A Step Ahead toward Measuring Pain in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Pain is a frequent complication of autosomal dominant polycystic kidney disease (ADPKD), afflicting most patients,¹ and is the most frequent symptom leading to a diagnosis of the disease.² The most frequently reported types of pain are low back, abdominal, and flank pain, along with a sensation of flank heaviness.¹ Causes of acute pain can include urinary tract infections, cyst infections, and nephrolithiasis, but the exact cause of chronic flank pain cannot always be determined.¹ Chronic pain may begin as an acute episode that persists as chronic pain following treatment of the initial cause or, alternatively, may gradually develop with increasing severity over several years.¹ It can often be localized by patients within one finger.¹ Pain is a core outcome of critical importance to patients with ADPKD.³ In fact, cyst-related pain has been identified as the most important patient-reported outcome for patients and caregivers,⁴ but only about one in five ADPKD trials have included this end point.⁵ Furthermore, pain has been identified as being often under-recognized as well as inadequately managed in patients with ADPKD.²

However, a validated disease-specific pain assessment tool has been notably lacking for patients with ADPKD, and the quantification of pain has varied widely across studies, with a lack of standardization and often a lack of specificity to ADPKD.³ Recently, the Standardized Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) initiative has been an international effort to engage patients in the development of a set of core outcomes for ADPKD trials, on the basis of consensus among patients, caregivers, and health professionals.³ Recently identified themes at an international SONG-PKD consensus workshop regarding fundamental issues for the measurement of pain in ADPKD included distressing and disrupting life participation; variability and ambiguity in defining pain; stigma, frustration, and adaptation to pain; and ensuring validity and feasibility of pain measures.² It was stressed that there was a critical need for a validated tool that is simple, is succinct, and addresses the impact of pain on quality of life.²

In this issue of CJASN, Oberdhan et al.⁶ present an ADPKD-specific pain questionnaire called the ADPKD Pain and Discomfort Scale (ADPKD-PDS). After concept identification from a comprehensive review of the literature and clinician discussions, a qualitative phase involved 46 semistructured focus groups conducted in 18 countries, for a total of 293 participants. The study also included a range of participant ages and levels of kidney function, further increasing generalizability across a diverse population of ADPKD patients. This phase developed a draft instrument that was further refined after cognitive debriefing interviews. During the focus groups, three conceptually distinct types of pain and discomfort related to ADPKD were identified: dull kidney pain, sharp kidney pain, and fullness/discomfort. Next, a quantitative phase was performed via an online survey administered to 298 adults with ADPKD from the United States; 108 participants also completed a follow-up survey. After iterative refinement of the survey, the final ADPKD-PDS survey contained 20 items, which assess pain severity and interference with daily activities over a recall period of the 7 days before administration.

The authors are commended for developing the first validated tool to systematically evaluate pain and discomfort in patients with ADPKD. While a comprehensive tool to evaluate ADPKD-related chronic pain was also recently validated in the Determining feasibility of Randomization to high versus ad libitum water Intake in polycystic Kidney disease (DRINK) trial,⁷ that tool is lengthy and requires a software application, limiting the feasibility of widespread implementation. Importantly, patients were engaged in the process of developing the ADPKD-PDS, including participants around the globe from various cultural backgrounds. In contrast with some other pain questionnaires, the tool focuses specifically on kidney pain and a fullness sensation. The tool also accounts for additional recommendations from the recent SONG-PKD workshop² regarding establishing core outcomes for the assessment of pain in ADPKD (Figure 1).

Figure 1.

Current recommendations, pain assessment tool, and research challenges with pain assessment. The Autosomal Dominant Polycystic Kidney Disease Pain and Discomfort Scale (ADPKD-PDS) considers most of the recommendations set by the Standardized Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) workshop.² However, gaps in knowledge and challenges remain that warrant future research.

Notably, 80% of participants in the study were women, highlighting the need for further research on sex differences in the evaluation of pain. Women are over-represented in the literature regarding symptomatic ADPKD, which is typically attributed to the more severe liver phenotype in females.⁸ Interestingly, pain did not associate with total kidney volume (TKV) in the HALT Progression of Polycystic Kidney Disease (HALT-PKD) trial, with the exception of very large kidneys (TKV >1000 mL), although TKV was not measured in individuals with an eGFR <60 ml/min per 1.73 m² (Study B).⁸ In addition, women reported greater pain and interference of pain with daily life compared with men, and abdominal fullness was associated with reduced eGFR only in women.⁸ In the Developing Interventions to Halt Progression of ADPKD 1 (DIPAK-1) study, the combination of TKV/liver volume or liver volume, but not TKV alone, was associated with severity of pain in patients with an eGFR of 30–60 ml/min per 1.73 m².⁹ Pain sensitivity has also been suggested to be greater in women compared with men within the general population.¹⁰

Additional limitations of the current study include that the quantitative phase was performed only in the United States and that there may be bias as to who answered the survey, limiting the generalizability and applicability of the tool to all socioeconomic and cultural backgrounds. Furthermore, limited information (yes or no) was collected regarding the use of pain medications and their impact on pain. Finally, the tool captures pain only over the past 7 days. Some patients had recommended a month recall period in the SONG-PKD consensus workshop²; while the dull pain questions effectively capture “chronic” kidney pain as well as the chronic nature of fullness/discomfort, a 7-day period could potentially miss some acute pain episodes, although it is an easier period for participants to recall.

Overall, the 20-item questionnaire should be readily implemented into trials with minimal patient burden, requiring only about 2 minutes to complete, which was an important consideration for patients in the SONG-PKD consensus workshop.² A standardized tool may also help facilitate conversation surrounding pain in a health care setting. Health care professionals acknowledge that pain is often under-recognized and inadequately managed in ADPKD, with barriers including a lack of effective treatments, time constraints, and a reluctance of patients to discuss due to perceived perceptions.³ We look forward to gaining future insight as to how the ADPKD-PDS performs over longer durations, is implemented within clinical trials, and is translated to a pediatric population of patients of ADPKD.

Disclosures

K.L. Nowak reports research funding from Corvidia Therapeutics, Otsuka Pharmaceutical Development and Commercialization (data analysis), and Verdure Sciences and interactions with the PKD Foundation. K.L. Nowak has collaborated with Otsuka on investigator-initiated research outside the scope of the discussed manuscript and has been a consultant for Otsuka. K.L. Nowak also participated in the SONG-PKD consensus workshop. The remaining author has nothing to disclose.

Funding

None.

Author Contributions

K.L. Nowak and C.N. Steele wrote the original draft and reviewed and edited the manuscript.