Cystic Diseases of the Kidney

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

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.

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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.

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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]

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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
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