Acquired cystic disease of the kidney in adults

INTRODUCTION — Chronic kidney disease (CKD), particularly in patients on maintenance hemodialysis or peritoneal dialysis, is frequently associated with the development of multiple and bilateral kidney cysts, which are usually <0.5 cm in diameter but can be as large as 2 to 3 cm [1,2]. The diagnosis of acquired cystic disease (ACD) of the kidney is established by ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI), although each procedure can produce false-negative results. CT and MRI offer increased sensitivity over ultrasonography in detecting small cysts [3,4]. A diagnosis of ACD of the kidney requires involvement of both kidneys, with three or more cysts being present. ACD can be easily distinguished from autosomal dominant polycystic kidney disease (ADPKD) in patients with reduced glomerular filtration rate; the kidneys are small to normal in size among those with ACD, whereas they are typically extremely large among individuals with ADPKD.

The epidemiology, pathogenesis, detection, and management of ACD of the kidney are presented in this topic. Diagnosis and management of ADPKD, autosomal recessive polycystic kidney disease, and other kidney lesions are discussed elsewhere:

●(See "Autosomal dominant polycystic kidney disease (ADPKD) in adults: Epidemiology, clinical presentation, and diagnosis".)

●(See "Autosomal dominant polycystic kidney disease (ADPKD): Treatment".)

●(See "Autosomal recessive polycystic kidney disease in children".)

●(See "Diagnostic approach, differential diagnosis, and management of a small renal mass".)

●(See "Renal angiomyolipomas (AMLs): Management".)

EPIDEMIOLOGY — Often, acquired cystic disease (ACD) of the kidney can be detected prior to end-stage kidney disease (ESKD), and has been reported in patients with creatinine clearance as high as 70 mL/min [5]. However, most cases occur in patients with creatinine clearance <50 mL/min [5], and the majority of patients diagnosed with ACD of the kidney have been on dialysis for 10 years or more [1,6,7].

The incidence of ACD increases progressively with duration of CKD and is present in most patients who have had CKD for a prolonged period [8]. In one study of 130 patients with advanced kidney disease or ESKD, the incidence of multiple cysts was 7 percent among those with CKD and 22 percent among those on maintenance dialysis [2]. An additional 30 to 50 percent had one to three kidney cysts, potentially representing an early form of the disease. The mean duration of dialysis was 15 months in patients with no cysts, 28 months in those with one to three cysts, and 49 months in those with ACD [2]. The risk may be higher in men as compared with women and in Black patients as compared with non-Black patients [7,9-11].

ACD of the kidney can occur in children as well as in adults; various reports have suggested that it is present in between 21 and 46 percent of pediatric patients with ESKD [12].

Although the incidence of ACD of the kidney depends upon the duration of CKD, it does not appear to be associated with the cause of CKD [9].

PATHOGENESIS — The pathogenesis of acquired cystic disease (ACD) is incompletely understood. Nephron loss of any cause leads to compensatory hypertrophy in the remaining normal nephrons [6,9]. (See "Secondary factors and progression of chronic kidney disease".)

The cysts are limited to the kidney (in comparison with autosomal dominant polycystic kidney disease [ADPKD]), suggesting that local, intrarenal events are of primary importance [9]. The cyst fluid, which is thought to derive from fluid secreted into the cyst, typically has a composition similar to that in the plasma; this finding, plus the presence of a brush border on the luminal membrane, suggests that the cysts arise primarily from proliferation of proximal tubular epithelial cells [6,9].

Compensatory kidney hypertrophy is driven by activation of proto-oncogenes and release of growth factors (such as epidermal and hepatocyte growth factors), which, over a prolonged period of time, can lead to tubular hyperplasia and cyst formation [13,14]. In addition, one of these proto-oncogenes has been implicated in the pathogenesis of renal cell carcinoma (RCC) in ACD [15].

Analysis of acquired cysts from patients with end-stage kidney disease (ESKD) demonstrates vacuolated cells with eosinophilic cytoplasm and also calcium oxalate crystals within cyst walls. These findings are consistent with malignant potential [16].

The cysts may stabilize or regress following successful kidney transplantation, a setting in which the level of growth factors is reduced due to the restoration of normal kidney function. As a result, the outcome of ACD in patients following kidney transplantation is generally better than in patients maintained on chronic dialysis. In one prospective study, the incidence of cystic disease was lower (39 versus 56 percent), and the native kidneys were smaller and had lower cyst grades in transplant recipients when compared with patients treated with maintenance hemodialysis [17]. This benefit was limited to patients not receiving cyclosporine. Those treated with cyclosporine had an incidence of cystic disease similar to the patients on dialysis.

MANIFESTATIONS AND COMPLICATIONS

Clinical manifestations — Nearly 90 percent of patients with acquired cystic disease (ACD) are asymptomatic [1]. In one review, for example, only 14 percent of patients developed symptoms, with hematuria being most common, followed by lumbar pain and urinary tract infection [18].

However, even in asymptomatic patients, longitudinal radiologic studies demonstrate a progressive increase in the number and size of cysts [19]. Rupture of a cystic blood vessel occurs in up to 50 percent of cases at some time. Although most such episodes are asymptomatic, local pain and gross hematuria can occur [19]. Less often, the hemorrhage may extend into the perirenal area and be severe enough to induce hypotension or death [6,10,20-22]. This complication is most likely to occur in patients with very large cysts.

Renal cell carcinoma — The incidence of renal cell carcinoma (RCC) as a complication of ACD varies in different reports [10,18,19,23]. Two prospective studies found an incidence of 4 percent (2 of 57) and 7 percent (2 of 30) over a 7- to 10-year period [10,19]. A review of published reports estimated an incidence of 0.18 percent per year [18].

Most reports, however, may misrepresent the true incidence of RCC because they primarily rely upon screening radiography, particularly ultrasonography, for detection. Perhaps a better estimate was provided by a single-center study in which most kidney transplant patients underwent ipsilateral native nephrectomy at the time of transplant surgery [24]. Based upon strict pathologic criteria, RCC was found in 4.2 percent of 260 nephrectomies, which may be lower than the true incidence given that only one kidney was removed.

The carcinomas are usually limited to the kidney and, in approximately 25 to 50 percent of cases, are multiple and bilateral, a finding that is consistent with the diffuse nature of the disease [6,9,18,25,26]. Importantly, the bilateral presentation may not influence prognosis. Malignancy generally develops after at least 8 to 10 years of dialysis, although a shorter interval can be seen [27]. Men (male-to-female ratio 7:1) and patients with large cysts and an increased kidney size are at increased risk for malignant transformation [18,28]. Malignancy associated with ACD also can occur after transplantation [7]. Kidney transplant patients with ACD should be closely followed for this complication. Recommendations for the surveillance of such patients are discussed elsewhere. (See "Malignancy after solid organ transplantation".)

It has been suggested, however, that ACD and RCC are two disorders that represent separate diseases [29]. The overall incidence of RCC and distant metastases in all patients with end-stage kidney disease (ESKD) is approximately 1 to 2.6 percent and 0.2 to 0.5 percent, respectively [25,29]. Two large, prospective studies showed similar prevalence rates of RCC in Japan (1.7 percent) and the United States (1.6 percent) [23,30]. Although these values are more than 30 times higher than in the general population, they are not much higher than those reported in autopsy studies in the general population [18]. In addition, some patients with cancer do not have cystic disease, and some develop the malignancy prior to the institution of dialysis [25,31].

One study assessed the genetic abnormalities in RCCs occurring in patients with ESKD [32]. These patients did not have the changes that are frequently seen in patients with sporadic RCC: inactivation of a tumor suppressor gene on the short arm of chromosome 3 or a mutation in the von Hippel-Lindau tumor suppressor gene. Somatic mutations in von Hippel-Lindau have been found in 1.3 percent of RCCs in hemodialysis patients [33]. Another study of 33 RCCs obtained from patients with ESKD and ACD demonstrated amplification of chromosome 16q [34]. However, in a study of 79 tumor samples from 69 patients with ESKD who have RCC, there were no genomic profile differences between the sporadic versus ESKD cases of clear-cell and papillary RCC.

ACD presents differently in kidney transplant recipients compared with the general population. A review of 1000 transplant recipients followed for 28 years showed that ACD is less common among transplant recipients compared with patients with ESKD as a whole (23 versus 80 percent, respectively). The prevalence of RCC is higher among transplant recipients with ACD as compared with those without (19 versus 0.5 percent), and 26 percent of those patients may have bilateral RCCs, indicating the need for a higher level of scrutiny [35].

DIAGNOSIS — Patients with clinical manifestations of acquired cystic disease (ACD) of the kidney, such as hematuria, pain, or urinary tract infection, typically undergo kidney imaging with an ultrasound (image 1 and image 2) or CT (image 3) to evaluate their symptoms. However, since ACD of the kidney is typically asymptomatic, the diagnosis is usually made when patients with long-standing chronic kidney disease (CKD) undergo surveillance for ACD, during evaluation for kidney transplantation, or as an incidental finding when patients with CKD undergo imaging for a different indication.

ACD of the kidney is diagnosed when three or more cysts are present in each kidney in a patient with CKD and small- or normal-sized kidneys [1].

Most cysts are small (usually 0.5 cm or less in diameter), although some may be as large as 3 cm. The kidney cortex usually appears thin and, by ultrasound, echogenic, which corresponds to the long-standing CKD in affected patients.

ACD can be easily distinguished from autosomal dominant polycystic kidney disease (ADPKD) in patients with CKD; patients with ADPKD have enlarged kidneys and, frequently, cysts in other organs, such as the liver (image 4).

SURVEILLANCE — Surveillance for acquired cystic disease (ACD) and renal cell carcinoma (RCC) among patients with long-standing chronic kidney disease (CKD) depends in part upon the duration and severity of CKD and the anticipated life expectancy.

Patients without a diagnosis of acquired cystic disease — In patients without a known diagnosis of ACD of the kidney, our approach to surveillance depends in part upon whether the patient is a kidney transplant candidate and upon the patient's anticipated life expectancy:

●Potential kidney transplant candidates – In patients who are potential candidates for kidney transplantation, two of the authors of this topic obtain imaging with contrast-enhanced CT or contrast-enhanced MRI as part of the transplant evaluation to identify ACD and assess for RCC. The other author obtains an ultrasound as part of the transplant evaluation, rather than a CT or MRI, and performs a contrast-enhanced CT or MRI if a suspicious lesion is detected by ultrasound.

High-risk lesions (eg, Bosniak class III and IV), if identified, should be evaluated and managed appropriately (table 1); this is discussed in detail elsewhere. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass" and "Simple and complex kidney cysts in adults".)

If a kidney transplant candidate has ACD without evidence for RCC, then two of this topic's authors repeat the contrast-enhanced CT or MRI annually thereafter while the patient is on the waiting list. A third author of this topic repeats an ultrasound every six months while the patient is on the waiting list (and obtains a contrast-enhanced CT or MRI if a malignancy is suspected).

The management of patients with ACD once they have received a kidney allograft is presented separately. (See "Overview of care of the adult kidney transplant recipient", section on 'Malignancy'.)

If the patient does not have ACD, then imaging should be repeated every three to five years [1,36].

●Younger, healthier patients who are not undergoing kidney transplant evaluation – In patients who are not undergoing an evaluation for a kidney transplant, but who are younger and have few other comorbidities (and therefore a longer life expectancy), we perform surveillance for ACD and RCC. However, the benefit of surveillance in this setting is unproven, and not all experts recommend it [37]. (See "Cancer screening in patients on maintenance dialysis".)

The authors of this topic take different approaches to surveillance:

•Two of the authors of this topic obtain a kidney ultrasound at the time of dialysis initiation or when the need for dialysis is expected within one year.

•The other author obtains a kidney ultrasound in patients when their estimated glomerular filtration rate (eGFR) falls below 30 mL/min/1.73 m² or when they have had CKD for three years or longer.

•Other experts initiate surveillance for ACD later in the course of CKD, specifically in patients who have been on dialysis for three to five years [6,9,28,31].

In patients without ACD, a repeat ultrasound can be performed every three to five years. In patients identified as having ACD, but in whom all cysts are simple and <3 cm in diameter, repeat imaging can be performed every three years. (See 'Patients with documented acquired cystic disease' below.)

However, some patients identified as having cysts by ultrasound should undergo contrast-enhanced ultrasound, CT, or MRI to further classify the lesions; specifically, one of these additional imaging modalities should be obtained if (see "Evaluation of the incidental kidney lesion"):

•The ultrasound reveals one or more cysts that are 3 cm or larger

or

•The ultrasound reveals one or more cysts that have a solid component, are heterogeneous, have nodular walls, or that contain calcifications or septations.

High-risk lesions (eg, Bosniak class III and IV), if identified, should be evaluated and managed appropriately (table 1); this is discussed in detail elsewhere. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass" and "Simple and complex kidney cysts in adults".)

●Patients with poor overall health and short life expectancy – Death from metastatic RCC among patients on dialysis is relatively uncommon and, therefore, only relatively young patients with longer expected lifespans would be expected to benefit from RCC surveillance. The benefit is likely to be negligible in older patients with significant comorbid diseases. As an example, the mortality rate among patients aged 75 years or older who are initiating dialysis is approximately 33 percent at 1 year, 50 percent at two years, 63 percent at 3 years, and 81 percent at 5 years. The mortality rate is substantially higher if the patient also has significant comorbidities such as diabetes or cardiovascular disease. This contrasts with lower mortality rates due to metastatic RCC among patients identified as having a small renal mass (<1 percent at two to three years). (See "Diagnostic approach, differential diagnosis, and management of a small renal mass", section on 'Natural history'.)

In addition, older patients with significant comorbidities or who are frail, and who are diagnosed with a small renal mass that is suspicious for RCC, are often selected for active surveillance rather than immediate intervention with thermal ablation or partial or complete nephrectomy. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass", section on 'Management approach'.)

Thus, many experts do not obtain kidney imaging in such patients with ESKD who have limited life expectancies, unless they present with new signs or symptoms (eg, hematuria or flank pain) [29,38,39]. However, the approach should be individualized and based upon shared decision making between the patient and clinician. (See "Cancer screening in patients on maintenance dialysis".)

The optimal imaging modality to evaluate for ACD is uncertain. Contrast-enhanced CT, contrast-enhanced MRI, and ultrasound may all be used (image 5) [3]. In general, contrast-enhanced CT and MRI have greater sensitivity as compared with ultrasound [40-42], and contrast-enhanced CT can be used to characterize cysts using the Bosniak criteria [43]. However, in patients with advanced kidney disease, these benefits must be weighed against the risk from receiving either iodinated contrast or gadolinium. (See "Prevention of contrast-induced acute kidney injury associated with computed tomography" and "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease" and "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography", section on 'Patients with impaired kidney function' and "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging", section on 'Approach to preventing nephrogenic systemic fibrosis'.)

In patients who cannot receive intravenous iodinated contrast or gadolinium, contrast-enhanced ultrasound (if available) and noncontrast MRI may be superior to conventional ultrasound [44-48]:

●Contrast-enhanced ultrasound may detect RCC with a higher diagnostic accuracy than contrast-enhanced CT [46-48]. As an example, in a study of 18 dialysis patients with 19 suspicious kidney lesions, contrast-enhanced ultrasound accurately diagnosed 17 lesions (90 percent), whereas contrast-enhanced CT accurately diagnosed 10 (50 percent).

●In a pilot study of 215 kidney transplant recipients, 30 patients with ACD in the native kidneys (total of 54 kidneys) underwent noncontrast MRI (with diffusion-weighted sequences) and ultrasonography to evaluate for RCCs [44]. Three kidneys (6 percent) had RCCs, of which one was diagnosed by both methods and two were only diagnosed by MRI. There were also four suspicious lesions that were categorized as complex proteinaceous or hemorrhagic cysts on MRI and that stayed stable over a median follow-up period of 400 days.

Patients with documented acquired cystic disease — We continue surveillance in patients with documented ACD; the frequency of continued surveillance depends upon the characteristics and size of the kidney cysts:

●If a CT was performed, then high-risk lesions (eg, Bosniak class III and IV), if identified, should be evaluated and managed appropriately (table 1); this is discussed in detail elsewhere. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass" and "Simple and complex kidney cysts in adults".)

●If the patient had one or more kidney cysts that are larger than 3 cm that did not require reduction or resection, then we obtain annual imaging with a contrast-enhanced CT or MRI to follow the change in lesion characteristics. The same imaging modality should be used each time to optimize longitudinal comparisons.

●If the patient's cysts were all smaller than 3 cm, then we obtain repeat imaging every three years.

High-quality data to guide the frequency of imaging in patients with ACD are lacking. Once the ultrasound demonstrates cysts, yearly follow-up with the more sensitive contrast-enhanced CT or MRI without gadolinium has been suggested by some experts (particularly in patients with good life expectancies and very large cysts) [7,19,31,49,50]. However, based upon a growth rate of 1 cm per year and the observation that lesions smaller than 3 cm are unlikely to be metastatic, we perform imaging every three years, rather than annually [1,36].

TREATMENT — The management and prognosis of renal cell carcinoma (RCC) is presented in detail separately. (See "Overview of the treatment of renal cell carcinoma" and "Prognostic factors in patients with renal cell carcinoma".)

If a malignant tumor has been removed and the patient is being considered for a kidney transplant, a waiting period of one to two years after the surgery seems prudent to ensure the patient is disease free. (See "Malignancy after solid organ transplantation".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Overview – Chronic kidney disease (CKD), particularly in patients on maintenance hemodialysis or peritoneal dialysis, is frequently associated with the development of multiple and bilateral kidney cysts; this is called acquired cystic disease (ACD) of the kidney. (See 'Introduction' above.)

●Epidemiology – The incidence of ACD increases progressively with duration of CKD and is present in most patients who have had CKD for a prolonged period. Although the incidence of ACD of the kidney depends upon the duration of CKD, it does not appear to be associated with the cause of CKD. ACD of the kidney can occur in children as well as in adults. (See 'Epidemiology' above.)

●Pathogenesis – The pathogenesis of ACD is incompletely understood. The cysts are limited to the kidney, suggesting that local, intrarenal events are of primary importance. The cyst fluid, which is thought to derive from fluid secreted into the cyst, typically has a composition similar to that in the plasma; this finding, plus the presence of a brush border on the luminal membrane, suggests that the cysts arise primarily from proliferation of proximal tubular epithelial cells. (See 'Pathogenesis' above.)

●Manifestations and complications – Nearly 90 percent of patients with ACD are asymptomatic. Symptoms, when present, can include hematuria, lumbar pain, and urinary tract infection. Patients with ACD of the kidney may also develop renal cell carcinoma (RCC). RCCs are usually limited to the kidney and, in up to 50 percent of cases, are multiple and bilateral. (See 'Manifestations and complications' above.)

●Diagnosis – ACD of the kidney is diagnosed when three or more cysts are present in each kidney in a patient with CKD and small- or normal-sized kidneys. (See 'Diagnosis' above.)

●Surveillance

•In patients without a known diagnosis of ACD of the kidney, our approach to surveillance for RCC depends in part upon whether the patient is a kidney transplant candidate and on anticipated life expectancy. (See 'Patients without a diagnosis of acquired cystic disease' above.)

-Potential kidney transplant candidates – In patients who are potential candidates for kidney transplantation, two of the authors of this topic obtain imaging with contrast-enhanced CT or contrast-enhanced MRI as part of the transplant evaluation to identify ACD and assess for RCC. The other author obtains an ultrasound as part of the transplant evaluation, rather than a CT or MRI, and performs a contrast-enhanced CT or MRI if a suspicious lesion is detected by ultrasound.

If a kidney transplant candidate has ACD without evidence for RCC, then two of this topic's authors repeat the contrast-enhanced CT or MRI annually thereafter while the patient is on the waiting list. A third author of this topic repeats an ultrasound every six months while the patient is on the waiting list.

If the patient does not have ACD, then imaging should be repeated every three to five years.

-Younger, healthier patients who are not undergoing kidney transplant evaluation – In patients who are not undergoing an evaluation for a kidney transplant, but who are younger and have few other comorbidities (and, therefore, a longer life expectancy), we perform surveillance for ACD and RCC. However, the benefit of surveillance in this setting is unproven, and not all experts recommend it.

-Patients with poor overall health and short life expectancy – In patients with end-stage kidney disease and significantly comorbidity, mortality from kidney and cardiovascular disease is likely to far exceed the risk of dying from metastatic RCC. Thus, most experts do not obtain kidney imaging in such patients who have limited life expectancies, unless they present with new signs or symptoms (eg, hematuria or flank pain).

•In patients with an established diagnosis of ACD, we continue surveillance; the frequency of continued surveillance depends upon the characteristics and size of the kidney cysts. (See 'Patients with documented acquired cystic disease' above.)

-If a CT was performed, then high-risk lesions (eg, Bosniak class III and IV), if identified, should be evaluated and managed appropriately (table 1).

-If the patient had one or more kidney cysts that are larger than 3 cm that did not require reduction or resection, then we obtain annual imaging.

-If the patient's cysts were all smaller than 3 cm, then we obtain repeat imaging every three years.