Cystic Diseases of the Kidney 

Updated: Mar 28, 2017
Author: Thomas Patrick Frye, DO; Chief Editor: Bradley Fields Schwartz, DO, FACS 

Overview

Practice Essentials

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[1] :

  • 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)

The most common larger cysts include acquired cysts, simple cysts, and cysts associated with ADPKD. Smaller cysts characterize ARPKD, JNPHP, MCKD, and MSK. In adults, renal angiomyolipomas and RCC may also have cystic components.

The presentation and workup in patients with renal cysts varies with the underlying disease. Treatment is aimed at symptom control. In general, therapy is reserved for pain, hypertension, infection, renal salt wasting, and nephrolithiasis.

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

MCDK represents abnormal development or formation of the kidney and may involve part, or all of, one or both kidneys. This condition is thought to be secondary to dysfunctional genetics, abnormal differentiation of the metanephros or in utero ureteral obstruction. Patients are observed unless complications arise directly from the kidney or its associated conditions.

Inherited cystic renal disease

ADPKD is due to mutations in the genes PKD1 and PKD2, which encode polycystin proteins. Mutations in these genes can be inherited in autosomal dominant or recessive forms, with varying levels of penetrance. The genetic mechanism of cyst development requires a "second hit," a somatic mutation of the normal PKD allele, which accounts for the onset of ADPKD, usually in those aged 30-50 years.

Symptoms primarily include pain, hypertension and renal failure. The goal of treatment is to control blood pressure and to slow the onset of renal failure. ADPKD is associated with involvement of other organs, particularly intracranial aneurysms, which have an asymptomatic prevalence of 8% overall and 23% in patients 60-69 years old.[2]

ARPKD is due to mutations in PKHD1, a large gene that encodes fibrocystin/polyductin, which plays critical roles in collecting-tubule and biliary development. This disease carries a high neonatal mortality rate, and many individuals who survive eventually require renal transplantation. Symptoms include hypertension and liver disease. Diagnosis is often made in utero. Treatment is supportive in severe cases but otherwise is similar to that for ADPKD.

GCKD is often confused with ADPKD, as it is common in individuals with a family history of ADPKD. This disease is distinguished histologically and symptoms and treatment are similar to those in ADPKD.

JNPHP and medullary cystic disease are two diseases that some consider a disease complex.[3] They share similar pathologic features but are due to different genetic mutations and have different inheritance patterns. JNPHP is inherited in an autosomal recessive manner and presents in childhood, while MCKD is inherited autosomal dominantly and affects adults. Both diseases present with symptoms of salt wasting and polyuria.

Systemic disease with associated renal cysts

TS is caused by mutations in the suppressor genes TSC1 and TSC2, which encode hamartin and tuberin, respectively.  Mutations of TSC2 are much more frequent than mutations of TSC1 and are associated with more severe disease.[4]  Renal cysts and angiomyolipomas are part of a syndrome that includes seizures and dermatologic findings.

VHLS is due to mutations in the VHL gene, which increases the risk for malignancy, including RCC. Affected individuals develop cysts in multiple organs, including the kidney, pancreas, liver, and epididymis.

Acquired cystic renal disease

The exact cause of this disease is not known. It occurs exclusively in patients on dialysis. The severity of disease is directly related to the duration of therapy. Typically, acquired cystic renal disease is asymptomatic but it is known to subsequently increase the risk of RCC.

Etiology

The etiology of renal cysts includes the following:

  • Developmental cystic renal disease

  • Inherited cystic renal disease

  • Systemic disease with associated renal cysts

  • Acquired cystic renal disease

  • Unilateral renal cystic disease

Developmental cystic renal disease

Multicystic dysplastic kidney (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.[5] 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

See the list below:

  • Inherited cystic renal diseases include the following:

  • Autosomal dominant polycystic kidney disease (ADPKD)

  • Autosomal recessive polycystic kidney disease (ARPKD)

  • Glomerulocystic kidney disease (GCKD)

  • Juvenile nephronophthisis (JNPHP)

  • Medullary cystic kidney 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.

Autosomal dominant polycystic kidney disease

Inheritance of ADPKD is autosomal dominant, with close to 100% penetrance. PKD1 (chromosome 16p13) 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 4q21), a calcium channel important for PC1 localization and function, account for the remaining 10-15%.[7]

Interestingly, while ADPKD 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.[3] Five to 8% of cases do not involve a family history and are the result of spontaneous mutations.

Autosomal recessive polycystic kidney disease

All cases of ARPKD 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.[8] 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.[7]

Glomerulocystic kidney disease

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.[9]

Juvenile nephronophthisis

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.[10, 7, 11] Ten to 20% of cases are associated with retinal disease and are termed Senior-Loken syndrome.

Genes involved in JNPHP are as follows:

  • 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. It is inherited in an autosomal dominant manner.[7]

Systemic disease with associated renal cysts

Tuberous sclerosis (TS) is inherited in autosomal dominant fashion, 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, 3] 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.

Inheritance of von Hippel-Lindau syndrome is autosomal dominant, with variable penetrance. The genetic defect has been localized to chromosome band 3p25.

Biochemical analyses[12, 13] have identified a protein (mammalian target of rapamycin [mTOR]) that may be part of a common pathway in several of the genetic forms of cystic disease. Activity of mTOR is related to cell growth, proliferation, apoptosis, and differentiation. Increased levels of mTOR have been found in cyst epithelium. Under normal conditions, PC1 (mutated in ADPKD) and TSC2 (mutated in TS) suppress or inactivate mTOR. Mutations in these genes, as well as in others that relate to the primary cilia, result in dysregulation of mTOR activity, possibly allowing cyst formation.

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.[3] The disease occurs in patients on all types of dialysis and appears to regress after transplantation.

Unilateral renal cystic disease

This is a rare disease characterized by multiple cysts with intervening normal parenchyma in one kidney. It looks similar to ADPKD on both imaging and pathologic examination. Patients may present with hematuria, pain, or a flank mass. This is a benign entity and is not associated with cysts or malformations in other organs.[14]

Epidemiology

Frequency

United States

The epidemiology of disorders associated with renal cysts is as follows:

  • MCDK has an incidence of one per 1000-4000 live births[5]

  • ADPKD has an incidence of one per 500-1000 persons, affecting 12.5 million worldwide, and accounts for 8-10% of all cases of end-stage renal disease (ESRD) and 5-10% of renal transplants[15]

  • ARPKD has an incidence of one per 6000-55,000 live births, corresponding to one per 70 unaffected carriers in the general population

  • JNPHP affects one per 5000 persons[10]

  • 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 one per 10,000-50,000 persons, and 20-25% of these patients have renal cysts[16]

  • VHLS has an incidence of approximately one 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, in 10-20% of patients after 3 years of dialysis, in 40-60% after 5 years, and in more than 90% after 10 years[17]

  • MSK has an estimated incidence of one 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 fewer than 1% of RCC cases

Mortality/Morbidity

Neonatal mortality secondary to ARPKD approaches 25-35% and is usually related to respiratory compromise.[6] In many forms of cystic renal disease, morbidity and mortality is secondary to end-stage renal disease (ESRD) and renal cell carcinoma (RCC).

End-stage renal disease

Rates of ESRD are as follows:

  • Cystic renal disease accounts for approximately 10% of all ESRD cases

  • ADPKD is one of the top four 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

  • More than 50% of patients with ARPKD require kidney transplant before age 20 years[8]

  • JNPHP is the most common cause of genetic ESRD in children[11]

Malignancy

Risk of RCC in cystic diseases of the kidney is as follows:

  • Tuberous sclerosis: RCC occurs in a small percent of patients with TS (< 5%)

  • Von Hippel-Lindau syndrome: 70% of patients with VHLS who survive to age 60 years develop RCC; the tumor is frequently bilateral and multicentric

  • Patients with acquired cystic disease are more likely to develop RCC (5-25%); additionally, tumors are commonly bilateral, and 15% are metastatic[17]

Although a causal relationship between acquired renal cystic disease (ARCD) and RCC 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 that enlarge the kidney outside the normal range.

Cancer incidence in patients receiving renal transplants for polycystic kidney disease (PKD) was 48% higher than that expected in the general population, in a study of 10,166 renal transplant recipients with PKD and 107,339 transplant recipients without PKD; but after adjustment for age and other factors, cancer incidence was lower in PKD transplant recipients than non-PKD recipients[18]

Other morbidity

Multicystic dysplastic kidney

Concerns in MCDK include the following:

  • Cyst rupture

  • Infection

  • Calcification

  • 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. Berry aneurysms often are stressed by concomitant hypertension, and they bleed in 5-10% of patients.

Acquired renal cystic disease

Patients with ARCD may 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.

Medullary sponge kidney

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 cysts

A simple cyst can become 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. Cyst infection may result from disseminated hematogenous infection, ascending urinary tract infection, or urologic instrumentation.

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

Sex-related demographics of disorders associated with renal cysts are as follows:

  • 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

Age-related demographics of disorders related to renal cysts are as follows:

  • ADPKD has a bimodal distribution of onset, with some cases presenting in infancy and 2% presenting before the age of 15 years[10]

  • 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 in children but increase in frequency with age

 

Presentation

History

Presentation in patients with renal cysts varies with the underlying disease.

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.[19] 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.[20]

Inherited cystic renal disease

Inherited cystic renal disease includes the following disorders:

  • Autosomal dominant polycystic kidney disease (ADPKD)
  • Autosomal recessive polycystic kidney disease (ARPKD)
  • Glomerulocystic kidney disease (GCKD)
  • Juvenile nephronophthisis (JNPHP)
  • Medullary cystic kidney disease

Autosomal dominant polycystic kidney disease

Manifestations of ADPKD vary by patient age, as follows:

  • 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
  • Patients progress to end-stage renal disease (ESRD) in the sixth decade of life
  • Hypertension is seen in 50% of patients with ADPKD aged 20-34 years

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.[21]

All aspects of the disease appear to develop more significantly in patients with the PKD1 genotype. Despite similar rates of cystic growth, these patients develop more cysts at a younger age than patients with PKD2 mutations, and subsequently develop hypertension and ESRD 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.[7]

In addition, studies have suggested that the type of PDK1 mutation also affects prognosis. In one series, patients with non-truncating mutations (about 20%) developed ESRD 12 years later than those with truncating mutations, at 67.9 versus 55.6 years of age, respectively.[22]

Hepatic cysts are the most common extrarenal manifestation of 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.

In a study of 558 patients with ADPKD, hepatomegaly was common even in early-stage disease and was not accounted for by cysts alone. Compared with the liver volumes of patients without ADPKD, parenchymal volumes were larger, even in patients who did not have cysts. Polycystic liver disease severity was associated with altered biochemical and hematologic laboratory tests and a lower quality of life.[23]

Other clinical associations in ADPKD include the following:

  • Cardiac valve disease (particularly mitral valve prolapse [25%])
  • Diverticulosis
  • Cerebral aneurysms (5-10%)
  • Pancreatic cysts
  • Seminal vesicle cysts [6]

Autosomal recessive polycystic kidney disease

ARPKD affects renal and hepatic development (dysgenesis of the portal triad). However, 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 or pulmonary hypoplasia. This presentation may result in neonatal death.

Symptoms in infancy include hypertension (80%), diminished urine-concentrating ability, renal insufficiency, and subsequent electrolyte abnormalities. Most affected children develop hypertension within the first few years of life. Growth retardation has been reported in one fourth of children. Up to 26.5% develop significant hyponatremia.[24] 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 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.[9]

Juvenile nephronophthisis

JNPHP 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 (polyuria and polydipsia), skeletal dysplasia, anemia, and progressive renal failure. Additionally, some degree of hepatic fibrosis and biliary duct enlargement is usually present.[3] Cysts usually occur secondary to ESRD and in the corticomedullary junction.

Medullary cystic kidney disease

This disorder 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.[3]

Systemic disease with associated renal cysts

Clinical features of tuberous sclerosis (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.

Clinical features of von Hippel-Lindau syndrome (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.[25]

Acquired cystic renal disease

Acquired renal cystic disease (ARCD) may be found in patients with all etiologies of ESRD, particularly in those 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.[16]

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. Occasionally, however, they hemorrhage and cause acute pain.

Physical Examination

In developmental cystic renal disease, MCDK may be palpable as a flank mass in an otherwise healthy infant. MCDK is the most common cause of a renal mass and the second most common cause of a palpable abdominal mass in neonates.[26, 5]

Inherited cystic renal disease produces the following findings:

  • 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

In acquired cystic renal disease, simple cysts rarely become large enough to be palpable.

 

DDx

Diagnostic Considerations

Other problems to be considered include the following:

  • Angiomyolipomas

  • Cysts of the renal sinus (including peripelvic cysts, parapelvic cysts, parapelvic lymphatic cysts, and parapelvic lymphangiectasia)

  • Hemangioma

  • Multilocular cystic nephroma

Differential Diagnoses

 

Workup

Laboratory 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.

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 two 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.[27]

Autosomal recessive polycystic kidney disease (ARPKD)

Genetic testing for mutations at PKHD1 is currently available, with 80-85% detection rates in patients with strong clinical and/or histopathological evidence.[8] Current guidelines do not recommend the use of PKHD1 mutational analysis as a first-line diagnostic test, due to the large number of similar disorders that involve mutations in other genes (eg, HNF1B, which is responsible for disorders including hepatorenal fibrocystic disease).[28] However, early prenatal diagnosis is feasible only by single-gene testing. Additionally, genotype is currently not a predictor for clinical course. Correlations are complicated by inheritance of different mutations from each parent.

On prenatal ultrasound, Erger et al reported sonographically visible kidney cysts in only 3% of ARPKD cases. Pulmonary hypoplasia, oligohydramnois or anhydramnios, and kidney enlargement were associated with a significantly worse neonatal prognosis.[29]

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. Annual complete blood cell counts (CBCs) should be performed, with attention to the platelet count, due to the risk of portal hypertension and splenic dysfunction.

See also Imaging in Autosomal Recessive Polycystic Kidney Disease

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 weeks' gestation.[16] Sonography demonstrates multiple variably sized, noncommunicating cysts outlined by hyperechoic intervening renal parenchyma.[30] The corresponding ureter and renal pelvis are typically not visualized. See the image below.

A prenatal sonogram of a fetus with a multicystic 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 1 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.[20]

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.[16]

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. More 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.[20]

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 computed tomography (CT), ultrasonography, or magnetic resonance imaging (MRI). The Consortumium for Radiologic Imaging for the Study of Polycycstic Kidney Disease has demonstrated a mean increase in renal volume of 63.4 mL per year in an exponential fashion in their cohort of 200 patients.[31]

Sonographic criteria for ADPKD depend on patient age. Sonographic diagnosis in individuals at 50% risk for the disease involves two unilateral or bilateral cysts in patients younger than 30 years, two cysts in each kidney in individuals aged 30-59 years, and four cysts in each kidney in individuals 60 years or older. See the images below.

CT examination of the abdomen of a 70-year-old wom 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 wit 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.

Recommendations do not exist for intracranial aneurysm screening but it is advised, especially in patients with a positive family history.[16] The screening can be readily accomplished noninvasively with magnetic resonance angiography (MRA).

Autosomal recessive polycystic kidney disease

Second-trimester ultrasound imaging of bilateral hyperechogenic kidneys with poor corticomedullary differentiation suggests a diagnosis of ARPKD. Other features include enlarged kidneys that maintain their reniform shape and have increased echogenicity. Finding large echogenic kidneys with poor corticomedullary differentiation and coexisting liver disease by ultrasound is sufficient for diagnosis. Genetic testing is needed only in cases ambiguous by imaging.[32]

With severe renal disease, absence of urine in the bladder, 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 two standard deviations greater than normal and diffusely hyperechogenic. In 29% of cases, bilateral cysts of 5-7 mm are found at presentation.[33] 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.

If severe oligohydramnios is seen, fetal MRI should be used, as it better shows renal anatomy. ARPKD is associated with signal void in a contracted bladder on a T2-weighted sequence.[34] Furthermore, MRI can be used to predict nonsurvival. In one series of 46 fetuses, a ratio of MRI-calculated lung volume to gestational age of 0.90 (in fetuses with a gestational age of over 26 weeks) demonstrated a sensitivity and specificity of 77.8% and 95%, respectively, for predicting mortality.[35]

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 can be visualized with ultrasonography, which demonstrates hepatomegaly with echogenic parenchyma (secondary to fibrosis), hepatic cysts, and dilatation of the peripheral hepatic ducts with fibrous bridging.[16] Magnetic resonance cholangiography is more sensitive in detecting dilated biliary ducts. Patients at the age of 5 years should have abdominal ultrasound performed, with followup every 2-3 years.[32]

Once a diagnosis is made by imaging, serial assessment by ultrasound should be performed every 2-3 weeks. Particular attention should be paid to the onset of oligohydramnios, as it is a predictor for nonsurvival. In one series, oligohydramnios in the presence of kidney size >4 standard deviations above the mean was associated with 100% mortality in the perinatal period.[36]

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.[9]

On CT and MRI, glomerulocystic kidney disease (GCKD) appears as numerous small cortical cysts. These do not enhance with gadolinium during MRI.[37]

Juvenile nephronophthisis and medullary cystic kidney disease

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.[16]

Acquired cystic renal disease

Acquired renal cystic disease (ARCD) can be diagnosed if involvement is bilateral, with at least four 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. See the image below.

This CT scan demonstrates acquired renal cystic di 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

In medullary sponge kidney (MSK), findings on plain radiographs may be normal, or radiographs may reveal 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) homogeneous 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.

Computed tomography

CT remains the gold standard for investigation of renal cysts, as it has been able to delineate malignancy and is the basis of the intitial Bosniak classification. Predictors of malignancy include thickened irregular wall or septa, enchancing soft tissue, and internal cyst heterogeneity. Of these factors, septal and nodular enchancements provide a sensitivity of 100% and sensitivity of 86%. Furthermore, contrast enhancement of 42 Hounsfield units (HU) between the corticomedullary phase and the pre-contrast phase is an independent predictor of malignancy.[38]

The use of CT is more difficult for small and intermediate lesions. New techniques to better define these lesions have surfaced, including dual-energy CT, thinner slicing (3 mm), and delayed-contrast CT.[39] Dual-energy CT is better able to expose vascularity which is a predictor for malignancy. Thinner slicing at 3 mm used in overlapping sections improves detection of renal cysts < 5 mm. Finally, using delayed contrast enhancement can better differentiate renal cell carcinomas from non-neoplastic cysts.[40] These new techniques help address challenging cases of psuedoenhancement.

Magnetic resonance imaging

MRI can be used for the classification of renal cysts as studies have confirmed that MRI results correlate with histopathology. Where MRI gains favor over CT is in the evaluation of cystic fluid; different compositions of fluid, such as blood or protein, have higher predictors of malignancy. These factors can provide upgrading on Bosniak criteria based on CT.[41]

New techniques focus on multiparametric MRI with focus on diffusion weighted imaging (DWI). DWI measures the motion and diffusion of water, which will be different in malignant and benign tissue. Further investigation of this technique is needed due to lack of standardization and determination of the appropriate amount of weighting (b value).

Bosniak classification

Bosniak has described a classification scheme for renal cysts based on CT scan findings. The categories are as follows[42] :

  • 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)

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.[43]

A multi-institutional review of Bosniak IIF and III cystic lesions has been performed. The malignancy rate of resected Bosniak IIF lesions was 25% (4/16) and that of Bosniak III lesions was 54% (58/107). Thirteen percent of Bosniak IIF lesions progressed at follow-up with half of them being malignant at resection. Risk factors for having malignancy seen with a Bosniak III lesions were: history of primary renal malignancy, coexisting Bosniak category IV lesion and/or solid renal mass, and multiplicity of Bosniak III lesions. Importantly, all patients had localized disease with either Bosniak IIF or III lesion.[44]

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.

Procedures

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.[45]

Histologic Findings

Developmental cystic renal disease

In 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.[20] The ureter is often stenotic or hypoplastic, and the renal artery is often small or absent.[16]

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. See the image below.

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

Inherited cystic renal disease

In 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.[46] 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. See the images below.

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

In 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.[9]

Juvenile nephronophthisis and medullary cystic kidney disease 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.[10] The renal cortex is uniformly thinned, and cysts are located at the corticomedullary junction and are derived from the collecting ducts and distal tubules.[7]

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

In tuberous sclerosis, 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.[3]

In 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

In 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.

In medullary sponge kidney, 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 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. See the image below.

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

Treatment

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 with autosomal dominant polycystic kidney disease (ADPKD) have decreased ability to concentrate urine and should be encouraged to drink 1-2 L of water daily.

Generally, a blood pressure of 130/80 mm Hg 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 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.

Hypertension appears to correlate with the size of the cyst, and aspiration of renal cysts results in a reduction of blood pressure.[47]

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

Infants with autosomal recessive polycystic kidney disease (ARPKD) should be delivered at a facility with a neonatal intensive care unit of level IV.[48] The newborn should be provided supportive therapy while the degree of pulmonary insufficiency and the etiology is reviewed.

Pulmonary hypoplasia is common and is responsible for 30-40% of mortality.[49] Pulmonary insufficiency can be treated with-high frequency ventilation. Pulmonary hypertension can be reversed with inhaled nitric oxide.

Dialysis may be required for renal failure. In one case series, neonates with ESRD before 28 days of age had 1-year survival of 52% and 5-year survival of 48% with peritoneal dialysis.[50]

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.

The ESCAPE trial (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke) demonstrated that maintaining a mean arterial blood pressure below the 50th percentile for age, height, and sex in children with stage 2-4 chronic kidney disease can increase the length of time before patients progress to ESRD.[51] Currently, there are no specific guidelines for an ideal target blood pressure.[32]

Hypersplenism and associated thrombocytopenia should not be treated with splenectomy. Limitation from contact sports is recommended. Cholangitis secondary to hypersplenism should be treated with a prolonged course of intravenous antibiotics.

Juvenile nephronophthisis (JNPHP) and medullary cystic kidney disease

In patients with severe salt wasting, salt supplementation may improve renal function and slow renal demise. ESRD necessitates dialysis or renal transplantation.

Acquired cystic renal disease

In acquired renal cystic disease (ARCD), mild bleeding episodes may be managed with bed rest and analgesics.

In medullary sponge kidney (MSK), encourage patients with nephrolithiasis to produce 2 L of urine daily. Patients with hypercalciuria may benefit from oral thiazide diuretics. Patients may develop urinary tract infections and should be taught preventative measures.

In patients with simple cysts, a cyst infection usually requires a combination of antimicrobial and surgical management. Pathogens encountered most frequently in infected simple cysts include Enterobacteriaceae, staphylococci, and Proteus species.

Investigational therapy

Research has identified biochemical targets that may allow disease-modifying therapy for renal cystic disease, and several agents have been tested in randomized clinical trials. Results with mammalian target of rapamycin (mTOR) inhibitors were disappointing: In adults with ADPKD and early chronic kidney disease, 18 months of treatment with sirolimus did not halt polycystic kidney growth.[52] Studies of somatostatin analogues (octreotide, lanreotide, pasireotide) have yielded more encouraging results, and additional drugs are being tested.[53]

Vasopressin receptor activation results in increased levels of cyclic adenosine monophosphate (cAMP), and cAMP has been shown to be cystogenic. This provides the rationale for vasopressin receptor blockade. Tolvaptan is a vasopressin receptor antagonist with high affinity in humans. In a 3-year phase III clinical trial in patients with ADPKD, tolvaptan slowed the increase in total kidney volume and the decline in kidney function, compared with placebo, but was associated with a higher discontinuation rate, owing to adverse events.[54]

New candidate drugs are currently being investigated in the preclinical phase. Promising therapies include metformin, rosiglitazone, calcimimetics (R-568), and roscovitine, all of which have shown efficacy in animal models. Metformin and rosiglitazone both have mTOR-inhibiting effects but act on additional pathways. R-568 combats defective Ca2+ intracellular regulation, which favors proliferation, and has been shown to decrease renal fibrosis and late stage cystic volume but has no effect on overall cystic burden. Roscovitine is a cyclin-dependent kinase inhibitor that initiates cell cycle arrest and inhibits cystic disease in mouse models.[55, 56]

Surgical Care

Surgical indications in renal cystic disease vary with the underlying disorder.

Multicystic dysplastic kidney (MCDK)

Previously, the involved kidney in patients with MCDK was routinely removed to prevent the subsequent development of symptoms. Currently, 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

In autosomal dominant polycystic kidney disease (ADPKD), significant chronic pain may result from expansion of renal cysts. Needle aspiration is usually the first-line approach to symptomatic cysts.

Initial resolution and then return of symptoms with reaccumulation of cyst fluid increases the chance that a laparoscopic cyst decortication will eliminate the patient's pain.[57] However, for the management of severe pain, hypertension, hematuria, or infection, surgical excision may be preferred.

Complex cysts can be explored laparoscopically and treated appropriately based on intraoperative frozen sections. Laparoscopic techniques have been used with good results. Studies have reported good outcomes of laparoscopic cyst decortication using a retroperitoneal approach especially for posterior or lower pole lesions.[58, 59]

Percutaneous endocystolysis is another technique described for treatment of symptomatic cysts. The technique involves obtaining percutaneous access, dilating the tract, and then introducing a resectoscope with rollerball electrode to cauterize the internal surface of the cyst. A 13-year experience with this technique reported clinical improvement in 100% of the patients with minimal complications.[60]

Nephrectomy may be performed simultaneously with renal transplantation to create space for the transplanted kidney and to relieve symptoms associated with the native polycystic kidney. The timing of performing the nephrectomy in the transplant patient has been debated. Data suggest that open ipsilateral nephrectomy at the time of transplantation with staged contralateral native nephrectomy has fewer perioperative complications than performing a laparoscopic bilateral nephrectomy.[61] In extreme cases of liver enlargement, severe pain and wasting may result. Partial hepatectomy may alleviate these symptoms.

In autosomal recessive polycystic kidney disease 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. Patients with ESRD can be treated successfully with kidney transplantation. In combination with peritoneal dialysis, kidney transplantation in one series was associated with a 5-year survival of 83%.[50]

In juvenile nephronophthisis (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

In acquired renal cystic disease, 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 renal cysts rarely require surgical management to relieve pain or obstruction. Treatment options include the following:

  • Aspiration

  • Sclerosis

  • Open resection

  • Endoscopic marsupialization and fulguration

  • Percutaneous resection

  • Laparoscopic resection

A randomized trial by Agarwal et al that compared percutaneous sclerotherapy versus laparoscopic unroofing for symptomatic renal cysts determined that both procedures were safe and had equal efficacy. These investigators also concluded that cyst aspiration with sclerotherapy was associated with lower morbidity and shorter hospital stay.[62]

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.

Cystic clear cell renal cell carcinoma

Whether the patient has known pathologically diagnosed malignancy from biopsy or suspected malignancy based on Bosniak classification, a urologist can anticipate good surgical outcomes after resection. In a study of laparoscopic nephrectomy for cystic clear cell RCC, all patients treated were alive after 5 years and no patient had extrarenal disease at the time of surgery. These data suggest that patients with cystic RCC should expect to be cured after surgical resection, and furthermore should undergo nephron-sparing surgery when possible.[63]

 

Medication

Medication Summary

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.

Angiotensin-converting enzyme inhibitors

Class Summary

These agents reduce aldosterone secretion.

Lisinopril (Zestril, Prinivil, Qbrelis)

Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Angiotensin II receptor antagonists

Class Summary

These agents antagonize the effects of angiotensin II.

Losartan (Cozaar)

Nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.

Calcium channel blockers

Class Summary

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.

Diltiazem (Cardizem, Tiazac, Matzim LA, Taztia XT, Cartia XT)

During depolarization, inhibits calcium ions from entering the slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium.

Antimicrobials

Class Summary

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

Ampicillin

Bactericidal activity against susceptible organisms. Alternative to amoxicillin when patients are unable to take medication orally. Used to treat parenchymal infection.

Gentamicin

Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Not the DOC, but consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms. Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be administered IV/IM.

Sulfamethoxazole and trimethoprim (Bactrim, Bactrim DS)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antibacterial activity of TMP-SMZ includes common urinary tract pathogens, except Pseudomonas aeruginosa. Used to treat infected renal cyst.

Ciprofloxacin (Cipro)

Fluoroquinolone with activity against pseudomonas, streptococci, MSSA, S epidermidis, and most gram-negative organisms, but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth.

Used to treat infected renal cyst either in patients intolerant to or not adequately covered by trimethoprim-sulfasalazine.

Thiazide diuretics

Class Summary

These agents are beneficial in the treatment of fluid retention.

Hydrochlorothiazide (Microzide)

Inhibits reabsorption of sodium in distal tubules, increasing excretion of sodium and water, as well as potassium and hydrogen ions.

Analgesics

Class Summary

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

Oxycodone and acetaminophen (Percocet, Endocet, Xartemis XR, Primlev)

Drug combination indicated for the relief of moderate-to-severe pain.

 

Follow-up

Further Outpatient Care

Patients with multicystic dysplastic kidney should be observed with periodic sonography to monitor for neoplastic changes.

Patients with autosomal dominant polycystic kidney disease (ADPKD) should be screened for intracranial saccular aneurysms with magnetic resonance angiography (MRA) or another imaging modality.

In patients with medullary sponge kidney (MSK), regular follow-up care with sonography and urinalysis is recommended to monitor for calculi or infection.

In patients with 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).

Patients with tuberous sclerosis (TS) should be screened 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.

In patients with von Hippel-Lindau syndrome (VHLS), perform renal sonography annually to monitor cyst or other mass development. Biochemical pheochromocytoma screening starting at age 5 with annual lifelong screening.[25]  In patients with multiple cysts, perform CT scan or MRI every 1-3 years to monitor for RCC.

Acquired cystic renal disease

The value of screening patients with chronic kidney disease for the development of acquired renal cystic disease (ARCD) 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 ARCD.[17]

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. This screening may be most valuable in younger patients and in patients with large cysts.

Prognosis

Bilateral multicystic dysplastic kidney (MCDK) is incompatible with life. More typically, the disease is unilateral or segmental and is discovered on prenatal sonogram.

In autosomal dominant polycystic kidney disease (ADPKD), renal insufficiency typically develops in people older than 30 years, and 50% 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, and 6-10% die secondary to subarachnoid hemorrhage.

Neonates presenting with autosomal recessive polycystic kidney disease (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.

In juvenile nephronophthisis (JNPHP) and medullary cystic kidney disease (MCKD), patients typically progress to renal failure within 5-10 years of presentation. In von Hippel-Lindau syndrome, as many as 40% of patients develop renal cell carcinoma, which is the leading cause of death.

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.[17]

Medullary sponge kidney carries an excellent prognosis and is typically nonprogressive.

Patient Education

Genetic counseling is important in all of the heritable cystic renal 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 patient education information, see Blood in the Urine.