Burden of Autosomal Dominant Polycystic Kidney Disease: Systematic Literature Review

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder and typically leads to end-stage renal disease (ESRD) by late middle age (fourth to sixth decade).^1,2 ADPKD arises from mutations at PKD1 (85% of cases) and PKD2 (15% of cases), which code for transmembrane proteins polycystin-1 and polycystin-2, respectively, and are involved in calcium signaling.^2,3

Defects of these proteins lead to the formation of distinctive fluid-filled cysts in the kidneys, as is the case for other heritable polycystic kidney diseases.⁴ ADPKD is complex in its interaction of genetic heterogeneity, allelic heterogeneity, and environmental effects, leading to large phenotypic variability and a wide range of age at onset.^2,4 ADPKD is generally diagnosed via family history and imaging testing to detect renal cysts. There are no pharmacologic treatments currently indicated for ADPKD, but testing may be beneficial for family planning and for early detection and treatment of disease

complications.²

ADPKD is a systemic disease, with cysts developing in other organs as well—most frequently, in the liver and pancreas. Additional extrarenal manifestations associated with ADPKD include cardiac disease and intracranial aneurysms.^2,5-7 Progression of the disease leads to an increase in the number and volume of cysts and an increase in kidney volume, which lead to a decline in renal function,8 renal inflammation, fibrosis, and ESRD.⁹ By the time there is a decline in renal function, the enlarged kidney is distorted, with little recognizable parenchyma.² Along with renal decline, disease complications include polycystic liver disease, cardiac disease, hypertension, hematuria, urinary tract infections, renal stones, and renal pain.^2,5

ADPKD is a chronic disease that evolves over a lifetime. Mild symptoms in early stages typically go undiagnosed as ADPKD. The majority of cases are due to PKD1 mutations, and by definition, progress more rapidly.^3,10 The symptoms caused by ADPKD contribute to substantial morbidity and impairment of quality of life, as well as costs to society, as these undiagnosed symptoms progress. Although few studies have investigated the impact of symptoms on quality of life in patients with ADPKD, chronic pain is evidently a significant complication; therefore, pain management is an important consideration in patients with ADPKD.^11,12 A recent study of patients with early ADPKD from the Polycystic Kidney Disease Treatment Network (the HALT PKD Trial) demonstrated that symptoms relating to abdominal fullness and pain are greater in patients with more advanced disease, possibly due to organ enlargement.¹³ Similarly, little has been reported on the economic burden of ADPKD.¹⁴ In contrast, chronic kidney disease (CKD) has been investigated extensively and is recognized as a source of substantial morbidity and economic burden with clear associations between kidney dysfunction and adverse outcomes, leading to hospitalizations, resource utilization, and mortality.¹⁵

As ADPKD is both among the leading causes of ESRD and the leading heritable cause,^2,16,17 it is important for US healthcare payers to understand this genetic disorder and the healthcare resource utilization and costs associated with it. Here we review the available ADPKD literature, published between 2003 and 2013, to characterize the impact of ADPKD on patients and healthcare systems, and to assess any current gaps in the available evidence that hinder either a better understanding of the disease or the need for effective therapies, as there is currently no treatment for ADPKD. Better understanding and earlier diagnosis of the disease may lead to improved treatment of complications. Information on ADPKD incidence and prevalence, diagnostic criteria and risk factors, and the humanistic and economic burden of this genetic disorder are summarized.

METHODSSearch Parameters

PubMed and EMBASE databases from January 2003 to March 2013 were searched for potentially relevant articles published in English. Search terms included “autosomal dominant polycystic kidney disease” and “ADPKD” alone and in combination with “chronic kidney disease,” “CKD,” or “chronic renal insufficiency,” and “polycystic kidney disease” and “PKD/polycystic.”

Study Inclusion/Exclusion Criteria

Studies were included for screening if they were identified as a study of either ADPKD or PKD. As ADPKD is a disease subset of PKD, both search terms were used in the screening process to ensure that all ADPKD studies would be included, even those classified as “PKD.” Studies removed from the analysis through screening included studies that were: 1) not in English; 2) not conducted in human patients; 3) not conducted in a population generalizable to the United States, Canada, France, Germany, Italy, Spain, or the United Kingdom; or 4) not full-text articles.

Studies excluded from eligibility for analysis were those that were: 1) not ADPKD studies (to eliminate any studies on only PKD); 2) limited to analysis of basic science or genetic risk factors only; 3) case studies (with samples of ≤20 patients); or 4) unrelated to the specific topics of the review: incidence/prevalence, diagnostic criteria and risk factors, humanistic burden, and economic burden. Any information on treatment patterns, treatment adherence and compliance, symptoms, and comorbidities was noted while analyzing articles based on the 4 specific topics of the review.

Data Extraction and Qualitative Assessment

A single reviewer evaluated publications for inclusion and performed data extraction, and a second reviewer performed a quality check of included studies and extracted data for accuracy. For the selected publications, data extracted included information on publication details, study design and methods, study population size and characteristics, diagnostic criteria, disease progression, quality of life, costs, and study outcomes. All data were analyzed qualitatively. The estimates of the rates of prevalence, incidence, and disease progression were extracted and summarized as reported without adjustment.

RESULTS

Through the initial search, 2459 articles were identified, with 1835 remaining after the removal of duplicates (

Figure

). In the course of study review, 379 articles were removed through an initial screening, and 1401 were removed through assessment for eligibility, leaving 55 studies included in the qualitative synthesis (

eAppendix Table

, available at www.ajmc.com).

Epidemiology of ADPKD: Incidence and Prevalence

No primary epidemiology studies for ADPKD, including incidence and prevalence or other important measures (ie, age at onset, disease severity by age, mortality by age) were conducted during the period covered in this analysis (January 2003 to March 2013). ADPKD prevalence rates were cited frequently, but few articles referenced a primary study, and many had no citation (

Table 1

,^18-62 bottom section).

Only 3 primary research studies were cited in the articles covered in this review (Table 1, top section).^18-20 The majority of papers that included a reference cited 2 primary studies, which were conducted in Denmark¹⁹ in 1957 and in the United States¹⁸ in 1983. The US study was the only one to investigate incidence; the estimated incidence of symptomatic and family-screen cases was 1.38 per 100,000 person-years and the incidence of observed and estimated cases based on autopsy was 2.75 per 100,000 person-years. The Danish study found prevalence rates of 1:773 (adult autopsy) and 2.2:1000 (newborn autopsy) in comparing hospital statistics of PKD with relevant population figures. The other primary research study cited in the selected articles was a study conducted in Wales in 1991,²⁰ which found a prevalence rate of 1:2459 in a population study using a genetic register of all known cases of ADPKD.

Characteristics of the geographic regions and periods in which these primary studies were conducted most likely contributed to the variance of rates reported. Diagnostic criteria for ADPKD were developed in 1994 and refined in 2009, occurring in each case after the ADPKD incidence and prevalence studies were published.^1,63 Additional studies in more globally diverse populations using the updated ADPKD diagnostic criteria are needed to establish a more accurate estimate of the prevalence of ADPKD.

ADPKD Diagnostic Criteria/Risk Factors for Progression

ADPKD diagnostic criteria based on ultrasound imaging for patients with a family history of ADPKD (and therefore with a 1 in 2 risk of developing the disease) were initially established in a study by Ravine and colleagues (

Table 2

).⁶³ Criteria were based on patient age and the number of cysts identified. However, patients with the PKD2 mutation who usually present with less severe renal disease tended to be underdiagnosed with the criteria established by Ravine.64 The ultrasound criteria for diagnosis was subsequently modified by Pei in 2009 to take into consideration the less severe renal disease presented with PKD2 mutations and to reduce false negative rates for diagnosis (Table 2).^1,64 Ultrasonography techniques can identify cysts of 1 centimeter or larger, while more sensitive imaging techniques of T2-weighted magnetic resonance imaging (MRI) and contrast-enhanced computed tomography (CT) can identify cysts as small as 3 millimeters.^5,64 Although these techniques are more sensitive, ultrasound remains the initial choice for diagnosis owing to the cost of these tests and factors related to radiation and contrast exposure.^2,64

Following imaging diagnostics, diagnosis of ADPKD is confirmed by the identification of associated liver cysts, pancreatic cysts, or both.^2,5 Additionally, in the absence of family history, the occurrence of bilateral renal enlargement and cysts, or the presence of multiple bilateral cysts, can indicate a diagnosis of ADPKD. While genetic testing is available for diagnosis, it is not as accurate as radiographic screening since in many patients, variants of unknown clinical significance are identified, making a definite diagnosis uncertain.^2,64 Genetic testing is also expensive and technically challenging, particularly for the genomically complex PKD1 gene.^2,64 However, genetic testing can be useful to aid the diagnostic process in younger patients with equivocal imaging data of the kidneys—particularly in living related donor cases.

Monitoring for disease progression in ADPKD is extremely important because renal function declines rapidly at later stages of the disease, creating an imperative need for the identification of risk factors and early symptoms of progression to inform patient care. Earlier detection and treatment before the glomerular filtration rate (GFR) declines, signifying renal insufficiency, may provide benefit to the patient. Possible risk factors identified in the literature include genetic factors, age, hypertension, total renal volume, renal cyst size, and proteinuria (

Table 3

^65-74).

Genetic factors are cited frequently in the literature as key risk factors. Patients with PKD1 typically have more cysts and progress faster than PKD2 patients, developing ESRD almost 20 years earlier.^3,10 While gene modifiers and polymorphisms of PKD1 have been investigated and angiotensin-converting enzyme polymorphism has been implicated in having a slight influence on the age of onset of ESRD, no genetic modifiers have been validated.⁷³ Family history provides important prognostic value for predicting PKD mutation. Specifically, having at least 1 family member with early-onset (aged ≤58 years) ESRD is predictive of a PKD1 mutation, while having a family member who developed late-onset (aged >70 years) ESRD is predictive of a PKD2 mutation and therefore a lower risk of more rapid disease progression.⁴⁵ Moreover, a recent study showed that obtaining a detailed family history in addition to testing for the PKD2 mutation could provide useful prognostic information.⁵⁸

Physiologic characteristics are also prognostic factors. Kidney size is a predictor of rate of progression and risk of renal insufficiency.⁸ Kidney enlargement due to the expansion of cysts is linked to a decline in renal function, while baseline total kidney volume is seen as predictive of subsequent kidney volume expansion and GFR decline. Additionally, the extrarenal manifestations of ADPKD, such as the development of arterial hypertension, can be prognostic of progressive disease.⁵ In a multivariate analysis, systolic blood pressure and young age at diagnosis were factors that maintained independent predictive value for CKD progression in patients with ADPKD.⁵⁰ Biomarkers may also help to identify the risk of disease progression. Recently, a unique urinary biomarker profile was investigated in young patients with ADPKD, which may prove to be a promising tool for prognostic evaluation.³³

Humanistic Burden of Illness

ADPKD patients experience a variety of serious extrarenal manifestations, including polycystic liver disease, vascular events, cardiac events, and intracranial aneurysms.^2,6,7 In addition, renal manifestations of the disease leading up to renal insufficiency include urinary tract infections, renal stones, and renal pain.⁵ Both classes of manifestations may have a negative impact on patient function and quality of life.

Very few formal studies have quantified the humanistic burden of ADPKD on patients, and no studies have evaluated the effect of rapid progression on quality of life or functioning. One study investigated the pain associated with ADPKD in 22 patients using semistructured patient interviews.¹¹ Early-stage kidney disease was associated with less intense and durable pain; however, all levels of pain and fatigue had a negative impact on daily living, restricting everyday activities and adding an increased level of uncertainty to patients’ lives. Furthermore, the pain was not eliminated by the use of analgesics. In a prospective study using the Short Form-36 questionnaire, no difference in quality of life for both physical component summary (PCS) and mental component summary (MCS) was found between predialysis patients with ADPKD and the overall general US population.¹² However, exclusion criteria in this study may have resulted in an underrepresentation of more severely affected patients, as only predialysis patients were included. Comparisons showed both PCS and MCS scores were significantly higher in these patients compared with a clinical trial hemodialysis group and a community-based dialysis group. Patients with ESRD had significantly lower PCS and MCS scores than those reported in the predialysis population, and although renal volume was not associated with changes in PCS or MCS, PCS scores correlated with levels of renal insufficiency. The study concluded that this questionnaire may not have the sensitivity or specificity to assess physical and mental well-being in patients with ADPKD and that the development of disease-specific questionnaires is warranted.

Economic Burden

It has been well demonstrated that CKD is associated with significant economic burden and that disease progression, along with deterioration of health, increases resource utilization and escalates cost, specifically costs due to hospitalizations.¹⁵ The economic burden associated with ADPKD has only been investigated in 1 study, which used claims analysis from 1913 patients from 2003 to 2006 to characterize the relationship of kidney function to healthcare costs.¹⁴ The results showed 5-fold higher costs in ADPKD patients with estimated GFR (eGFR) <15 mL/min versus eGFR ≥90 mL/min, and each decline of <30 mL/min in the eGFR was associated with higher annual charges of approximately $5435. The study suggests that preventing the loss of renal function to below 30 mL/min has the potential to substantially reduce medical charges.

DISCUSSION

The analysis presented here evaluates information on ADPKD currently available in the literature concerning incidence and prevalence, diagnostic criteria and risk factors, humanistic burden, and economic burden. Prevalence estimates for the US population indicate that this disease is a substantial concern. However, studies thus far have generally been in small populations. Diagnostic criteria are now well established and have been modified to accommodate patients with PKD2 mutation-positive disease and to reduce false negatives. A few prognostic factors for disease progression are presently available to aid in the identification of earlier supportive treatment needs. The most commonly recognized element of the humanistic burden is pain, which has been shown to interfere with daily living and may not be controlled by analgesics. The only available analysis of the economic burden of ADPKD demonstrated a correlation between reduced kidney function and increased healthcare costs.

In assessing the information on ADPKD currently available in published literature, some gaps were identified. Although extensive reference is made to the incidence and prevalence of ADPKD, there is no consensus on rates, and most studies are based on small, regional patient cohorts. Moreover, there is a lack of primary studies on ADPKD incidence and prevalence following the updated diagnostic criteria in 2009.^1,64 Better estimates of humanistic burden are needed to understand the extent of the need for supportive care treatments and to accurately quantify the economic burden of ADPKD. Additionally, although diagnostic criteria for ADPKD are well established, there is potential for improvement. Currently, ultrasonography remains the standard method due to cost, safety, and availability. Expected improvements on this technique include high-resolution 3-dimensional ultrasonography. Future improvements in the diagnostic process may include testing modalities that are more sensitive, such as MRI and contrast-enhanced computerized tomography, especially if ADPKD-specific treatments become available.^5,64 Currently, ADPKD diagnostic and treatment guidelines to assist with the consistent application of these criteria do not exist.

Earlier detection and treatment prior to GFR decline and renal insufficiency may provide substantial benefit to patients and may lessen both the humanistic and economic burden of the disease. Data on the risk factors for early onset and rapid progression are needed to promote the development of prognostic scoring tools to identify patients with ADPKD who are likely to progress to ESRD rapidly. A few prognostic factors associated with disease progression have been established, including PKD1/PKD2 genotype, kidney volume, and age at onset.^3,10,45,50 However, research on factors associated with rapid disease progression is less definitive, and more information is needed to explain the heterogeneity of ADPKD.

ADPKD is a systemic disease with various renal and extrarenal manifestations, and it therefore confers a heavy burden on patients and caregivers, leading to increased healthcare resource utilization and costs. Despite this impact, there is a clear lack of studies in the literature directly evaluating the humanistic or economic burden of ADPKD. While pain is consistently reported by patients with ADPKD,¹¹ no evidence was identified that established a definitive correlation between disease severity or progression and health-related quality of life. However, a recent report of the HALT-PKD trials showed that symptoms relating to abdominal fullness and pain are greater in patients with more advanced disease.¹³ Additionally, while a relationship between loss of kidney function and increasing healthcare costs has been shown,¹⁴ definitive cost-of-care data for patients with ADPKD has not been reported. Knowledge of specific costs associated with

ADPKD would be of benefit in assessing the economic burden of ADPKD. Of particular importance are the costs associated with symptom management (including hypertension and pain), because there is no current treatment for the disease itself, as well as costs associated with hospitalizations and dialysis.

CKD is a more widespread disease of kidney failure with a wealth of information on the disease impact on both the humanistic and economic burden, but it typically affects a very different population than that of ADPKD.¹⁵ As such, it is unlikely that the studies used to investigate the humanistic and economic burden of CKD can be used to accurately model the burden in patients with ADPKD. Additionally, CKD is a complicated disease with an interwoven set of risk factors and comorbid illnesses; the impact of these on patients and healthcare systems has been extensively investigated.¹⁵ ADPKD, like CKD, presents with serious, albeit different, comorbidities, and an investigation of these on humanistic and economic burden is warranted.

CONCLUSIONS

ADPKD is a serious health condition, and more information is needed to better understand the effects of the disease on patients and healthcare systems. While no pharmacologic treatments are currently approved for ADPKD, it is possible that earlier supportive treatment of symptoms to slow disease progression would be beneficial to patients to reduce disease burden, as well as to potentially reduce healthcare utilization and costs. Additional studies are needed to evaluate the disease burden of ADPKD on patients—especially the effect of rapid progression on quality of life&mdash;along with the actual costs associated with ADPKD.