Clinical Kidney Journal, 2021, vol. 14, no. 10, 2281 –2284 doi: 10.1093/ckj/sfab132 Advance Access Publication Date: 10.7.2021 Editorial Comment Clinical Kidney Journal EDITORIAL COMMENT Autosomal dominant polycystic kidney disease: possibly the least silent cause of chronic kidney disease 1 Roser Torra , Maria Vanessa Pérez-Gómez2 and Mónica Furlano1 1 Inherited Kidney Diseases Nephrology Department, Fundació Puigvert IIB-Sant Pau Medicine Department, Universitat Autónoma de Barcelona, REDinREN, Barcelona, Spain and 2Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, REDinREN, Madrid, Spain Correspondence to: Roser Torra; E-mail: rtorra@fundacio-puigvert.es ABSTRACT Pain is the highest prioritized patient-reported outcome in people with autosomal dominant polycystic kidney disease (ADPKD) but it remains infrequently and inconsistently measured across countries, studies and trials. The study by El- Damanawi et al. integrated a network of ADPKD expert clinicians, pain specialists, researchers and patient representatives from the national UK PKD charity, with the aim of addressing the lack of validated ADPKD-specific pain assessment tools (APATs). The APAT designed by the authors included several pain measurement tools and was tested in ADPKD patients, although further validation through assessment in larger cohorts is needed. Establishing a standardized instrument for pain measurement will ensure that pain is measured and reported in a consistent way to inform decision-making and identify effective interventions aimed at managing pain and minimizing the impact pain has on patients with ADPKD. In this context, the APAT established by the authors is to be warmly welcomed. Keywords: ADPKD, assessment, pain, patient-reported outcome, trials Chronic kidney disease (CKD) is commonly referred to as a ‘si- ADPKD is the most prevalent genetic kidney disease and the lent epidemic’. When CKD patients complain that their ‘kid- reason for kidney replacement therapy (KRT) in a significant neys’ hurt, we try to explain that the kidneys, even if they are percentage of patients, ranging between 7% and 15%, depending not working, do not hurt and that the source of patients’ pain is on the prevalence of the other causes of CKD in each country likely to be their back. Autosomal dominant polycystic kidney [1]. In the majority of studies and clinical trials, the interest in disease (ADPKD), however, represents an exception and is pos- this disease lies in its progression and the ultimate need for sibly the least silent cause of CKD. Increased kidney size, cystic KRT. In addition, extrarenal manifestations such as polycystic bleeding, cystic infections and the higher prevalence of lithiasis, liver disease and intracranial aneurysms are often studied. among other lesser-known factors, rightly cause patients to Beyond KRT, which obviously has the greatest impact, quality complain of kidney-related pain. of life is probably most affected by pain and liver involvement in the form of massive polycystic liver disease. Received: 21.6.2021; Editorial decision: 5.7.2021 C The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 2282 | R. Torra et al. While massive polycystic liver disease is fortunately rela- chronic pain [19]. Hopefully this guideline will also impact on tively rare, abdominal pain and discomfort are very prevalent. pain management in ADPKD patients. Acute and chronic pain is a common complaint in patients with Patients have a very legitimate claim in proposing that these ADPKD and afflicts >60% of patients [2–4]. Acute pain may be re- debilitating symptoms should be included in ADPKD clinical tri- lated to cyst haemorrhage, cyst rupture, nephrolithiasis and uri- als and studies [20, 21]. Of note, the International Standardized nary tract infection. These are all disease-related situations, but Outcomes in Nephrology (SONG) initiative [22], SONG-PKD, was they may also be unrelated to the disease and require a differ- launched in 2017 to establish a set of core outcomes for trials in ential diagnosis. Pain is considered chronic when it lasts patients with ADPKD based on consensus among patients, care- >4 weeks. The exact cause of chronic pain in ADPKD patients givers and health professionals. It should be noted that the cannot always be elucidated [5]. The most feasible explanation TEMPO 3:4 clinical trial did include pain within the composite is that increased organ volume causes distension of the renal endpoint and that post hoc analyses have shown efficacy of tol- and hepatic capsules and/or compresses the adjacent tissues [6, vaptan in alleviating pain [23]. One reason why pain has been 7]. Also, back pain may be produced by the adaptive stance little taken into account in most studies and clinical trials is the adopted due to increased abdominal volume [2]. ADPKD great subjectivity of this symptom. While for one patient a spe- patients report chronic pain located in the low back (71%), abdo- cific physical situation causes ‘discomfort’, for another this men (61%), head (49%), chest (30%) and legs (27%), often with ra- same situation causes ‘excruciating pain’ [24, 25]. The way in dicular features [2]. Glomerular filtration rate (GFR) decreases which the professional asks about this symptom and how the when the kidneys are large, so it is to be expected that in the patient’s response is transcribed into the medical record also presence of a lower estimated GFR (eGFR), the kidneys will be play an important role. There seems to be a disconnect between larger and cause more pain. In a subanalysis of the HLAT-PKD patients’ experiences and physicians’ awareness of the burden (HALT Progression of Polycystic Kidney Disease) study, in of pain in ADPKD and this highlights the need for more patient– patients with an eGFR >60 mL/min/1.73 m2 there was no rela- physician discussion of symptoms and disease management tionship between pain and height-adjusted total kidney volume [26]. For these reasons, the objective measurement of pain is an (htTKV) unless the patients had very large kidneys (htTKV unmet need in ADPKD as well as in most diseases that cause >1000 mL/m). In the group of patients with an eGFR of 20– pain. Consequently the article by El-Damanawi et al. [14] is of 60 mL/min/1.73 m2, htTKV was not measured, therefore the re- great interest. lationship with pain was not evaluated. However, patients with The study by El-Damanawi et al. [14] integrated an interest- an eGFR of 20–44 mL/min/1.73 m2 more often reported that pain ing network of ADPKD expert clinicians, pain specialists, had affected their daily life and had lower scores on the 36-item researchers and patient representatives from the national UK Short Form Health Survey compared with the 45–60 mL/min/ PKD Charity, with the aim of addressing the lack of validated 1.73 m2 eGFR group [8]. The few studies that have assessed qual- ADPKD-specific pain assessment tools (APATs). The APAT ity of life specifically in patients with ADPKD have found that designed by the authors was tested in ADPKD patients, covering pain, abdominal distension and sleep disturbances impair over- CKD Stages 1–4 (n ¼ 39), although further validation through as- all quality of life [9, 10]. Similarly, Tong et al. [11] identified an sessment in larger cohorts is needed. Self-reported health sta- immediate impact of pain on lifestyle, but also highlighted tus scores were worse among those with greater pain severity longer-term repercussions, including social isolation, loss of and advanced CKD, and these effects were more pronounced in employment potential and family burden. Recently males. The participants who had pain also showed anxiety and Winterbottom [12] disclosed preliminary results of the collabo- depression, but pain was additionally related to CKD Stage 4, so rative European CYSTIC 1 study. In a cohort of 465 patients with the anxiety and depression could have been due to the a mean age of 44 years, flank pain showed significant negative approaching need for KRT rather than the pain itself. Patients associations with the highest number of Kidney Disease Quality with CKD Stage 5 or with kidney transplantation were not in- of Life Short Form subscale scores assessed [12]. cluded in the study. As bilateral nephrectomy is not routinely Pain management varies greatly among countries in terms performed, patients may continue to suffer from abdominal or of both initiation and choice of treatment. Even taking into ac- back pain following KRT, with an associated impact on quality count that populations are not exactly comparable among stud- of life. In the study by El-Damanawi et al. [14], the APAT used ies, very significant differences are evident in the management seems to have been more applicable to chronic pain, as the of symptoms. The abstract by Sanon [13] highlights that 70% of scales used do not assess acute pain: it would be very interest- North American patients with ADPKD consume analgesics, ing if future studies could assess both acute and chronic pain. whereas a British study reported that only 29% do so [14]. The majority [87.6% (113/129)] of the questionnaires were sub- Similarly, only 7.7% of UK ADPKD patients receive opioid treat- mitted through the smartphone application. This is a very im- ment, while in North American studies, the percentage reaches portant point because the adoption of this approach in studies up to 50% [13]. Furthermore, ~3–4% of the adult US population involving quality of life questionnaires facilitates the participa- are prescribed long-term opioid therapy [15], while this ap- tion of patients by allowing them to fill in the questionnaire at proach is much less common in European countries. In this con- any time, without leaving their home and without having to go text it should be noted that most clinical guidelines and to the hospital. It also avoids patient forgetfulness when asked consensus documents recommend not using opiates for pain about symptoms during visits to the doctor, which may be 2 attributable to ADPKD [16]. More generally, harm due to opioid weeks apart. medications increased dramatically during the 2000s and early The use of many different pain scales in PATs is very enrich- part of the 2010s in the USA. Fatal overdoses from natural and ing but may be time-consuming and confusing for patients. El- semisynthetic opioids increased from 1.0 per 100 000 adults in Damanawi et al. [14] used the European Quality of Life 5- 1999 to 4.4 per 100 000 in 2016 [17]. In order to address the prob- Dimensions questionnaire (EQ-5D) scale, which is a standard- lem, the Centers for Disease Control and Prevention released ized instrument for health status [27] and is the preferred UK the Guideline for Prescribing Opioids for Chronic Pain in March measure of health-related quality of life [28]. They also used the 2016 [18]. This guideline was intended to improve therapy for Modified Short-Form Brief Pain Inventory, which is a validated ADPKD: least silent cause of CKD | 2283 clinical PAT [29] that assesses pain severity and interference REFERENCES with affective (mood, sleep and enjoyment) and activity (walk- 1. Akoh JA. Current management of autosomal dominant poly- ing and work) subdimensions. This inventory enriches the cystic kidney disease. World J Nephrol 2015; 4: 468–479 global understanding of pain in ADPKD by providing greater de- 2. Bajwa ZH, Sial KA, Malik AB et al. Pain patterns in patients tail than has previously been available. 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