A systematic review of the predictors of disease progression in patients with autosomal dominant polycystic kidney disease

A systematic review of the literature was conducted to identify publications that detail the natural history of ADPKD, including diagnosis, prognosis and progression. In the absence of a definitive measure of disease progression, all measures linked to the progression of ADPKD were considered, although it was anticipated that those linked to cyst development/renal enlargement and renal function would be the most relevant.

The systematic review was conducted and reported according to the principles in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [12] (Additional file 1). A search was conducted in the following electronic databases:

Electronic databases were searched on 7th April 2014 using a structured search string, including terms for ADPKD and study type (Additional file 2). The search was restricted to publications from the previous 10 years in all databases except BIOSIS, which was limited to the past 3 years. Publications in the field of ADPKD have become significantly more numerous in recent years; therefore, it was considered that a sufficient number of relevant articles would be identified and that any earlier studies containing key information would be identified through reference explosion. In addition, diagnostic and prognostic techniques have progressed with the advancement of technology, with earlier publications often relying on subjective measures of progression, including kidney palpation.

‘Grey literature’ searches of relevant congresses, limited to the past 3 years, were also conducted (World Congress of Nephrology, American Society of Nephrology, American Academy of Nephrology, British Renal Society, European Renal Association and International Society for Pharmacoeconomics and Outcomes Research). Reference lists of systematic reviews and meta-analyses identified by the search were reviewed to identify additional relevant articles that were not identified in the systematic search due to study type restrictions.

Studies meeting the following criteria were considered for inclusion in the review:

Identified articles were screened by one reviewer, according to the criteria specified above. Articles were filtered using a positive exclusion method, whereby articles with insufficient information to warrant their exclusion remained in the review [13].

Initially, titles and abstracts of identified articles were reviewed (title/abstract screening) according to a checklist; full-text papers of the publications remaining after title/abstract screening were reviewed according to the same checklist (full text screening). Papers assessing HRQoL were excluded at full text screening if they did not report data on the progression of ADPKD.

Publications that included assessment of the link between ADPKD progression and genetic markers were only included in the review if they assessed the link with genotype (PKD1/PKD2). Publications assessing genetic markers at a molecular level, i.e. studies assessing specific single nucleotide polymorphisms, were excluded because this level of detail is not readily available to nephrologists in clinical evaluations. An independent reviewer checked a random selection of articles (10 %) at both title/abstract and full text screening to ensure consistency and accuracy.

Data were extracted from studies that met the inclusion criteria. If more than one article was found to present data from the same study population, results were collated as appropriate.

Extracted data consisted of:

For the purposes of this review, ‘patient characteristics’ were demographic data and ‘clinical characteristics’ were defined as baseline clinical parameters, baseline measures of renal size and function, and characteristics that were not influenced by changing renal parameters, e.g. genotype (Table 1). ‘Outcomes’ were defined as any measures or markers of disease progression, such as parameters reported over a time period, or measurements taken at both baseline and end of the study. The reporting of symptoms of ADPKD, such as pain, may have been considered as patient characteristics if only reported at baseline, but may also have been considered as outcomes if reported over time.

Glomerular filtration rate (GFR) was a recognised measure of renal function, and was either estimated based on serum creatinine concentration using equations such as the Modification of Diet in Renal Disease (MDRD) equation or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (estimated GFR [eGFR]), or measured by creatinine clearance (measured GFR [mGFR]). For simplicity, we used the term ‘GFR’ to refer to studies that used either eGFR or mGFR or both, or where methods of determining GFR were not defined. Change in GFR was used as a measure of renal function and change in total kidney volume (TKV) was used for renal volume in this review.

The majority of the identified studies were observational studies (63.0 %), including case studies, registry reviews and patient surveys with durations ranging from 6 months to more than 40 years. The studies employed a range of different objectives, with many aiming to increase understanding of ADPKD. Most studies reported baseline patient characteristics, including average age and gender (65 and 58.8 % of studies, respectively), while symptoms of ADPKD frequently reported at baseline included hypertension and proteinuria (21.3 and 10.6 % studies, respectively). The most commonly reported measure of renal function, described in 66 (41.3 %) observational studies, was GFR. The most frequent measure of renal size was TKV (34 studies, 21.3 %).

Of the 38 (23.8 %) publications that reported outcomes of ADPKD measured over time, disease progression was measured in 32 studies (84.2 %) by GFR, estimated most commonly by the MDRD equation (41.6 %). Change in TKV was reported as a measure of disease progression in 12 studies (31.6 %), with 11 publications using magnetic resonance imaging (MRI) and one publication using computed tomography. Renal enlargement over time as a surrogate marker of disease progression was also measured by total cyst volume (TCV) (five studies) [14‐18], volume of each kidney (four studies) [19‐22], and total renal volume (TRV) (three studies) [19, 22, 23].

In total, 19 studies reported patient and clinical characteristics of patients with ESRD. Of these studies, 18 reported age at ESRD and 11 reported the number of ADPKD patients reaching ESRD. Baseline characteristics of patients in each of the study groups were not reported in eight studies [24‐31], but others reported a number of parameters including age (seven studies) [32‐37], serum creatinine (four studies) [37‐40], GFR (three studies) [33, 35, 38], TKV (three studies) [33, 36, 40], hypertension (one study) [41] and PKD mutation (one study) [42].

Publications were identified that measured GFR decline or increase in TKV (disease progression) and assessed the associated patient and clinical characteristics, defined in Table 1. If the association with patient and clinical characteristics was significant, these were then defined as prognostic indicators in the prediction of disease progression (Table 2).

TKV and age at baseline were the two factors most commonly cited as significantly associated with a faster rate of ADPKD progression, each cited in ten studies (Table 3). A wide range of prognostic indicators (a total of 26) were reported, many of which were only reported by one study, indicating a lack of consensus in the literature on the parameters implicated in ADPKD progression.

Seventeen publications from the Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) study were identified by the systematic review [15‐17, 43‐56]. CRISP is a prospective, long-term observational study, including 241 ADPKD patients with normal renal function who were considered at high risk of renal insufficiency. The study was initiated to increase the knowledge and understanding of ADPKD prognosis by establishing reliable measures of disease progression [2]. Patients were diagnosed due to a positive family history (asymptomatic family screening) or based on signs and symptoms related to the disease. The study includes patients with defined hypertension diagnosed before the age of 35 years; ADPKD diagnosed in utero or in the first year of life; 24-h urinary protein excretion greater than 300 mg/day; or an episode of gross haematuria in men before the age of 30 years (CRISP I population) [57]. A range of measurements have thus far been reported, and patients have been stratified by several different criteria across the CRISP publications, demonstrating the relevance of a number of prognostic factors, such as gender and age at diagnosis (Table 2). CRISP has identified the importance of TKV as a key prognostic indicator, particularly in the early stages of ADPKD where significant renal enlargement can occur prior to the loss of renal function [2, 46]. The CRISP study is ongoing, with 203 patients having been re-enrolled in CRISP II from July 2007 [15].

Patients were stratified by rate of ADPKD progression, and groups defined as fast or slow progressors (large or small annual decline in GFR, respectively), in four observational studies (Additional file 3) [56, 58‐60]. Although this concept is important in the clinical setting, there is no definitive conclusion in the literature as to how the rate of progression should be measured or stratified. Across the four studies, a range of prognostic indicators were reported, including initial GFR, high blood pressure, age at diagnosis and TKV at a given time point.

Disease severity was correlated with HRQoL in a single study [11]. In general, for patients with a lower GFR, Short Form-36 health survey scores were lower, indicating reduced HRQoL [11].

A research group in Brest, France, conducted an observational study assessing 26 clinical, biological and genetic variables (not specified) for use in a prognostic model. The model was based on data from 1017 patients with ADPKD, and was tested in a sub-population of 255 patients who had either reached ESRD or were aged over 60 years [41]. The presence of hypertension along with at least one urologic complication, or the presence of a truncating PKD1 mutation was reported to be associated with poorest renal outcome [41].

The 33 clinical trial publications were reviewed to ensure the same data were not extracted from multiple reports of the same study. Of these 33, 24 unique reports were identified. The trials assessed the efficacy of three main drug types to slow the progression of ADPKD:

Further drugs were:

In the clinical trials assessing treatments to halt or slow the development of ADPKD, efficacy was assessed using measures of disease progression. Change in TKV or renal function, measured by GFR or serum creatinine concentration, were the most commonly used primary endpoints in the identified trials.

Other primary endpoints considered in studies of disease-modifying interventions in patients with ADPKD included change in liver volume, change in TCV and change in urinary fatty acid-binding protein. The number of different primary endpoints used in the identified trials demonstrated inconsistencies in the measurement of efficacy due to the paucity of data on the progression of ADPKD.

In the 21 publications that reported data at multiple time points, the most frequently reported outcomes were TKV (14 reports, 66.7 %), eGFR (12 reports, 57.1 %), serum creatinine (7 reports, 33.3 %) and systolic blood pressure (9 reports, 42.9 %). Of these, 12 studies reported data at two time points and eight studies reported data at three or four time points. Data were recorded at baseline and after 6 months in six studies [62, 65, 68, 71‐73], at baseline and after 12 months in one study [70], at baseline and after 24 months in three studies [61, 66, 82], and at baseline and after 36 months in two studies [83, 84].

Due to the short study duration and lack of suitable sub-analyses or patient level data, disease progression data from these trials were not appropriate for the assessment of the prognostic potential of the variables measured at baseline.

Hypertension was targeted as a manifestation of ADPKD in the Halt Progression of Polycystic Kidney Disease (HALT-PKD) study, a clinical trial studying the intensive blockade of the renin-angiotensin system with combination ACEIs and angiotensin receptor blockers (ARBs). The study aimed to test the hypothesis that rigorous blood pressure control was more effective in slowing progression of renal disease in early ADPKD than moderate blood pressure control, by comparing the combination treatment to ACEI monotherapy alone. The primary endpoint was annual change in TKV, which was lower with rigorous blood pressure control than with moderate blood pressure control (P = 0.006). The rate of change in GFR was similar for the two treatment groups [85, 86].

The 61 non-systematic and systematic reviews and meta-analyses identified were mainly focussed around new and potential treatment options, as well as reviews of the genetics, pathophysiology and manifestations of the disease. In general, the identified reviews acknowledged and discussed a range of different prognostic indicators, but did not provide conclusive agreement on these factors.