Cystic Diseases of the Kidney Workup

• 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. Some authors suggest that until effective treatments become available, the adverse effects from presymptomatic diagnosis in children (psychological, educational, career, and insurability issues) outweigh the benefits.^[17]
  • 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.

• 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.^[18] The corresponding ureter and renal pelvis are typically not visualized. A prenatal sonogram of a fetus with a multicystic dysplastic kidney. The right kidney is appreciated as a large multicystic paraspinal mass. The left kidney and bladder are normal, and a normal amount of amniotic fluid is present.
  • 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. Sonographic diagnosis in individuals at 50% risk for the disease involves 2 unilateral or bilateral cysts in patients younger than 30 years, 2 cysts in each kidney in individuals aged 30-59 years, and 4 cysts in each kidney in individuals 60 years or older. CT examination of the abdomen of a 70-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) is shown. The kidneys are bilaterally enlarged with multiple cysts. CT scan of the same patient (70-year-old woman with autosomal dominant polycystic kidney disease [ADPKD]) demonstrating multiple hepatic cysts.
    • 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). Symptomatic episodes of gross hematuria underestimate the true incidence of hemorrhage, as up to 90% of patients with ADPKD have cysts that are hyperdense on CT. 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.^[19]
  • 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. This CT scan demonstrates acquired renal cystic disease (ARCD) in a 70-year-old man who is dialysis-dependent. The CT scan demonstrates bilateral atrophic kidneys with multiple renal cysts.
  • 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.^[20]
    • 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)
  • Multiphasic CT in combination with Bosniak class can improve diagnostic accuracy. To predict a renal cell carcinoma, a corticomedullary phase minus precontrast phase value of >42 HU resulted in 97.1% sensitivity and 85.7% specificity. This technique can further help guide treatment options.^[21]
  • Another option for patients with renal impairment or allergy to iodinated contrast is contrast-enhanced ultrasound (CE-US). CE-US is a technique that has been shown to be equivalent to CT, and in one experience CE-US was found to be better than CT in the diagnosis of malignancy in Bosniak IIF and III renal cysts.^[22]
  • 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.

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 enzyme CA9 is being studied as a new marker for clear cell renal cell carcinoma. One report showed that CA9 can be detected in the fluid of malignant cystic, but not benign, renal tumors. This marker may be useful to help guide decisions of treatment versus observation in select populations.^[23]

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. Cut surface of a nephrectomy specimen from a patient with a multicystic dysplastic kidney (MCDK).

Inherited cystic renal disease

• 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.^[24] 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. External surface of a nephrectomy specimen from a patient with autosomal dominant polycystic kidney disease (ADPKD). Cut surface of the same nephrectomy specimen from a patient with autosomal dominant polycystic kidney disease (ADPKD).
• 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.

Systemic disease with associated renal cysts

• 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 cystic renal disease

• 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. Nephrectomy specimen from a patient with a large benign simple cyst. Cut section of nephrectomy specimen demonstrating renal cell carcinoma (RCC), with an adjacent simple cyst. Close-up photograph of the cut surface of the same nephrectomy specimen demonstrating a simple cyst adjacent to a renal cell carcinoma (RCC).