Burden of Autosomal Dominant Polycystic Kidney Disease: Systematic Literature Review

Transcription

1 At a Glance Practical Implications e28 Author Information e34 Full text and PDF Burden of Autosomal Dominant Polycystic Kidney Disease: Systematic Literature Review Original Research Christopher M. Blanchette, PhD, MBA; Susanna Matter, MA, MBA; Anita Chawla, PhD; Dave Nellesen, PhD; Sandro Rossetti, MD; and Benjamin Gutierrez, PhD 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 ABSTRACT Objectives: Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary kidney disorder, is a leading cause of end-stage renal disease. While there is no pharmacologic ADPKD therapy indicated, earlier supportive treatment may reduce disease burden, which may lead to the reduction or prevention of healthcare utilization and costs. To help US healthcare payers to understand this genetic disorder and the related healthcare utilization and costs, we performed a literature review on ADPKD. Study Design: This literature review includes information on ADPKD incidence and prevalence, diagnostic criteria and risk factors, and the humanistic and economic burden. The information was summarized to characterize the impact of ADPKD on patients and healthcare systems. Methods: PubMed and EMBASE databases from January 2003 to March 2013 were searched for articles containing relevant key terms, which were then screened for exclusion criteria to focus on data for ADPKD. For the selected publications, data were extracted and summarized. Results: The results indicate that prevalence studies are outdated and have generally been on small populations. Additionally, diagnostic criteria are established, and a few possible disease progression prognostic factors have been identified. Pain is a commonly recognized element of humanistic burden, and a correlation between reduced kidney function and increased healthcare costs has been demonstrated. Conclusions: ADPKD is a serious health condition. Additional studies are needed to evaluate the disease burden of ADPKD on patients, especially the effect of rapid progression on quality of life, and the actual costs associated with ADPKD. Am J Pharm Benefits. 2015;7(2):e27-e36 Vol. 7, No. 2 The American Journal of Pharmacy Benefits e27

2 n Blanchette Matter Chawla Nellesen PRACTICAL IMPLICATIONS Autosomal dominant polycystic kidney disease (ADPKD) is a serious health condition, and more information is needed to better understand the effects of the disease on patients and healthcare systems. n No treatments are currently approved for ADPKD. n Early supportive treatment of symptoms to slow disease progression may reduce healthcare utilization and costs by reducing disease burden. n Additional studies are needed to evaluate the disease burden of ADPKD on patients, including the costs associated with ADPKD. 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. METHODS Search 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 ). e28 The American Journal of Pharmacy Benefits March/April 2015

3 ADPKD Literature Review Figure. PRISMA Flow Chart of the Targeted ADPKD Literature Search Identification Screening 2459 records identified through PubMed and Embase database search 1835 records after duplicates were removed 1835 records screened 379 records removed through screening Not in English, n = 3 Not human, n = 272 Not in the United States, Canada, Germany, France, Italy, Spain or the United Kingdom, n = 102 Not full-text articles, n = 2 Eligibility 1456 records assessed for eligibility 1401 removed through assessment for eligibility Not on ADPKD, n = 809 Basic science, n = 55 Genetic risk factors, n = 41 Small or unknown sample, n = 359 Not on a priority topic, n = 137 Included 55 studies included in qualitative synthesis ADPKD indicates autosomal dominant polycystic kidney disease; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. 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, bottom section). Only 3 primary research studies were cited in the articles covered in this review (Table 1, top section) The majority of papers that included a reference cited 2 primary studies, which were conducted in Denmark 19 in 1957 and in the United States 18 in 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 Vol. 7, No. 2 The American Journal of Pharmacy Benefits e29

4 n Blanchette Matter Chawla Nellesen Table 1. Primary Studies and Reported ADPKD Rates of Prevalence and/or Incidence Cited in the Literature Along With Source Origination Path Primary Source Prevalence/Incidence Rate Citation Brief Study Description 1.38 per 100,000 person-years Iglesias et al 18, a Population study for incidence of Olmstead County, Minnesota, based on hospital records for diagnosis of PKD and evidence of ADPKD, estimated as 2.75 per 100,000 person-years, adding observed and estimated autopsy cases. (May be an overestimate due to a reliance on autopsy results and, therefore, may include patients who were nonsymptomatic in life, with milder disease progression.) 1:773 (adult autopsy); 2.2:1000 (newborn autopsy) Dalgaard 19 Localized Danish population study that compared hospital statistics of PKD with relevant population figures 1:2459 Davies et al 20 Population study in South and Mid Wales (population 2.1 million), using a genetic register of all known cases of ADPKD (may be an underestimate because it did not include benign cases) Reported Prevalence/ Incidence Rate ADPKD Systematic Literature Review Citation(s) Originating Source and Level of Evidence (primary sources in bold) 1:300 to 1:1000 Mosetti et al 21 Asplin et al 22 : textbook 3:1000 to 1:1000 Hajj et al 23 Wing et al 24 : EU report on dialysis and transplantation; Zeier et al 25, b : review article 1:400 to 1:1000 Cadnapaphornchai et al Meijer et al 30 ; Driscoll et al 31 Kistler et al 33,34 ; Casal et al 35, a ; Taylor et al 36 ; Kelleher et al 37 ; Schrier et al 38 Perez Dominguez et al 40 Irazabal et al 7 ; Gronwald et al 42, a ; Cadnapaphornchai et al 43 ; Chapman 16 1:500 to 1:1000 Shamshirsaz et al 44 Barua et al 45 ; Pei et al 1, a ; Boyer et al 46, a Ecder et al 29, b,c : textbook Liapis et al 32 : textbook; Torres et al 2, b,c,d : review article Dalgaard 19 (see Brief Study Description, above); Iglesias et al 18 (see Brief Study Description, above); Gabow 39 : review article Torres et al 41 : molecular analysis study in Spain that does not investigate prevalence No citation Iglesias et al 18 (see Brief Study Description, above) No citation 1:600 to 1:1000 Garcia-Gonzalez et al 47 Gabow 39 : review article (listed as 1:400 to 1:1000) 1:700 to 1:1000 Rizk et al 12 Gabow 39 : review article (listed as 1:400 to 1:1000) Patel et al 48 US Renal Data System 49 : US statistics on CKD and ESRD 1:800 to 1:1000 Panizo et al 50 Bleyer et al 51, e : editorial of Wilson 52, which was a review article 1:1000 Corradi et al 53 Paterson et al 54, a Sulikowski et al 56 Robinson et al 58 ; Boertien et al 59 Davies et al 20 (see Brief Study Description, above) Gabow 39 : review article; Harris 55 : review article Igarashi et al 57 : review article No citation 1:400 to 1:2500 Tee et al 60, a Iglesias et al 18 (see Brief Study Description, above); Davies et al 20 (see Brief Study Description, above) 500,000 to 600,000 US Lentine et al 14 Helal et al 6 Kelleher et al 37 Grantham et al 61 : textbook US Renal Data System 62 : US statistics on CKD and ESRD Gabow 39 : review article 10 million to 12.5 million worldwide Lentine et al 14 Patel et al 48 Grantham et al 61 : textbook US Renal Data System 49 : US statistics on CKD and ESRD ADPKD indicates autosomal dominant polycystic kidney disease; CKD, chronic kidney disease; ESRD, end-stage renal disease; EU, European Union; PKD, polycystic kidney disease. a Listed as incidence rate. b Primary reference Dalgaard. 19 c Primary reference Iglesias et al. 18 d Primary reference Davies et al. 20 e Bleyer et al 51 is an editorial regarding the Wilson 52 article. e30 The American Journal of Pharmacy Benefits March/April 2015

5 ADPKD Literature Review 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 Table 2. Ultrasonography Diagnostic Criteria for ADPKD Patients With a Family History of ADPKD Original Criteria Established by Ravine et al 63 Aged <30 years Aged years Aged 60 years 2 unilateral or bilateral cysts 2 cysts in each kidney 4 cysts in each kidney Modified Criteria in Families of Unknown Genotype Established by Pei et al 1, a Aged years Aged years Aged 60 years 3 renal cysts (unilateral or bilateral) 4 cysts (2 or more in each kidney) 8 cysts (4 or more in each kidney) ADPKD indicates autosomal dominant polycystic kidney disease. a Disease exclusion criteria are fewer than 2 renal cysts in at-risk individuals aged 40 years. 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 ). 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 Vol. 7, No. 2 The American Journal of Pharmacy Benefits e31

6 n Blanchette Matter Chawla Nellesen Table 3. Risk Factors Associated With ADPKD Disease Progression Risk Factor Frequency in Risk Factor References References a Demographics b 17 Panizo et al 50 ; Kistler et al 34,65 ; Reed et al 66 ; Torres et al 2 ; Dicks et al 67 ; Grantham et al 8 ; Age 10 Young et al 68 ; Chapman et al 10,69 ; King et al 70 ; Schrier et al 38 Sex 6 Renal pathophysiology 18 Boertien et al 59 ; Kistler et al 33,34,65 ; Chapman et al 10,69 ; Panizo et al 50 ; Meijer et al 30 ; Total renal volume 13 Torres et al 2 ; Grantham et al 8 ; Young et al 68 ; King et al 70 ; Schrier et al 38 Renal cyst size/number 5 Hemodynamic factors 17 Panizo et al 50 ; Meijer et al 30 ; Kistler et al 34 ; Torres et al 2 ; Ahmed et al 71 ; Dicks et al 67 ; Hypertension 11 Young et al 68 ; Kelleher et al 37 ; Chapman et al 69 ; King et al 70 ; Schrier et al 38 Renal vascular resistance 3 Renal blood flow 3 Urinary biomarkers c 17 Kistler et al 33,34,65 ; Chapman et al 10,69 ; Panizo et al 50 ; Meijer et al 30 ; Torres et al 2 ; Ahmed et al 71 ; Albuminuria 6 Dicks et al 67 ; Schrier et al 38 Proteinuria 4 Hematuria 2 Urinary proteomic patterns 2 Serum biomarkers d 9 Boertien et al 59 ; Chapman et al 10 ; Panizo et al 50 ; Kistler et al 34 ; Torres et al 2 ; Ahmed et al 71 ; Serum creatinine/creatinine clearance 5 Dicks et al 67 Hyperuricemia 2 Other factors e 14 Chapman et al 10 ; Panizo et al 50 ; Robinson et al 58 ; Barua et al 45 ; Courtney et al 72 ; Reed et al 66 ; Family history/genetic factors 10 Tazón-Vega et al 73 ; Torres et al 2 ; Ahmed et al 71 ; Dicks et al 67 ; Grantham et al 8 ; Paterson et al 54 ; Persu et al 74 Hypercholesterolemia 2 ADPKD indicates autosomal dominant polycystic kidney disease. a More than 1 factor may be listed in a reference. b One reference for body mass index. c One reference each for monocyte chemotactic protein-1 excretion, sodium excretion, and 24-hour urine volume. d One reference each for blood urea nitrogen and copeptin concentration. e One reference each for urinary tract infection and oral contraceptive pill. 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 e32 The American Journal of Pharmacy Benefits March/April 2015

7 ADPKD Literature Review 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 ,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 Vol. 7, No. 2 The American Journal of Pharmacy Benefits e33

8 n Blanchette Matter Chawla Nellesen 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 along with the actual costs associated with ADPKD. Author Affiliations: University of North Carolina (CMB), Charlotte, NC; Analysis Group, Inc (SM), Boston, MA; Analysis Group, Inc (AC, DN), Menlo Park, CA; Otsuka America Pharmaceutical, Inc (SR, BG), Princeton, NJ. Funding Source: This study was sponsored by Otsuka America Pharmaceutical, Inc, Princeton, NJ. Medical writing and editorial support for the preparation of this manuscript was provided by Scientific Connexions, Inc, Lyndhurst, NJ, funded by Otsuka America Pharmaceutical, Inc. Author Disclosures: Dr Rossetti is an employee of Otsuka America Pharmaceutical, Inc. Drs Blanchette and Gutierrez were employed by Otsuka America Pharmaceutical, Inc, at the time of the study. Ms Matter and Drs Chawla and Nellesen are employees of Analysis Group, which has received funds from Otsuka America Pharmaceutical, Inc, in connection with conduction of this study. Authorship Information: Concept and design (CMB, SM, AC, DN, BG, SR); acquisition of data (SM); analysis and interpretation of data (CMB, SM, AC, DN, BG, SR); drafting of the manuscript (CMB, DN, BG, SR); critical revision of the manuscript for important intellectual content (CMB, AC, DN, BG, SR); administrative, technical, or logistic support (CMB); and supervision (CMB). Address correspondence to: Christopher M. Blanchette, PhD, MBA, 9201 University City Blvd, Charlotte, NC cblanche@uncc.edu. REFERENCES 1. Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20(1): Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007; 369(9569): Harris PC, Bae KT, Rossetti S, et al. Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2006;17(11): Hildebrandt F. Genetic kidney diseases. 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9 ADPKD Literature Review 24. Wing AJ, Brunner FP, Brynger H, et al. Combined report on regular dialysis and transplantation in Europe, VIII, Proc Eur Dial Transpl Assoc. 1978;15: Zeier M, Geberth S, Ritz E, Jaeger T, Waldherr R. Adult dominant polycystic kidney disease clinical problems. Nephron. 1988;49(3): Cadnapaphornchai MA, George DM, Masoumi A, McFann K, Strain JD, Schrier RW. Effect of statin therapy on disease progression in pediatric ADPKD: design and baseline characteristics of participants. Contemp Clin Trials. 2011;32(3): Cadnapaphornchai MA, Masoumi A, Strain JD, McFann K, Schrier RW. Magnetic resonance imaging of kidney and cyst volume in children with ADPKD. Clin J Am Soc Nephrol. 2011;6(2): Cadnapaphornchai MA, McFann K, Strain JD, Masoumi A, Schrier RW. Increased left ventricular mass in children with autosomal dominant polycystic kidney disease and borderline hypertension. Kidney Int. 2008;74(9): Ecder T, Fick-Brosnahan G, Schrier RW. Polycystic kidney disease. In: Schrier RW, ed. Diseases of the Kidney and Urinary Tract, Vol. 2. 8th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2007: Meijer E, Rook M, Tent H, et al. Early renal abnormalities in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2010;5(6): Driscoll JA, Bhalla S, Liapis H, Ibricevic A, Brody SL. Autosomal dominant polycystic kidney disease is associated with an increased prevalence of radiographic bronchiectasis. Chest. 2008;133(5): Liapis H, Winyard P. Cystic kidney diseases and developmental kidney defects. In: Jennette JC, Olson JL, Schwartz MM, Silva F, eds. Heptinstall s Pathology of the Kidney. 6th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2007: Kistler AD, Serra AL, Siwy J, et al. Urinary proteomic biomarkers for diagnosis and risk stratification of autosomal dominant polycystic kidney disease: a multicentric study. PLoS One. 2013;8(1):e Kistler AD, Mischak H, Poster D, Dakna M, Wüthrich RP, Serra AL. Identification of a unique urinary biomarker profile in patients with autosomal dominant polycystic kidney disease. Kidney Int. 2009;76(1): Casal JA, Hermida J, Lens XM, Tutor JC. A comparative study of three kidney biomarker tests in autosomal-dominant polycystic kidney disease. Kidney Int. 2005;68(3): Taylor M, Johnson AM, Tison M, Fain P, Schrier RW. Earlier diagnosis of autosomal dominant polycystic kidney disease: importance of family history and implications for cardiovascular and renal complications. Am J Kidney Dis. 2005; 46(3): Kelleher CL, McFann KK, Johnson AM, Schrier RW. Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the general U.S. population. Am J Hypertens. 2004;17(11, pt 1): Schrier RW, McFann KK, Johnson AM. Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease. Kidney Int. 2003;63(2): Gabow PA. Autosomal dominant polycystic kidney disease. N Engl J Med. 1993;329(5): Pérez Dominguez TS, Rodríguez Pérez A, Buset Ríos N, et al; Grupo de Investigación Hiricare. Psychonephrology: psychology aspects in autosomal dominant polycystic kidney disease. Nefrologia. 2011;31(6): Torres MJ, Rodríguez Pérez JC, Hernández Socorro CR, et al. Molecular diagnosis of adult dominant polycystic kidney disease in the Canary Islands. Nefrologia. 2006;26(6): Gronwald W, Klein MS, Zeltner R, et al. Detection of autosomal dominant polycystic kidney disease by NMR spectroscopic fingerprinting of urine. Kidney Int. 2011;79(11): Cadnapaphornchai MA, McFann K, Strain JD, Masoumi A, Schrier RW. Prospective change in renal volume and function in children with ADPKD. Clin J Am Soc Nephrol. 2009;4(4): Shamshirsaz AA, Reza Bekheirnia M, Kamgar M, et al. Autosomal-dominant polycystic kidney disease in infancy and childhood: progression and outcome. Kidney Int. 2005;68(5): Barua M, Cil O, Paterson AD, et al. Family history of renal disease severity predicts the mutated gene in ADPKD. J Am Soc Nephrol. 2009;20(8): Boyer O, Gagnadoux MF, Guest G, et al. Prognosis of autosomal dominant polycystic kidney disease diagnosed in utero or at birth. Pediatr Nephrol. 2007;22(3): Garcia-Gonzalez MA, Jones JG, Allen SK, et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab. 2007:92(1-2): Patel P, Horsfield C, Compton F, Taylor J, Koffman G, Olsburgh J. Native nephrectomy in transplant patients with autosomal dominant polycystic kidney disease. Ann R Coll Surg Engl. 2011;93(5): annual data report. United States Renal Data System website. Published Accessed March 25, Panizo N, Goicoechea M, García de Vinuesa S, et al. Chronic kidney disease progression in patients with autosomal dominant polycystic kidney disease. Nefrologia. 2012;32(2): Bleyer AJ, Hart TC. Polycystic kidney disease. N Engl J Med. 2004;350(25): 2622; author reply Wilson PD. Polycystic kidney disease. N Engl J Med. 2004;350(2): Corradi V, Gastaldon F, Virzì GM, et al. Clinical pattern of adult polycystic kidney disease in a northeastern region of Italy. Clin Nephrol. 2009;72(4): Paterson AD, Magistroni R, He N, et al. Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2005;16(3): Harris PC. Autosomal dominant polycystic kidney disease: clues to pathogenesis. Hum Mol Genet. 1999;8(10): Sulikowski T, Tejchman K, Zietek Z, et al. Experience with autosomal dominant polycystic kidney disease in patients before and after renal transplantation: a 7-year observation. Transplant Proc. 2009;41(1): Igarashi P, Somolo S. Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol. 2002;13(9): Robinson C, Hiemstra TF, Spencer D, et al. Clinical utility of PKD2 mutation testing in a polycystic kidney disease cohort attending a specialist nephrology outpatient clinic. BMC Nephrol. 2012;13: Boertien WE, Meijer E, Li J, et al; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease CRISP. Relationship of copeptin, a surrogate marker for arginine vasopressin, with change in total kidney volume and GFR decline in autosomal dominant polycystic kidney disease: results from the CRISP cohort. Am J Kidney Dis. 2013;61(3): Tee JB, Acott PD, McLellan DH, Crocker JF. Phenotypic heterogeneity in pediatric autosomal dominant polycystic kidney disease at first presentation: a single-center, 20-year review. Am J Kidney Dis. 2004;43(2): Grantham J, Cowley B Jr, Torres VE. Progression of autosomal dominant polycystic kidney disease to renal failure. In: Seldin DW, Geibisch G, eds. The Kidney: Physiology and Pathophysiology, Vol. 2. 3rd ed. Philadelphia: Lippincott Williams and Wilkins; 2000: annual data report. United States Renal Data System website. Accessed March 25, Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet. 1994;343(8901): Chapman AB, Wei W. Imaging approaches to patients with polycystic kidney disease. Semin Nephrol. 2011;31(3): Kistler AD, Poster D, Krauer F, et al. Increases in kidney volume in autosomal dominant polycystic kidney disease can be detected within 6 months. Kidney Int. 2009;75(2): Reed BY, McFann K, Bekheirnia MR, et al. Variation in age at ESRD in autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2008;51(2): Dicks E, Ravani P, Langman D, Davidson WS, Pei Y, Parfrey PS. Incident renal events and risk factors in autosomal dominant polycystic kidney disease: a population and family-based cohort followed for 22 years. Clin J Am Soc Nephrol. 2006;1(4): Young RL, Lee KB. Reliability of magnetic resonance imaging for measuring the volumetric indices in autosomal-dominant polycystic kidney disease: correlation with hypertension and renal function. Nephron Clin Pract. 2006;103(4):c173-c Chapman AB, Guay-Woodford LM, Grantham JJ, et al; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int. 2003;64(3): Vol. 7, No. 2 The American Journal of Pharmacy Benefits e35

10 n Blanchette Matter Chawla Nellesen 70. King BF, Torres VE, Brummer ME, et al; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease. Kidney Int. 2003;64(6): Ahmed ER, Tashkandi MA, Nahrir S, Maulana A. Retrospective analysis of factors affecting the progression of chronic renal failure in adult polycystic kidney disease. Saudi J Kidney Dis Transpl. 2006;17(4): Courtney AE, McNamee PT, Heggarty S, Middleton D, Maxwell AP. Association of functional haem oxygenase-1 gene promoter polymorphism with polycystic kidney disease and IgA nephropathy. Nephrol Dial Transplant. 2008;23(2): Tazón-Vega B, Vilardell M, Pérez-Oller L, et al. Study of candidate genes affecting the progression of renal disease in autosomal dominant polycystic kidney disease type 1. Nephrol Dial Transplant. 2007;22(6): Persu A, El-Khattabi O, Messiaen T, Pirson Y, Chauveau D, Devuyst O. Influence of ACE (I/D) and G460W polymorphism of alpha-adducin in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2003;18(10): e36 The American Journal of Pharmacy Benefits March/April 2015

11 eappendix Table. Publications Identified for Literature Analysis (N = 55) # Citation 1 Ahmed ER, Tashkandi MA, Nahrir S, Maulana A. Retrospective analysis of factors affecting the progression of chronic renal failure in adult polycystic kidney disease. Saudi J Kidney Dis Transpl. 2006;17(4): Bae KT, Zhu F, Chapman AB, et al; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease. Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Clin J Am Soc Nephrol. 2006;1(1): Barua M, Cil O, Paterson AD, et al. Family history of renal disease severity predicts the mutated gene in ADPKD. J Am Soc Nephrol. 2009;20(8): Boertien WE, Meijer E, Li J, et al; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). Relationship of copeptin, a surrogate marker for arginine vasopressin, with change in total kidney volume and GFR decline in autosomal dominant polycystic kidney disease: results from the CRISP cohort. Am J Kidney Dis. 2013;61(3): Boyer O, Gagnadoux MF, Guest G, et al. Prognosis of autosomal dominant polycystic kidney disease diagnosed in utero or at birth. Pediatr Nephrol. 2007;22(3): Cadnapaphornchai MA, George DM, Masoumi A, McFann K, Strain JD, Schrier RW. Effect of statin therapy on disease progression in pediatric ADPKD: design and baseline characteristics of participants. Contemp Clin Trials. 2011;32(3): Cadnapaphornchai MA, Masoumi A, Strain JD, McFann K, Schrier RW. Magnetic resonance imaging of kidney and cyst volume in children with ADPKD. Clin J Am Soc Nephrol. 2011;6(2): Cadnapaphornchai MA, McFann K, Strain JD, Masoumi A, Schrier RW. Increased left ventricular mass in children with autosomal dominant polycystic kidney disease and borderline hypertension. Kidney Int. 2008;74(9): Cadnapaphornchai MA, McFann K, Strain JD, Masoumi A, Schrier RW. Prospective change in renal volume and function in children with ADPKD. Clin J Am Soc Nephrol. 2009;4(4):

12 # Citation 10 Casal JA, Hermida J, Lens XM, Tutor JC. A comparative study of three kidney biomarker tests in autosomal-dominant polycystic kidney disease. Kidney Int. 2005;68(3): Chapman AB, Bost JE, Torres VE, et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2012;7(3): Chapman AB, Guay-Woodford LM, Grantham JJ, et al; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int. 2003;64(3): Chapman AB. Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT-PKD studies. Clin J Am Soc Nephrol. 2008;3(4): Corradi V, Gastaldon F, Virzi GM, et al. Clinical pattern of adult polycystic kidney disease in a northeastern region of Italy. Clin Nephrol. 2009;72(4): Courtney AE, McNamee PT, Heggarty S, Middleton D, Maxwell AP. Association of functional haem oxygenase-1 gene promoter polymorphism with polycystic kidney disease and IgA nephropathy. Nephrol Dial Transplant. 2008;23(2): Dicks E, Ravani P, Langman D, Davidson WS, Pei Y, Parfrey PS. Incident renal events and risk factors in autosomal dominant polycystic kidney disease: a population and family-based cohort followed for 22 years. Clin J Am Soc Nephrol. 2006;1(4): Driscoll JA, Bhalla S, Liapis H, Ibricevic A, Brody SL. Autosomal dominant polycystic kidney disease is associated with an increased prevalence of radiographic bronchiectasis. Chest. 2008;133(5): Garcia-Gonzalez MA, Jones JG, Allen SK, et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Gen Metab. 2007:92(1-2): Grantham JJ, Torres VE, Chapman AB, et al; CRISP Investigators. Volume progression in polycystic kidney disease. N Engl J Med. 2006;354(20):