Abstract
Levels of soluble IL-2 receptor can be discrepantly elevated in sarcoidosis patients with renal insufficiency http://ow.ly/ICVrY
To the Editor:
Sarcoidosis is a systemic, granulomatous disease that can manifest in multiple organs [1]. Several biomarkers are used to assess disease activity and monitor response to therapy, including soluble interleukin-2 receptor (sIL-2R) and angiotensin-converting enzyme (ACE) [2]. sIL-2R was previously shown to correlate with the amount of CD4+ T-lymphocytes in bronchoalveolar lavage fluid [3]. Furthermore, it was shown that sIL-2R >4000 pg·mL−1 was a significant predictor of relapse after discontinuation of infliximab therapy and that sIL-2R is a suitable prognostic marker for disease progression [4, 5]. We observed, however, that in a small number of patients with co-existing renal insufficiency, sIL-2R can be disproportionately high without marked signs of disease activity based on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), ACE and the clinical presentation. The aim of this pilot study is therefore to evaluate the influence of renal function on sIL-2R levels to determine if and how the marker can be used in sarcoidosis patients with renal insufficiency. In order to further illustrate the discrepancy, we first describe two cases.
The first case concerns a 56-year-old woman with pulmonary sarcoidosis, and a history of nephrotic syndrome and membranous glomerulonephritis resulting in moderate renal insufficiency (estimated glomerular filtration rate (eGFR) 50 mL·min−1 per 1.73 m2). ACE levels were repeatedly normal over a period of >2 years and no signs of sarcoidosis disease activity were present on the latest FDG-PET scan. However, sIL-2R levels remained highly elevated (>9000 pg·mL−1; normal reference value <3000 pg·mL−1) despite treatment with infliximab.
The second case involves a 50-year-old man with sarcoidosis and a complicated history of stage V diabetic nephropathy, heart failure and various infections. The patient was treated with peritoneal dialysis. ACE was normal but sIL-2R levels were repeatedly extraordinarily high (>50 000 pg·mL−1) despite immunosuppressive treatment. FDG-PET scans showed only moderately active sarcoidosis in the pulmonary parenchyma and mediastinal and hilar lymph nodes. Although this patient still had fairly active sarcoidosis, potentially leading to an elevation in sIL-2R, the exceptionally high levels measured in this patient are rarely observed.
Both patients showed a higher than expected level of sIL-2R in concurrence with more or less severely impaired renal function. The observation of these and similar cases over the past few years led to the question of whether renal insufficiency results in elevated sIL-2R levels in sarcoidosis patients.
It has been described that sIL-2R is cleared by the kidneys [6], and an association between sIL-2R and renal function has been reported in a few small studies in other diseases [7, 8]. However, the implications for clinical use of sIL-2R as a disease activity marker in sarcoidosis patients with renal insufficiency remain unknown. Renal insufficiency in sarcoidosis patients may occur in cases of disease-associated hypercalcaemia or renal sarcoidosis, or result from comorbid conditions such as hypertension or diabetic nephropathy, as illustrated here.
To investigate the relation between serum sIL-2R levels and renal function, we performed a retrospective analysis in a cohort that was previously described by Vorselaars et al. [9]. This cohort consists of patients treated with methotrexate at St Antonius Hospital, Nieuwegein, which is a tertiary referral centre for interstitial lung disease in The Netherlands. All patients were treated between June 2004 and September 2011. Medical records were retrospectively reviewed for relevant demographic data, treatment and disease activity parameters. eGFR, calculated using the Modification of Diet in Renal Disease formula [10], was used as a marker for renal function. It was split into the following categories: insufficient, <60; sufficient–normal, 60–90; and sufficient–high, >90 mL min−1 per 1.73 m2. Importantly, sIL-2R levels are highly variable between patients depending on the amount of disease activity present, as described above. Hence, in order to be able to measure the pure effect of renal function on sIL-2R levels, we attempted to eliminate the factor of disease activity as much as possible by collecting all disease parameters after a period of 6 months of methotrexate treatment. Levels of sIL-2R were determined with DIACLONE ELISA Kit Human sIL-2R/sCD25 (Sanquin, Amsterdam, The Netherlands) according to manufacturer's instructions. Values >3000 pg·mL−1 are considered increased.
To evaluate the effect of renal function on sIL-2R levels, a multiple linear regression analysis was performed. Independent variables in the analysis included eGFR and ACE. As eGFR was divided into categories, it was recoded into the dummy variables eGFR <60 and 60–90 mL·min−1 per 1.73 m2, where eGFR >90 mL·min−1 per 1.73 m2 was used as a reference category. ACE (divided into normal (<70 U·L−1) and high (>70 U·L−1)) was merely introduced into the model as another activity marker to adjust for remaining disease activity, for reasons described earlier. The study was approved by the local institutional review board (St Antonius Hospital, Nieuwegein, The Netherlands) with registration number LTME/Z-12.05 and acronym METHVERAZ.
In 86 patients out of the initial 145, data on renal function and disease activity markers at corresponding time-points were available. Of these, 63% were male and the treatment indication was related to pulmonary involvement in 66% of patients. In total, seven patients were classified as having renal insufficiency by an eGFR <60 mL·min−1 per 1.73 m2.
A significant association was found between sIL-2R and insufficient eGFR of <60 (p=0.001) relative to sufficient–high eGFR of >90 mL·min−1 per 1.73 m2. Importantly, no association was found between sIL-2R and sufficient–normal eGFR of 60–90 relative to a sufficient–high eGFR of >90 mL·min−1 per 1.73 m2 (p=0.992). Both results were adjusted for disease activity by ACE. Because of the small sample size of the eGFR <60 mL·min−1 per 1.73 m2 group and the resulting imperfect normal distribution, we also performed a nonparametric Kruskal–Wallis test, which gave similar results. Results are shown in figure 1.
These findings suggest that renal function impairment may indeed have a significant influence on sIL-2R levels in patients with sarcoidosis. Importantly, it also shows that sIL-2R levels do not correlate with normal renal function. Thus, in patients with renal insufficiency, sIL-2R levels may rise and probably also reflect accumulation through impaired renal clearance, instead of just sarcoidosis disease activity. This may lead to an overestimation of actual disease activity in this specific patient group. Therefore, we suggest caution regarding the interpretation of sIL-2R levels when renal function is impaired.
Theoretically, not only impaired clearance of sIL-2R but also increased production may lead to a higher than expected level of sIL-2R [11]. In patients with end-stage renal disease, T-cells appear to be pre-activated and, therefore, express more interleukin-2 receptor on their membrane. As a result, more shed sIL-2R appears in the blood. High sIL-2R levels in patients with stage V renal failure could thus be both the result of impaired clearance and increased production. In addition, it is worth mentioning that patients with chronic renal failure who are on maintenance dialysis show higher sIL-2R levels than undialysed patients [11, 12].
This study is limited by the small sample size and the retrospective design. In addition, this was a pilot study in an existing cohort. However, since renal insufficiency is a contraindication to the prescription of methotrexate, this cohort might underestimate the occurrence of renal insufficiency in the general sarcoidosis patient population. The effect will possibly be more substantial when a larger, more representative cohort is evaluated.
In conclusion, this pilot study shows that renal insufficiency has a significant influence on sIL-2R levels in sarcoidosis patients. Assessment of renal function when interpreting sIL-2R values is therefore warranted. Although this study only involved sarcoidosis patients, the results may likely be extended to other diseases in which sIL-2R is used as a biomarker for disease evaluation.
Acknowledgements
We thank Ellen Tromp, statistician at St Antonius Hospital, Nieuwegein, The Netherlands, for her statistical assistance.
Footnotes
Conflict of interest: None declared.
- Received January 13, 2015.
- Accepted January 25, 2015.
- Copyright ©ERS 2015