomal dominant polycystic kidney disease (ADPKD). However, ACE inhibitors have been associated with reversible renal failure in polycystic kidney disease. Calcium channel blockers also are effective in managing hypertension in ADPKD.
    • Prevention of infection with appropriate precautions is important, particularly in women. Avoid urinary tract instrumentation whenever possible.
    • Treatment of infection involving cystic kidneys requires a prolonged course of antibiotics. Most cyst walls are permeable to polar antibiotics, including cephalosporins, penicillin derivatives, and aminoglycosides. Occasionally, cysts are relatively impermeable to these agents and require parenteral lipophilic antibiotics, such as ciprofloxacin, erythromycin, chloramphenicol, or a tetracycline. Clinical evaluation findings, including sterile urine, lack of fever, and no renal pain on deep palpation, should guide the route and duration of antibiotic therapy.
  • Autosomal recessive polycystic kidney disease (ARPKD): The newborn is provided supportive therapy while the degree of pulmonary insufficiency and the etiology is reviewed. Dialysis may be required for renal failure. With less severe childhood disease, edema often is a problem and is managed with sodium restriction and loop diuretics. Hypertension is controlled with salt restriction and antihypertensives, with particular emphasis on the use of ACE inhibitors and ARBs.
  • Juvenile nephronophthisis (JNPHP) and medullary cystic kidney disease: With severe salt wasting, salt supplementation may improve renal function and slow renal demise. End-stage renal insufficiency necessitates dialysis or renal transplantation.
• Acquired cystic renal disease
• • Acquired renal cystic disease (ARCD): Mild bleeding episodes may be managed with bed rest and analgesics.
  • Medullary sponge kidney (MSK): Encourage patients with nephrolithiasis to produce 2 L of urine daily. Patients with hypercalcuria may benefit from oral thiazide diuretics. Patients may develop UTI and should be taught preventative measures.
  • Simple cyst: An infected simple cyst usually requires a combination of antimicrobial and surgical management. Pathogens encountered most frequently in infected simple cysts include Enterobacteriaceae, staphylococci, and Proteus species.

• Inhibitors of the EGF receptor tyrosine kinase have been shown to slow cyst development and extend the life span in polycystic mice. Clinical trials with these agents are underway.²¹
• The identification of mTOR as a possible common pathway to cyst development makes this protein an attractive target for therapy. Rapamycin inhibits mTOR and has been shown to stop kidney growth and even allow regression in kidney size in a mouse model. Additionally, a retrospective comparison of patients treated with rapamycin to those not treated demonstrated a 25% decrease in kidney volume in the treatment group.^{15, 16} Further study is required to determine the relevance and efficacy of such therapy in a clinical population.

Surgical Care

• Multicystic dysplastic kidney (MCDK): Previously, the involved kidney was routinely removed to prevent the subsequent development of symptoms. Today, however, surgical excision is indicated only if the dysplastic kidney interferes with respiratory or digestive function or if significant hypertension has developed. Additionally, cyst rupture, which can occur spontaneously or secondary to trauma, may require emergent surgical intervention.
• Inherited cystic renal disease
• • ADPKD: Significant chronic pain may result from expansion of renal cysts. Percutaneous aspiration and sclerosis may control these symptoms successfully. However, for the management of severe pain, particularly for large kidneys with innumerable cysts, surgical excision may be preferred. Laparoscopic techniques have been used with good outcomes. Nephrectomy may be performed simultaneously with renal transplantation in order to create space for the transplanted kidney and to relieve symptoms associated with the native polycystic kidney. Overall, patients may obtain relief that lasts several years with surgical intervention. In extreme cases of liver enlargement, severe pain and wasting may result. Partial hepatectomy may alleviate these symptoms.
  • ARPKD: In patients with severe portal hypertension, sclerotherapy or portosystemic shunt placement may be necessary to control bleeding. Splenectomy may be indicated for splenomegaly with significant complications.
  • JNPHP and medullary cystic kidney disease (MCKD): If transplantation is considered, selecting an older or unrelated donor is advisable to minimize the risk of the transplanted kidney also being affected with these diseases.
• Acquired cystic renal disease
• • ARCD: Persistent or severe hemorrhage may necessitate nephrectomy or renal embolization. If a 3-cm renal mass suggestive of renal cell carcinoma (RCC) is noted, a partial or radical nephrectomy is indicated.
  • Simple, intermediate, and suspicious cysts: Simple renal cysts rarely require surgical management to relieve pain or obstruction. Treatment options include aspiration, sclerosis, open resection, endoscopic marsupialization and fulguration, percutaneous resection, and laparoscopic resection.
  • Bosniak category III and IV renal cysts require surgical exploration. Approximately 50% of Bosniak category III cystic renal lesions are malignant. Management depends on the appearance of the lesion and varies from exploration and biopsy to nephrectomy. The current standard approach is open exploration with anticipated partial nephrectomy. However, as the experience with laparoscopic exploration and nephrectomy grows, this technique may prove equally reasonable.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

No specific medical therapies are available for the renal cysts themselves. Complications of cystic renal diseases, such as hypertension, infection, and pain, are treated with standard medical therapy. Some examples are listed below.

Drug Category: Angiotensin-converting enzyme inhibitors

These agents reduce aldosterone secretion.

Drug Category: Angiotensin II receptor antagonists

These agents antagonize the effects of angiotensin II.

Drug Category: Calcium channel blockers

In specialized conducting and automatic cells in the heart, calcium is involved in the generation of the action potential. The calcium channel blockers inhibit movement of calcium ions across the cell membrane, depressing both impulse formation (automaticity) and conduction velocity.

Drug Category: Antimicrobials

These agents are used to treat renal parenchymal infection (to be used in combination with gentamicin) and infected renal cysts.

Drug Category: Thiazide diuretics

These agents are beneficial in the treatment of fluid retention.

Drug Category: Analgesics

Pain control is essential to quality patient care. Analgesics ensure patient comfort and have sedating properties, which are beneficial for patients who experience pain.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Developmental cystic renal disease: Patients with multicystic dysplastic kidney should be observed with periodic sonography to monitor for neoplastic changes.
  
• Inherited cystic renal disease: Patients with autosomal dominant polycystic kidney disease (ADPKD) should be screened for intracranial saccular aneurysms with magnetic resonance angiography (MRA) or another imaging modality.
  
• Systemic disease with associated renal cysts
  
  • Acquired renal cystic disease (ARCD): Screen patients with chronic renal failure for acquired cystic disease because of the associated risk of renal cell carcinoma (RCC). Initial ultrasound or CT scan screening may be performed after 3 years of dialysis and is repeated every 1-2 years thereafter. In patients with ARCD, contrast-enhanced CT scan can be performed annually to screen for carcinoma. This screening may be most valuable in younger patients and in patients with large cysts.
    
  • Medullary sponge kidney (MSK): Regular follow-up care with sonography and urinalysis is recommended to monitor for calculi or infection.
    
  • Simple, intermediate, and suspicious renal cysts: If the CT identification of a simple cyst is equivocal, observe the cyst with repeat scans. For Bosniak category IIF lesions, perform contrast-enhanced renal CT scan studies in 6 months and annually thereafter for at least 5 years.
    
  • Some experts suggest that patients with Bosniak category II lesions require no follow-up. However, the data are confusing because reported larger cases series did not separate category IIF from category II lesions. Thus, these series report malignancy rates of up to 14% for category II lesions. Given these rates, some physicians also choose to follow up with patients with category II lesions (treating them as IIF lesions).
    
• Systemic disease with associated renal cysts
  
  • Tuberous sclerosis (TS): Screen patients with periodic CT scan or sonography to monitor for carcinoma development. A noncystic mass that lacks the fat of a typical angiomyolipoma or an enlarging cyst may suggest carcinoma.
    
  • Von Hippel-Lindau syndrome (VHLS): Perform renal sonography annually to monitor cyst or other mass development. In patients with multiple cysts, perform CT scan or MRI every 1-3 years to monitor for RCC.
    
• Acquired cystic renal disease
  
  • Acquired renal cystic disease (ARCD): The value of screening patients with chronic renal failure for the development of acquired cystic disease is debated. Some advocate screening because of the associated risk of RCC. Decision analyses have demonstrated that screening is valuable only in patients with a life expectancy of more than 25 years. Thus, in the United States, screening is limited to patients who have been on dialysis for more than 5 years, have extended expected survival, and are showing signs of acquired cystic renal disease.⁵ Ultrasonography or CT scan should be used for initial screening and repeated every 1-2 years thereafter. In patients with known ARCD, contrast-enhanced CT scan can be performed annually to screen for carcinoma.
    
  • MSK: Regular follow-up care with sonography and urinalysis is recommended to monitor for development of calculi or infection.
    
  • Simple, intermediate, and suspicious renal cysts: If the CT identification of a simple cyst is equivocal, observe the cyst with repeat scans. For Bosniak category IIF lesions, perform contrast-enhanced renal CT scan studies in 6 months and annually thereafter for at least 5 years.
    
  • Some experts suggest that patients with Bosniak category II lesions require no follow-up. However, the data are confusing because reported larger cases series did not separate category IIF from category II lesions. Thus, these series report malignancy rates of up to 14% for category II lesions. Given these rates, some physicians also choose to follow up with patients with category II lesions (treating them as IIF lesions).

Complications

• Developmental cystic renal disease: Concerns in patients with multicystic dysplastic kidney (MCDK) include cyst rupture, infection, calcification, and malignancy.
  
• Inherited cystic renal disease: If a patient experiences persistent pain, consider the possibility of renal infection, tumor, or nephrolithiasis. Ten to 20% of patients have urate or calcium oxalate nephrolithiasis. One third to one half of patients experience renal infection, including infected cyst and pyelonephritis (women are affected more frequently than men). Perinephric extension with abscess is a potential sequela and has a 60% mortality rate. Reports suggest increased rates of RCC, with carcinoma developing in 1-5% of patients with ADPKD. Berry aneurysms often are stressed by concomitant hypertension, and they bleed in 5-10% of patients.
  
• Systemic disease with associated renal cysts
  
  • TS: RCC occurs in a small percent of patients with TS (<5%).
    
  • VHLS: Seventy percent of patients with VHLS who survive to age 60 years develop RCC. The tumor is frequently bilateral and multicentric.
    
• Acquired cystic renal disease
  
  • ARCD: This condition is associated with RCC, although a causal relationship has not been established. The incidence of RCC is 30 times greater in people with ARCD than in the general population, 4-7% over a 7- to 10-year period. Notably, this rate is much higher in men than women (male-to-female ratio, 7:1) and in patients with cysts enlarging the kidney outside the normal range. Patients may also have cyst rupture and hemorrhage, although fewer than 14% of patients experience episodes of hematuria. With cyst rupture, hemorrhage into the pelvis or retroperitoneum can occur.
    
  • MSK: Nephrolithiasis and nephrocalcinosis are common in patients with MSK. MSK is found in 8.5-20% of patients with nephrolithiasis. The dilated collecting ducts may have relatively diminished flow, favoring calcium deposition. Other common complications of this disease include renal infection and hematuria. A rare complication is renal abscess, which requires a prolonged course of antibiotics and possible surgical drainage.
    
  • Simple cyst: A simple cyst can become either hemorrhagic or infected. The cause of the hemorrhage is often unclear, but it may be related to trauma, bleeding diatheses, or varices in the cyst wall. Infected cysts may be due to a disseminated hematogenous infection, ascending UTI, or urologic instrumentation.

Prognosis

• Developmental cystic renal disease: If bilateral, MCDK is incompatible with life. More typically, the disease is unilateral or segmental and is discovered on prenatal sonogram.
• Inherited cystic renal disease
  
  
  • ADPKD: Renal insufficiency typically develops in people older than 30 years, and 45% of patients progress to end-stage renal failure by the age of 60 years. One third of patients die secondary to renal failure, one third die due to complications from hypertensive nephropathy (HTN), and 6-10% die secondary to subarachnoid hemorrhage.
  • Autosomal recessive polycystic kidney disease (ARPKD): Neonates presenting with ARPKD often die within 6 weeks secondary to pulmonary disease and renal failure. If patients survive this first period, they have an 80% chance of living to 15 years. For patients presenting in infancy, approximately one third progress to severe renal insufficiency at age 5 years and nearly 100% progress by age 20 years.
  • Juvenile nephronophthisis (JNPHP) and medullary cystic kidney disease (MCKD): Patients typically progress to renal failure within 5-10 years of presentation.
• Systemic disease with associated renal cysts: As many as 40% of patients with VHLS develop RCC, which is the leading cause of death.
• Acquired cystic renal disease
  
  
  • Acquired cystic renal disease is progressive while the patient remains on dialysis. The disease often regresses after transplantation, but associated tumors may become more aggressive because of the patient's immunosuppression.⁵
  • MSK carries an excellent prognosis and is typically nonprogressive.

Patient Education

• Inherited cystic renal disease: Genetic counseling is important in all of the heritable diseases. Individuals with autosomal dominantly inherited diseases (eg, ADPKD) need to be counseled that their offspring have a 50% chance of developing the disease. Those with autosomal recessively inherited diseases (eg, ARPKD) should be counseled that all of their offspring will carry the disease. Parents of children with an autosomal recessively inherited disease should be counseled that subsequent children have a 25% chance of having the disease and a 50% chance of being an unaffected carrier of the gene.
• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Blood in the Urine.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• The Bosniak classification system greatly varies from observer to observer, particularly in the differentiation of Bosniak category II from Bosniak category III lesions. Additionally, a significant portion of Bosniak category II lesions may prove to be malignant. In one series, 14% of lesions so categorized were found to be malignant. Thus, adherence to classification standards and recommended follow-up care, particularly for Bosniak category IIF, should be strictly followed.

Special Concerns

• Avoid instrumentation of the lower urinary tract in patients with cystic renal diseases who have increased susceptibility to infection (ie, with autosomal dominant polycystic kidney disease [ADPKD], autosomal recessive polycystic kidney disease [ARPKD], medullary sponge kidney [MSK]).

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References