Autosomal recessive polycystic kidney disease (ARPKD) is a rare, but severe form of polycystic kidney disease with unexplained phenotypic variability and a considerable impact on affected patients and families as well as attending physicians. The disease is caused by mutations in a single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1) encoding a huge transmembrane protein of poorly understood function called fibrocystin (4074 amino acids) [1]. Fibrocystin localizes to primary cilia of cells, classifying ARPKD as ciliopathy [2].

Within the last years basic science approaches have brought tremendous progress in the understanding of the genetic basis and pathomechanisms of ciliopathies [2-5]. As a consequence first clinical trials on potential treatment approaches for the common adult-onset autosomal dominant polycystic kidney disease (ADPKD) have been conducted and have aroused much scientific attention [6-12]. Still, these trials have not yet established a clear-cut and safe general treatment therapy for ADPKD.

With an estimated incidence of 1 in 20.000 live births ARPKD is much rarer than ADPKD and lacks similar targeted therapeutic approaches. Furthermore, initiatives for randomized clinical trials on ARPKD are facing the difficulty of clinically highly variable cohorts for which reliable clinical study end points are hard to establish. The underlying molecular mechanisms of the observed clinical heterogeneity are currently poorly understood. Genotype-phenotype correlations are confined to an interrelation of two truncating mutations with a mostly severe phenotype with peri- or neonatal demise and the observation that most patients surviving the neonatal period carry at least one missense mutation as milder manifestation [13,14]. Mutations in modifier genes may be involved as it has been described in other ciliopathies [2]. Finally, PKHD1 is subject to a complex splicing pattern, adding another level of complexity to mechanisms controlling fibrocystin expression [15,16].

Clinically, the phenotypic spectrum of ARPKD ranges from severely affected newborns with a persisting high mortality of up to 30% often related to respiratory failure in pulmonary hypoplasia [17] to mild affected adults with predominant hepatic fibrosis.

Renal involvement in ARPKD is characterized by bilateral massive enlargement of the kidneys and microcystic kidney disease as a consequence of fusiform tubular dilatations usually deriving from the collecting duct. Kidney function deteriorates over time and kidney transplantation is required in up to 50% of patients within the first two decades of life [14].

Beneath renal involvement ARPKD obligatory encompasses congenital hepatic fibrosis (CHF) due to ductal plate malformation, with or without intrahepatic bile duct dilatation. Portal hypertension, potentially resulting in variceal bleeding, and cholangitis are leading clinical manifestations of liver involvement. Additional clinical manifestations include pronounced arterial hypertension, secondary pulmonary hypertension, and hyponatremia. For a detailed review of the broad spectrum of clinical manifestations we refer to the recent excellent review articles by Büscher et al. [18], Sweeney and Avner [19] and Hartung and Guay-Woodford [15].

Therapeutic management of the various challenging clinical problems is mainly based on the physician’s clinical experiences and from retrospective data or expert opinions, such as the recently published consensus recommendations on ARPKD treatment [20]. In summary, the management of ARPKD currently remains largely opinion-based.

Regarding the description of clinical courses we can refer to important previous studies by Guay-Woodford [17], Adeva [21] and Bergmann [14] who described American and European cohorts. Still, as previously pointed out, there are multiple remaining questions and despite the mentioned expert opinion recommendations [20], there is an urging need e.g. for evidence-based management guidelines and clinical descriptions of long-term follow-ups. Clinical or biochemical risk markers have not yet been established and current treatment approaches have not been systematically reviewed. Finally, the insights obtained from molecular studies on ciliopathies have opened a new understanding of the underlying pathomechanisms. These insights may sharpen our clinical view for subtle phenotypes and may help to classify defined subgroups of ARPKD patients in the future. As nicely pointed out by the Consortium for Radiologic Imaging Study of PKD (CRISP) in a very recent study, classification into different subgroups in ADPKD may have prognostic implications [22]. This may also apply for ARPKD.

To address these open questions on ARPKD two renowned clinical research consortia in pediatric nephrology, i.e. the German Society for Pediatric Nephrology (GPN) and the European Study Consortium for Chronic Kidney Disorders Affecting Pediatric Patients (ESCAPE Network) recently teamed up to start a joint initiative for a clinical registry study exclusively devoted to ARPKD. This registry study (ARegPKD) is now open for the inclusion of patients. Here, we present the details of ARegPKD for the first time.

ARPKD is one of the most severe pediatric renal diseases presenting with a substantial and poorly understood phenotypic variability. Still, current management approaches remain opinion-based [20], clinical or biochemical markers for disease progression are missing, and long-term courses have not yet been reviewed in large cohorts.

To promote and elaborate our understanding of ARPKD, the GPN and the ESCAPE Network jointly initiated an international registry study to pool data regarding ARPKD clinical courses as well as different management approaches in European countries. This database is supposed to serve as a basis for translational research. Due to networking of two European consortia ARegPKD is expected to collect one of the largest cohorts of ARPKD patients with longitudinal data acquisition.

A prominent strength of the study will be the coverage of the major proportion of European ARPKD patients treated in highly specialized centers. Patients will be characterized in a pro- and retrospective manner with detailed questionnaires. We aim to get data for a deep phenotypical characterization that may help to identify specific subcohorts of ARPKD patients. Work by various independent groups addressed the question of potential differences in hepatic and renal disease progression in ARPKD [14,17,24]. Our data may also become helpful to give insights into this field.

Precise clinical characterization will be refined by establishing a concomitant ARPKD specific biobank and reference histology. This approach will set basis for translational and clinical research within a phenotypically deeply-defined international cohort of patients.

As a registry study, ARegPKD will have substantial limitations. Potential infirmities could arise from varying data quality with respect to completeness and accuracy of data, especially in case of retrospectively obtained data. Investigator-dependency may be an issue for clinical or radiologic examinations. Registered patients will furthermore show variable extent of genetic testing with multiple techniques; in some patients without genetic testing it may pose a difficulty to uncover phenotypic overlaps (“phenocopies”) with other polycystic kidney disorders. We will in most cases not have access to data on ARPKD-fetuses in case of induced termination of pregnancy. Finally, data may be missed or limited in cases of perinatal or early neonatal mortality contributing to a selection bias that will also be seen due to the character of the participating centers.

Factors influencing disease course like the development of end stage renal disease (ESRD) or hepatic insufficiency have not yet been established. Current clinical management focuses on symptomatic treatment in an opinion-based manner. We are therefore interested in long-term data regarding e.g. the time to ESRD and the effect of sufficient control of arterial hypertension on the deterioration of renal function. The frequently applied RAAS-blockade with angiotensin converting enzyme inhibitors or angiotensin receptor blockers is based on preliminary evidence from animal models [25-27] and from the data on the positive effect of strict blood pressure control on renal failure in children obtained in the ESCAPE study [28]. Still in this study only a minor fraction of patients suffered from ARPKD. The effect of different pharmacological antihypertensive classes on cyst respective kidney size and renal function remains to be elucidated as well as the proof of efficacy of antihypertensive therapy on slowing progression to end-stage-renal-disease in the ARPKD-cohort. Parameters with accelerating or slowing influence on development of renal failure are still to be identified in the ARPKD-cohort.

Additionally, we expect longitudinal data regarding the impact of uni- and bilateral nephrectomy on dialysis regimen and -efficacy, as well as data on the frequency of potentially recovering kidney function within the first year of life. As recently pointed out the currently available level of evidence on the effects of nephrectomy in ARPKD children is very limited [20]. Furthermore, single-center reports regarding outcomes of and indications for simultaneous vs. sequential liver and kidney transplantation in individuals with severe renal and hepatic phenotype [29-31] require analyses in a larger ARPKD cohort as basis for decision-making.

For the common ADPKD recent international clinical trials have studied the effect of different therapeutic approaches on total kidney volume (TKV) and renal function (mTOR inhibitors, vasopressin V2-receptor antagonists, somatostatin analogues, statin [6-10]). In these trials TKV serves as a surrogate parameter for disease progression as data from the CRISP study have shown that increased TKV is associated with worse outcome in ADPKD [32]. Similar attempts for clinical trials in ARPKD are missing. There is limited experimental data on the role of mTOR activation in ARPKD [33-36]. Animal data in PCK rats regarding vasopressin V2-receptor antagonism and its effect on reducing kidney weight and cyst volume is more robust [37,38]. The transfer of the data and studies regarding cyst growth in ADPKD on a cohort of ARPKD patients seems to be obvious and sonographic assessment of kidney length is used as a surrogate of TKV in the ARegPKD questionnaires. Still, this transfer is hampered by the fact, that TKV has not been established as an indicator of renal function deterioration in patients with ARPKD. Furthermore, TKV seems to be no good marker for kidney function in ARPKD patients as the most rapid growth of kidney volume is usually seen in the early disease course while no continuous volume gain is observed during progressive disease with loss of renal function. As TKV cannot be used potential clinical trials will therefore need to establish novel and specific clear-cut primary end points for ARPKD. ARegPKD aims to address this issue by detailed characterization of long term patient courses to set roots for the establishment of clinical trials on targeted treatment approaches.

In summary ARegPKD is a novel web-based international registry study aiming to provide evidence base for clinical treatment decisions and contributing to the understanding of ARPKD.