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Copeptin is not useful as a marker of malignant disease in the syndrome of inappropriate antidiuresis

Copeptin is not useful as a marker of malignant disease in the syndrome of inappropriate... Objective: The syndrome of inappropriate antidiuresis (SIAD) is a common condition Key Words in hospitalized patients. It is crucial to establish the cause of SIAD, especially in order f hyponatremia to exclude underlying malignancy. As malignant SIAD may be due to a paraneoplastic f paraneoplastic syndrome synthesis of arginine vasopressin, we hypothesized that its stable surrogate marker f cancer copeptin can be used as a diagnostic tool to differentiate between malignant and f lung cancer non-malignant SIAD. f tumor Methods: Prospective observational study. We analyzed data from 146 SIAD patients of two different cohorts from Switzerland and Germany. Patients were included while presenting at the emergency department and underwent a standardized diagnostic assessment including the measurement of copeptin levels. Results: Thirty-nine patients (median age: 63 years, 51% female) were diagnosed with cancer-related SIAD and 107 (median age: 73 years, 68% female) with non-malignant SIAD. Serum sodium levels were higher in cancer-related versus non-malignant SIAD: median (IQR) 124 mmol/l (120; 127) versus 120 mmol/l (117; 123) (P<0.001). Median (IQR) copeptin levels of patients with cancer-related SIAD were 11.1 pmol/l (5.2; 37.1) and 10.5 pmol/l (5.2; 25.2) with non-malignant SIAD (P = 0.38). Among different cancer entities, patients suffering from small-cell lung cancer showed the highest copeptin values, but overall no significant difference in copeptin levels between cancer types was observed ( P = 0.46). Conclusions: Copeptin levels are similar in cancer-related and non-malignant SIAD. Therefore, Copeptin does not seem to be suitable as a marker of malignant disease Endocrine Connections in SIAD. (2020) 9, 20–27 Introduction Hyponatremia is the most common electrolyte antidiuresis (SIAD), characterized by water retention disturbance in hospitalized patients (15–30%) (1) and is and secondary natriuresis (4, 5). SIAD can be caused by associated with increased morbidity and mortality (2, 3). a variety of conditions (infections, CNS disorders, drugs, One of its main causes is the syndrome of inappropriate pain or stress (6)) and to large degree by cancers, whereby https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve -19-0431 PB–8 B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 21 et al. it is postulated that arginine vasopressin (AVP) is produced Swiss cohort paraneoplastically (6, 7, 8). Differentiation between these From June 2011 to August 2013, 298 adult patients etiologies is important, especially in order to exclude or admitted to the medical emergency department of the detect an underlying malignancy which is present in University Hospital Basel and Kantonsspital Aarau with a approximately one-third of patients with SIAD (9). So serum sodium value of <125 mmol/l and serum osmolality far, there are no evidence-based guidelines for differential of <280 mosmol/kg were recruited (NCT01456533) (14). diagnosis, and current diagnostic strategies are not well Of those patients, 104 were diagnosed with SIAD and characterized. Therefore, a simple, reliable predictive included in the present study. marker would be of great interest. Copeptin, the c-terminal part of the precursor peptide German cohort of AVP, is increasingly used as a reliable surrogate marker of the unstable AVP (10, 11). Copeptin has been postulated From March to November 2007, 106 adult patients admitted and evaluated as a diagnostic tool in hyponatremia but to the medical emergency department of the University showed limited utility to differentiate between SIAD and Hospital of Würzburg with a serum sodium value of ≤130 other causes of hyponatremia, such as hypovolemic and mmol/l and serum osmolality of <280 mosmol/kg were hypervolemic hyponatremia (12, 13, 14). While in the recruited (NCT01341665) (12). Patients with impaired latter two categories, copeptin levels are typically high; renal function (serum creatinine >3.0 mg/dl) and those in SIAD (14) copeptin levels vary widely. In line with whose previous pharmacotherapy could not be reliably this, Zerbe et al. and later Fenske et al. described different specified were excluded. Of the remaining patients, 42 SIAD subtypes according to different osmoregulatory were categorized as SIAD and included in the present study. defects (15, 16). The so-called subtype A, characterized by persistent high copeptin values (>38 pmol/l), was primarily Clinical and laboratory assessment observed in patients with lung cancer (16). These results point to the long-standing idea of malignant SIAD being At admission, patient’s medical history and symptoms, caused by autonomous extra-hypothalamic production of vital signs, body measures and fluid status were assessed AVP (e.g. in lung cancer tissue) (17, 18). Indeed, previous and routine blood and urine samples were collected. data indicated AVP mRNA and AVP peptide production in Additional blood samples for copeptin small-cell lung cancer cell lines (19) and in vivo studies measurements were immediately drawn and stored at showed significant elevations of AVP ( 20) and copeptin −70°C. All copeptin values were determined using a (21) in cancer patients. standard chemiluminescence sandwich immunoassay Based on these findings, we hypothesized that (B.R.A.H.M.S. Gmbh, Hennigsdorf/Berlin, Germany) (10). copeptin levels are higher in cancer-related SIAD compared The lower detection limit of the assay was 0.4 pmol/l with to non-malignant SIAD, and we aimed to explore whether a functional assay sensitivity (<20% interassay coefficient copeptin may be used as a diagnostic marker for malignant of variation) of 1 pmol/l. disease in patients with SIAD. Diagnostic criteria and classification of SIAD The classification of SIAD was determined in a Materials and methods standardized way in both studies: an expert panel of at least two certified specialists was given access to all Study design relevant clinical and laboratory patient information, We analyzed data from 146 SIAD patients from two different covering the entire inpatient course. Importantly, new prospective observational studies from Switzerland and findings (e.g. new cancer diagnosis) arising during Germany. Both studies evaluated the utility of copeptin in hospitalization and treatment response were included in the differential diagnosis of hypoosmolar hyponatremia; the final classification. the respective study designs have previously been Basic diagnostic criteria for SIAD included euvolemia, described in detail (12, 14). All subjects gave informed urine osmolality >200 mmol/l and normal adrenal and consent to take part in the studies, and the study was thyroid function. Further criteria were considered if approved by the Ethics Committee of Basel/Aarau and the available: urinary sodium >40 mmol/l, fractional excretion Ethics Committee of the University of Würzburg. of urea (>35%) and uric acid (>12%). https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 22 et al. Patients with SIAD were subclassified into cancer- t-test. To test for differences in copeptin levels between related SIAD and non-malignant SIAD. In the non- patients with cancer-related and non-malignant SIAD, a malignant group, SIAD was further divided into the linear regression model was fitted indicating the presence following categories: infectious SIAD, centrally induced of malignant disease as explanatory and log-transformed SIAD, medication-induced SIAD and idiopathic SIAD. copeptin levels as dependent variable. Due to right- For patients with cancer-related SIAD, the origin of skewness of copeptin values, copeptin was log-transformed the cancer and the disease stage (metastatic and non- and normality was checked by inspecting QQ-plots. To metastatic disease) were assessed. further analyze whether copeptin levels are predicted by different cancer subtypes, a linear model was fitted with log-transformed copeptin values as dependent and cancer Study objectives type as explanatory variable. Only patients with malignant disease were included in this analysis. A P-value of <0.05 The primary objective of this study was to compare was considered to be statistically significant. Analyses and copeptin levels in patients with cancer-related SIAD graphics were performed using the statistical software to those with non-malignant SIAD. Further objectives package R (22) and GraphPad Prism7. included the comparison of copeptin levels between the different cancer types and SIAD categories. Results Statistical analysis Baseline characteristics Baseline characteristics are described using summary characteristics. The difference in the baseline values In Table 1, baseline characteristics of both cohorts are between the two cohorts was calculated by applying a provided. Of the total of 146 patients, 92 (63%) were Table 1 Descriptive table of the Swiss and German cohort. Total Swiss cohort German cohort Characteristics  Number of SIAD patients 146 104 42  Female, n (%) 92 (63%) 70 (67%) 22 (53%)  Median age (years) 69 (60–78) 71 (61–78) 67 (57–78) Clinical parameters: median (IQR)  BMI 23.4 (20.7–26.3) 23.5 (20.7–26.3) 22.9 (20.3–25.6)  Systolic BP, mmHg 136 (120–157) 143 (125–161) 116 (105–131.5)  Diastolic BP, mmHg 77 (67–84) 75 (66–84) 70 (65–79)  Heartbeats/minute 74 (65–84) 77 (67–86) 70 (60–80) Laboratory parameters: median (IQR)  Serum copeptin (pmol/l) 10.3 (5–26.6) 10.6 (5.4–27.2) 10 (4.4–20.3)  Serum sodium (mmol/l) 121 (117–124) 120 (116–122) 126 (122–128)  Serum osmolality (mosmol/l) 254 (247–262) 251 (242–258) 262 (257–266)  Urine osmolality (mosmol/l) 423 (327–546) 402 (326–496) 464 (343–594) Categories of SIAD  Cancer-related, n (%) 39 (27%) 19 (18%) 20 (48%)   Metastatic disease, n (%) 36 (92%) 19 (100%) 17 (85%)  Infections, n (%) 17 (12%) 9 (9%) 8 (19%)  Central, n (%) 23 (16%) 18 (17%) 5 (12%)  Medication, n (%) 45 (31%) 43 (41%) 2 (5%)  Others, n (%) 22 (15%) 15 (14%) 7 (17%) Cancer types  Lung (SCLC), n (%) 11 (28%) 8 (42%) 3 (15%)  Lung (others), n (%) 12 (31%) 6 (32%) 6 (30%)  Gastrointestinal, n (%) 7 (18%) 2 (11%) 5 (25%)  Hematological, n (%) 6 (15.3%) 1 (5%) 5 (25%)  Others, n (%) 3 (8%) 2 (11%) 1 (5%) Data are presented as mean and interquartile range (IQR) or as percentage (%). BMI: body mass index, BP: blood pressure, SCLC: small cell lung cancer, SIAD: syndrome of inappropriate antidiuresis. https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve PB–8 B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 23 et al. Table 2 Descriptive table of patients with cancer-related and non-malignant SIAD. Cancer-related SIAD Non-malignant SIAD P-value Characteristics  Number of SIAD patients, n (%) 39 (26.7%) 107 (73.3%)  Female, n (%) 20 (51%) 72 (68%) 0.09  Median age, years (IQR) 63 (59–69) 73 (60–80) 0.09 Clinical parameters: median (IQR)  BMI 22.2 (20.4–24.8) 23.8 (21.1–26.3) 0.75  Systolic BP, mmHg 125 (116–142) 142 (122–160) 0.02  Diastolic BP, mmHg 72 (65–82) 77 (68–84) 0.24  Heart beats/minute 77 (64–83) 73 (65–84) 0.62 Laboratory parameters: median (IQR)  Serum copeptin, pmol/l 11.1 (5.2–37.1) 10.5 (5.2–25.2) 0.38  Serum sodium, mmol/l 124 (120–127) 120 (117–123) <0.001  Serum osmolality, mosmol/l 259 (250–266) 252 (243–258) 0.02  Urine osmolality, mosmol/l 499 (401–589) 393 (312–495) 0.01 Data are presented as mean and interquartile range (IQR) or percentage (%). P < 0.05 is considered to be significant. BP: blood pressure, SIAD: syndrome of inappropriate antidiuresis. female and the median age in the population was 69 years compared to 120 mmol/l (117–123) in the non-malignant – without a statistically significant difference between the group. Serum sodium and osmolality as well as urine two cohorts. osmolality were all significantly higher in patients with Overall, the median serum sodium level was 121 cancer-related SIAD than in patients with non-malignant mmol/l (IQR 117–124). According to the inclusion criteria, SIAD (Table 2). the median (IQR) serum sodium level was lower in the Median (IQR) copeptin levels were not higher in Swiss cohort, 120 mmol/l (116–122), compared to the patients with cancer-related versus non-malignant SIAD: German cohort, 126 mmol/l (122–128). German patients 11.1 pmol/l (5.2–37.1), with a range from 0.95 to 380 showed a higher median (IQR) urine osmolality compared pmol/l versus 10.5 (5.2–25.2), with a range of 0.4 and to Swiss patients: 464 mosmol/l (343–594) versus 402 254.0 pmol/l, respectively (P = 0.38, Fig. 1 and Table 2). mosmol/l (326–496), respectively. Overall, median (IQR) copeptin level was 10.3 pmol/l Copeptin values according to cancer types (5–26.6), with similar values in both data sets. When comparing copeptin levels between different According to SIAD categories, 39 (27%) patients cancer types (Fig. 2), overall no significant difference were found to have cancer-related SIAD with different was observed (P = 0.46). We found slightly higher values proportions in the German (48%) and the Swiss cohort in patients with small-cell lung cancer compared to (18%). Similarly, frequencies of other SIAD categories also other cancer entities, but without statistical significance differed between the two cohorts, for example, medication (P = 0.43). The highest copeptin values were found in induced SIADH was highly prevalent in the Swiss cohort two patients with newly discovered, highly proliferative (41%), but not in the German cohort (5%) (Table 1). small-cell lung cancer (380 and 278.2 pmol/l). In the 39 patients with cancer-related SIAD, metastatic disease was present in 100% of the Swiss and in 85% of the German cohort. The remaining 15% of the German Copeptin values in different SIAD categories patients suffered from hematologic diseases whose Within the different categories of non-malignant SIAD, progression is not defined by metastases. there was a large overlap in copeptin levels, with high values up to >230 pmol/l in all categories (Fig. 3). Cancer-related versus non-malignant SIAD Patients with cancer-related SIAD tended to be younger (median 63 years) and less often female (51%) compared Discussion to those with non-malignant SIAD (median 73 years, 68% female). Median (IQR) serum sodium levels were The main finding of our study is that copeptin values vary 124 mmol/l (120–127) in the cancer-related group widely in patients with cancer-related and non-malignant https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 24 et al. Figure 3 Copeptin values according to SIAD categories. Boxplot: central line Figure 1 indicates the median; the upper and lower lines indicate the interquartile Copeptin values in patients with cancer-related and non-malignant SIAD. range. Boxplot: central line indicates the median; the upper and lower lines indicate the interquartile range. SIAD ’subtype A’, characterized by erratic elevated AVP/ SIAD and do not differ between the two groups. Similarly, copeptin levels (15, 16). Accordingly, in previously we found no substantial difference of copeptin levels reported cases adjudicated to this subtype, copeptin levels according to different cancer types or in the subcategories were consistently above a cut-off of 38 pmol/l, and in of SIAD. four of five described cases even around 200–300 pmol/l The highest copeptin values (380 and 278 pmol/l) were (16). In contrast, in our small-cell lung cancer patients, observed in two patients with small-cell lung cancer. In the majority of patients had copeptin levels below 38 fact, small-cell lung cancer is the best-characterized tumor pmol/l. Thus, even in the subgroup of small-cell lung entity of paraneoplastic AVP release by neuroendocrine cancer, where all patients had active and mostly extended tumor cells (19, 23, 24). The high copeptin values in disease, copeptin levels were not throughout markedly these patients may therefore represent ectopic AVP elevated but varied widely. In the remaining cancer types, production and correspond to the previously described copeptin levels were in the IQR of 5.5–29 pmol/l. There are several possible explanations for our findings. First, in the context of small-cell lung cancer and paraneoplastic phenomena hormones other than AVP (e.g. ANP) may play a role in hyponatremia (25, 26). Second, hyponatremia, and especially SIAD, is highly prevalent in patients with all types of cancer (5–30%) (8, 27, 28, 29). Besides ectopic hormone secretion, hyponatremia in cancer patients may be caused by the same conditions as in non-cancer patients: comorbidities, medication or symptoms such as vomiting, nausea, dehydration or stress. Of note, cancer patients are often polymedicated (e.g. chemotherapy such as vincristine and cisplatin, pain killers) or in an unstable condition and may, therefore, be particularly prone to hyponatremia (30). Third, irrespective of SIAD, copeptin is known to be elevated due to stress and acute conditions such as pneumonia, stroke or heart failure (31, 32, 33). All patients in our study were recruited in an acute setting when presenting Figure 2 at the emergency department. Thus, many of our patients Copeptin values according to cancer types. Boxplot: central line indicates the median; the upper and lower lines indicate the interquartile range. might have had high copeptin values due to physical and https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve Cancer-related SIAD Non-malignant SIAD Lung (SCLC) Lung (others) Gastrointestinal Hematological Others Copeptin in pmol/l Copeptin in pmol/l PB–8 B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 25 et al. psychological stress. As previously shown by our group, patients may have been misclassified. Further, despite the the non-osmotic, stress-related copeptin stimulus in acute large number of SIAD patients studied, only 39 (27%) had hospitalized hyponatremic patients may overrule the an active malignancy. Of those, cancer origin was very osmotic impulse (13, 14). heterogeneous, leading to a very limited number in the Of note, markedly elevated copeptin levels above 230 various subcategories of cancer types. pmol/l were occasionally observed in all subcategories A suitable diagnostic marker should be sensitive at of non-malignant SIAD. These patients suffered from an early stage of a cancer-related disease. Our patients different health issues (i.e. acute exacerbation of COPD, with solid cancers were all in advanced stages, and we are nausea and vomiting, polymedication). therefore not able to draw conclusions about copeptin According to the Hyponatremia Registry, approximately values as a diagnostic tool in an early phase of disease. one-third of euvolemic hyponatremia cases are cancer Finally, copeptin measurements were performed in an related with lung cancer as the most common cancer type acute setting, where the stress-induced copeptin stimulus (around 50%) (9). The high prevalence of cancer in SIAD is may overrule or confound the paraneoplastic or osmotic also demonstrated by our results with 27% cancer-related stimulus. SIAD (of which 59% were due to lung cancer). The strength of our study comprises the prospective Interestingly, there were considerably more cases data collection which allowed insights in the distribution with cancer-related SIAD in the German compared to the of copeptin values in well-characterized SIAD patients Swiss cohort (48% vs 18%), and the cancer types varied with and without malignancy. between the cohorts. The main difference of our two In summary, copeptin levels widely overlap in cohorts was the severity of hyponatremia according to patients with cancer-related and non-malignant SIAD. the inclusion criteria: serum sodium <135 mmol/l in the This may be explained by the heterogeneity of SIAD and German and <125 mmol/l in the Swiss study. The high the multifarious factors leading to unspecific copeptin number of gastrointestinal and hematologic cancers in elevations in the acute setting. The use of copeptin as a German patients with less pronounced hyponatremia marker to detect cancer-related disease in SIAD patients corresponds to the findings of a Danish study observing can therefore not be recommended. that hematologic cancers are often associated with only mild hyponatremia (130–135 mmol/l), gastrointestinal Declaration of interest cancer with moderate hyponatremia (125–129 mmol/l) The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. and pulmonary as well as head and neck cancers with profound hyponatremia (<125 mmol/l) (28). Indeed, the severity of hyponatremia may differ Funding according to SIAD categories, as previously observed in our Laboratory measurement of copeptin was funded by Thermo Fisher Scientific. Swiss hyponatremia cohort: lower sodium values (<120 mmol/l) were more often associated with non-malignant hyponatremia categories (especially medication-induced Data availability statement SIAD) than higher levels (34). This observation, however, The data that support the findings of this study are available from the corresponding author upon reasonable request. contradicts the finding of balanced hyponatremia severity in different SIAD categories as found in the international Hyponatremia Registry (9). Acknowledgements Otherwise, our results are mostly in concordance with We thank the associated study teams in Basel, Aarau and Würzburg for the access to patient data and the helpful support during the creation of the Hyponatremia Registry (9): patients with malignancy this article. were generally younger, were more often male and had higher levels of urine osmolality than patients with non- malignant disease. 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Journal of the American Copeptin and arginine vasopressin concentrations in critically ill Society of Nephrology 2014 25 2376–2383. (https://doi.org/10.1681/ patients. Journal of Clinical Endocrinology and Metabolism 2006 91 ASN.2013080895) 4381–4386. (https://doi.org/10.1210/jc.2005-2830) https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve PB–8 B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 27 et al. 33 Balling L, Kistorp C, Schou M, Egstrup M, Gustafsson I, Goetze JP, 34 Winzeler B, Jeanloz N, Nigro N, Suter-Widmer I, Schuetz P, Arici B, Hildebrandt P & Gustafsson F. Plasma copeptin levels and prediction Bally M, Blum C, Bock A, Huber A, et al. Long-term outcome of of outcome in heart failure outpatients: relation to hyponatremia profound hyponatremia: a prospective 12 months follow-up study. and loop diuretic doses. Journal of Cardiac Failure 2012 18 351–358. European Journal of Endocrinology 2016 175 499–507. (https://doi. (https://doi.org/10.1016/j.cardfail.2012.01.019) org/10.1530/EJE-16-0500) Received in final form 25 November 2019 Accepted 2 December 2019 Accepted Manuscript published online 3 December 2019 https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Endocrine Connections Bioscientifica

Copeptin is not useful as a marker of malignant disease in the syndrome of inappropriate antidiuresis

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Abstract

Objective: The syndrome of inappropriate antidiuresis (SIAD) is a common condition Key Words in hospitalized patients. It is crucial to establish the cause of SIAD, especially in order f hyponatremia to exclude underlying malignancy. As malignant SIAD may be due to a paraneoplastic f paraneoplastic syndrome synthesis of arginine vasopressin, we hypothesized that its stable surrogate marker f cancer copeptin can be used as a diagnostic tool to differentiate between malignant and f lung cancer non-malignant SIAD. f tumor Methods: Prospective observational study. We analyzed data from 146 SIAD patients of two different cohorts from Switzerland and Germany. Patients were included while presenting at the emergency department and underwent a standardized diagnostic assessment including the measurement of copeptin levels. Results: Thirty-nine patients (median age: 63 years, 51% female) were diagnosed with cancer-related SIAD and 107 (median age: 73 years, 68% female) with non-malignant SIAD. Serum sodium levels were higher in cancer-related versus non-malignant SIAD: median (IQR) 124 mmol/l (120; 127) versus 120 mmol/l (117; 123) (P<0.001). Median (IQR) copeptin levels of patients with cancer-related SIAD were 11.1 pmol/l (5.2; 37.1) and 10.5 pmol/l (5.2; 25.2) with non-malignant SIAD (P = 0.38). Among different cancer entities, patients suffering from small-cell lung cancer showed the highest copeptin values, but overall no significant difference in copeptin levels between cancer types was observed ( P = 0.46). Conclusions: Copeptin levels are similar in cancer-related and non-malignant SIAD. Therefore, Copeptin does not seem to be suitable as a marker of malignant disease Endocrine Connections in SIAD. (2020) 9, 20–27 Introduction Hyponatremia is the most common electrolyte antidiuresis (SIAD), characterized by water retention disturbance in hospitalized patients (15–30%) (1) and is and secondary natriuresis (4, 5). SIAD can be caused by associated with increased morbidity and mortality (2, 3). a variety of conditions (infections, CNS disorders, drugs, One of its main causes is the syndrome of inappropriate pain or stress (6)) and to large degree by cancers, whereby https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve -19-0431 PB–8 B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 21 et al. it is postulated that arginine vasopressin (AVP) is produced Swiss cohort paraneoplastically (6, 7, 8). Differentiation between these From June 2011 to August 2013, 298 adult patients etiologies is important, especially in order to exclude or admitted to the medical emergency department of the detect an underlying malignancy which is present in University Hospital Basel and Kantonsspital Aarau with a approximately one-third of patients with SIAD (9). So serum sodium value of <125 mmol/l and serum osmolality far, there are no evidence-based guidelines for differential of <280 mosmol/kg were recruited (NCT01456533) (14). diagnosis, and current diagnostic strategies are not well Of those patients, 104 were diagnosed with SIAD and characterized. Therefore, a simple, reliable predictive included in the present study. marker would be of great interest. Copeptin, the c-terminal part of the precursor peptide German cohort of AVP, is increasingly used as a reliable surrogate marker of the unstable AVP (10, 11). Copeptin has been postulated From March to November 2007, 106 adult patients admitted and evaluated as a diagnostic tool in hyponatremia but to the medical emergency department of the University showed limited utility to differentiate between SIAD and Hospital of Würzburg with a serum sodium value of ≤130 other causes of hyponatremia, such as hypovolemic and mmol/l and serum osmolality of <280 mosmol/kg were hypervolemic hyponatremia (12, 13, 14). While in the recruited (NCT01341665) (12). Patients with impaired latter two categories, copeptin levels are typically high; renal function (serum creatinine >3.0 mg/dl) and those in SIAD (14) copeptin levels vary widely. In line with whose previous pharmacotherapy could not be reliably this, Zerbe et al. and later Fenske et al. described different specified were excluded. Of the remaining patients, 42 SIAD subtypes according to different osmoregulatory were categorized as SIAD and included in the present study. defects (15, 16). The so-called subtype A, characterized by persistent high copeptin values (>38 pmol/l), was primarily Clinical and laboratory assessment observed in patients with lung cancer (16). These results point to the long-standing idea of malignant SIAD being At admission, patient’s medical history and symptoms, caused by autonomous extra-hypothalamic production of vital signs, body measures and fluid status were assessed AVP (e.g. in lung cancer tissue) (17, 18). Indeed, previous and routine blood and urine samples were collected. data indicated AVP mRNA and AVP peptide production in Additional blood samples for copeptin small-cell lung cancer cell lines (19) and in vivo studies measurements were immediately drawn and stored at showed significant elevations of AVP ( 20) and copeptin −70°C. All copeptin values were determined using a (21) in cancer patients. standard chemiluminescence sandwich immunoassay Based on these findings, we hypothesized that (B.R.A.H.M.S. Gmbh, Hennigsdorf/Berlin, Germany) (10). copeptin levels are higher in cancer-related SIAD compared The lower detection limit of the assay was 0.4 pmol/l with to non-malignant SIAD, and we aimed to explore whether a functional assay sensitivity (<20% interassay coefficient copeptin may be used as a diagnostic marker for malignant of variation) of 1 pmol/l. disease in patients with SIAD. Diagnostic criteria and classification of SIAD The classification of SIAD was determined in a Materials and methods standardized way in both studies: an expert panel of at least two certified specialists was given access to all Study design relevant clinical and laboratory patient information, We analyzed data from 146 SIAD patients from two different covering the entire inpatient course. Importantly, new prospective observational studies from Switzerland and findings (e.g. new cancer diagnosis) arising during Germany. Both studies evaluated the utility of copeptin in hospitalization and treatment response were included in the differential diagnosis of hypoosmolar hyponatremia; the final classification. the respective study designs have previously been Basic diagnostic criteria for SIAD included euvolemia, described in detail (12, 14). All subjects gave informed urine osmolality >200 mmol/l and normal adrenal and consent to take part in the studies, and the study was thyroid function. Further criteria were considered if approved by the Ethics Committee of Basel/Aarau and the available: urinary sodium >40 mmol/l, fractional excretion Ethics Committee of the University of Würzburg. of urea (>35%) and uric acid (>12%). https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 22 et al. Patients with SIAD were subclassified into cancer- t-test. To test for differences in copeptin levels between related SIAD and non-malignant SIAD. In the non- patients with cancer-related and non-malignant SIAD, a malignant group, SIAD was further divided into the linear regression model was fitted indicating the presence following categories: infectious SIAD, centrally induced of malignant disease as explanatory and log-transformed SIAD, medication-induced SIAD and idiopathic SIAD. copeptin levels as dependent variable. Due to right- For patients with cancer-related SIAD, the origin of skewness of copeptin values, copeptin was log-transformed the cancer and the disease stage (metastatic and non- and normality was checked by inspecting QQ-plots. To metastatic disease) were assessed. further analyze whether copeptin levels are predicted by different cancer subtypes, a linear model was fitted with log-transformed copeptin values as dependent and cancer Study objectives type as explanatory variable. Only patients with malignant disease were included in this analysis. A P-value of <0.05 The primary objective of this study was to compare was considered to be statistically significant. Analyses and copeptin levels in patients with cancer-related SIAD graphics were performed using the statistical software to those with non-malignant SIAD. Further objectives package R (22) and GraphPad Prism7. included the comparison of copeptin levels between the different cancer types and SIAD categories. Results Statistical analysis Baseline characteristics Baseline characteristics are described using summary characteristics. The difference in the baseline values In Table 1, baseline characteristics of both cohorts are between the two cohorts was calculated by applying a provided. Of the total of 146 patients, 92 (63%) were Table 1 Descriptive table of the Swiss and German cohort. Total Swiss cohort German cohort Characteristics  Number of SIAD patients 146 104 42  Female, n (%) 92 (63%) 70 (67%) 22 (53%)  Median age (years) 69 (60–78) 71 (61–78) 67 (57–78) Clinical parameters: median (IQR)  BMI 23.4 (20.7–26.3) 23.5 (20.7–26.3) 22.9 (20.3–25.6)  Systolic BP, mmHg 136 (120–157) 143 (125–161) 116 (105–131.5)  Diastolic BP, mmHg 77 (67–84) 75 (66–84) 70 (65–79)  Heartbeats/minute 74 (65–84) 77 (67–86) 70 (60–80) Laboratory parameters: median (IQR)  Serum copeptin (pmol/l) 10.3 (5–26.6) 10.6 (5.4–27.2) 10 (4.4–20.3)  Serum sodium (mmol/l) 121 (117–124) 120 (116–122) 126 (122–128)  Serum osmolality (mosmol/l) 254 (247–262) 251 (242–258) 262 (257–266)  Urine osmolality (mosmol/l) 423 (327–546) 402 (326–496) 464 (343–594) Categories of SIAD  Cancer-related, n (%) 39 (27%) 19 (18%) 20 (48%)   Metastatic disease, n (%) 36 (92%) 19 (100%) 17 (85%)  Infections, n (%) 17 (12%) 9 (9%) 8 (19%)  Central, n (%) 23 (16%) 18 (17%) 5 (12%)  Medication, n (%) 45 (31%) 43 (41%) 2 (5%)  Others, n (%) 22 (15%) 15 (14%) 7 (17%) Cancer types  Lung (SCLC), n (%) 11 (28%) 8 (42%) 3 (15%)  Lung (others), n (%) 12 (31%) 6 (32%) 6 (30%)  Gastrointestinal, n (%) 7 (18%) 2 (11%) 5 (25%)  Hematological, n (%) 6 (15.3%) 1 (5%) 5 (25%)  Others, n (%) 3 (8%) 2 (11%) 1 (5%) Data are presented as mean and interquartile range (IQR) or as percentage (%). BMI: body mass index, BP: blood pressure, SCLC: small cell lung cancer, SIAD: syndrome of inappropriate antidiuresis. https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve PB–8 B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 23 et al. Table 2 Descriptive table of patients with cancer-related and non-malignant SIAD. Cancer-related SIAD Non-malignant SIAD P-value Characteristics  Number of SIAD patients, n (%) 39 (26.7%) 107 (73.3%)  Female, n (%) 20 (51%) 72 (68%) 0.09  Median age, years (IQR) 63 (59–69) 73 (60–80) 0.09 Clinical parameters: median (IQR)  BMI 22.2 (20.4–24.8) 23.8 (21.1–26.3) 0.75  Systolic BP, mmHg 125 (116–142) 142 (122–160) 0.02  Diastolic BP, mmHg 72 (65–82) 77 (68–84) 0.24  Heart beats/minute 77 (64–83) 73 (65–84) 0.62 Laboratory parameters: median (IQR)  Serum copeptin, pmol/l 11.1 (5.2–37.1) 10.5 (5.2–25.2) 0.38  Serum sodium, mmol/l 124 (120–127) 120 (117–123) <0.001  Serum osmolality, mosmol/l 259 (250–266) 252 (243–258) 0.02  Urine osmolality, mosmol/l 499 (401–589) 393 (312–495) 0.01 Data are presented as mean and interquartile range (IQR) or percentage (%). P < 0.05 is considered to be significant. BP: blood pressure, SIAD: syndrome of inappropriate antidiuresis. female and the median age in the population was 69 years compared to 120 mmol/l (117–123) in the non-malignant – without a statistically significant difference between the group. Serum sodium and osmolality as well as urine two cohorts. osmolality were all significantly higher in patients with Overall, the median serum sodium level was 121 cancer-related SIAD than in patients with non-malignant mmol/l (IQR 117–124). According to the inclusion criteria, SIAD (Table 2). the median (IQR) serum sodium level was lower in the Median (IQR) copeptin levels were not higher in Swiss cohort, 120 mmol/l (116–122), compared to the patients with cancer-related versus non-malignant SIAD: German cohort, 126 mmol/l (122–128). German patients 11.1 pmol/l (5.2–37.1), with a range from 0.95 to 380 showed a higher median (IQR) urine osmolality compared pmol/l versus 10.5 (5.2–25.2), with a range of 0.4 and to Swiss patients: 464 mosmol/l (343–594) versus 402 254.0 pmol/l, respectively (P = 0.38, Fig. 1 and Table 2). mosmol/l (326–496), respectively. Overall, median (IQR) copeptin level was 10.3 pmol/l Copeptin values according to cancer types (5–26.6), with similar values in both data sets. When comparing copeptin levels between different According to SIAD categories, 39 (27%) patients cancer types (Fig. 2), overall no significant difference were found to have cancer-related SIAD with different was observed (P = 0.46). We found slightly higher values proportions in the German (48%) and the Swiss cohort in patients with small-cell lung cancer compared to (18%). Similarly, frequencies of other SIAD categories also other cancer entities, but without statistical significance differed between the two cohorts, for example, medication (P = 0.43). The highest copeptin values were found in induced SIADH was highly prevalent in the Swiss cohort two patients with newly discovered, highly proliferative (41%), but not in the German cohort (5%) (Table 1). small-cell lung cancer (380 and 278.2 pmol/l). In the 39 patients with cancer-related SIAD, metastatic disease was present in 100% of the Swiss and in 85% of the German cohort. The remaining 15% of the German Copeptin values in different SIAD categories patients suffered from hematologic diseases whose Within the different categories of non-malignant SIAD, progression is not defined by metastases. there was a large overlap in copeptin levels, with high values up to >230 pmol/l in all categories (Fig. 3). Cancer-related versus non-malignant SIAD Patients with cancer-related SIAD tended to be younger (median 63 years) and less often female (51%) compared Discussion to those with non-malignant SIAD (median 73 years, 68% female). Median (IQR) serum sodium levels were The main finding of our study is that copeptin values vary 124 mmol/l (120–127) in the cancer-related group widely in patients with cancer-related and non-malignant https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 24 et al. Figure 3 Copeptin values according to SIAD categories. Boxplot: central line Figure 1 indicates the median; the upper and lower lines indicate the interquartile Copeptin values in patients with cancer-related and non-malignant SIAD. range. Boxplot: central line indicates the median; the upper and lower lines indicate the interquartile range. SIAD ’subtype A’, characterized by erratic elevated AVP/ SIAD and do not differ between the two groups. Similarly, copeptin levels (15, 16). Accordingly, in previously we found no substantial difference of copeptin levels reported cases adjudicated to this subtype, copeptin levels according to different cancer types or in the subcategories were consistently above a cut-off of 38 pmol/l, and in of SIAD. four of five described cases even around 200–300 pmol/l The highest copeptin values (380 and 278 pmol/l) were (16). In contrast, in our small-cell lung cancer patients, observed in two patients with small-cell lung cancer. In the majority of patients had copeptin levels below 38 fact, small-cell lung cancer is the best-characterized tumor pmol/l. Thus, even in the subgroup of small-cell lung entity of paraneoplastic AVP release by neuroendocrine cancer, where all patients had active and mostly extended tumor cells (19, 23, 24). The high copeptin values in disease, copeptin levels were not throughout markedly these patients may therefore represent ectopic AVP elevated but varied widely. In the remaining cancer types, production and correspond to the previously described copeptin levels were in the IQR of 5.5–29 pmol/l. There are several possible explanations for our findings. First, in the context of small-cell lung cancer and paraneoplastic phenomena hormones other than AVP (e.g. ANP) may play a role in hyponatremia (25, 26). Second, hyponatremia, and especially SIAD, is highly prevalent in patients with all types of cancer (5–30%) (8, 27, 28, 29). Besides ectopic hormone secretion, hyponatremia in cancer patients may be caused by the same conditions as in non-cancer patients: comorbidities, medication or symptoms such as vomiting, nausea, dehydration or stress. Of note, cancer patients are often polymedicated (e.g. chemotherapy such as vincristine and cisplatin, pain killers) or in an unstable condition and may, therefore, be particularly prone to hyponatremia (30). Third, irrespective of SIAD, copeptin is known to be elevated due to stress and acute conditions such as pneumonia, stroke or heart failure (31, 32, 33). All patients in our study were recruited in an acute setting when presenting Figure 2 at the emergency department. Thus, many of our patients Copeptin values according to cancer types. Boxplot: central line indicates the median; the upper and lower lines indicate the interquartile range. might have had high copeptin values due to physical and https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-19-0431 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from Bioscientifica.com at 01/22/2022 03:10:57AM via Deepdyve Cancer-related SIAD Non-malignant SIAD Lung (SCLC) Lung (others) Gastrointestinal Hematological Others Copeptin in pmol/l Copeptin in pmol/l PB–8 B Winzeler, M Steinmetz Copeptin in malignant SIAD 9:1 25 et al. psychological stress. As previously shown by our group, patients may have been misclassified. Further, despite the the non-osmotic, stress-related copeptin stimulus in acute large number of SIAD patients studied, only 39 (27%) had hospitalized hyponatremic patients may overrule the an active malignancy. Of those, cancer origin was very osmotic impulse (13, 14). heterogeneous, leading to a very limited number in the Of note, markedly elevated copeptin levels above 230 various subcategories of cancer types. pmol/l were occasionally observed in all subcategories A suitable diagnostic marker should be sensitive at of non-malignant SIAD. These patients suffered from an early stage of a cancer-related disease. Our patients different health issues (i.e. acute exacerbation of COPD, with solid cancers were all in advanced stages, and we are nausea and vomiting, polymedication). therefore not able to draw conclusions about copeptin According to the Hyponatremia Registry, approximately values as a diagnostic tool in an early phase of disease. one-third of euvolemic hyponatremia cases are cancer Finally, copeptin measurements were performed in an related with lung cancer as the most common cancer type acute setting, where the stress-induced copeptin stimulus (around 50%) (9). The high prevalence of cancer in SIAD is may overrule or confound the paraneoplastic or osmotic also demonstrated by our results with 27% cancer-related stimulus. SIAD (of which 59% were due to lung cancer). The strength of our study comprises the prospective Interestingly, there were considerably more cases data collection which allowed insights in the distribution with cancer-related SIAD in the German compared to the of copeptin values in well-characterized SIAD patients Swiss cohort (48% vs 18%), and the cancer types varied with and without malignancy. between the cohorts. The main difference of our two In summary, copeptin levels widely overlap in cohorts was the severity of hyponatremia according to patients with cancer-related and non-malignant SIAD. the inclusion criteria: serum sodium <135 mmol/l in the This may be explained by the heterogeneity of SIAD and German and <125 mmol/l in the Swiss study. The high the multifarious factors leading to unspecific copeptin number of gastrointestinal and hematologic cancers in elevations in the acute setting. The use of copeptin as a German patients with less pronounced hyponatremia marker to detect cancer-related disease in SIAD patients corresponds to the findings of a Danish study observing can therefore not be recommended. that hematologic cancers are often associated with only mild hyponatremia (130–135 mmol/l), gastrointestinal Declaration of interest cancer with moderate hyponatremia (125–129 mmol/l) The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. and pulmonary as well as head and neck cancers with profound hyponatremia (<125 mmol/l) (28). Indeed, the severity of hyponatremia may differ Funding according to SIAD categories, as previously observed in our Laboratory measurement of copeptin was funded by Thermo Fisher Scientific. Swiss hyponatremia cohort: lower sodium values (<120 mmol/l) were more often associated with non-malignant hyponatremia categories (especially medication-induced Data availability statement SIAD) than higher levels (34). This observation, however, The data that support the findings of this study are available from the corresponding author upon reasonable request. contradicts the finding of balanced hyponatremia severity in different SIAD categories as found in the international Hyponatremia Registry (9). Acknowledgements Otherwise, our results are mostly in concordance with We thank the associated study teams in Basel, Aarau and Würzburg for the access to patient data and the helpful support during the creation of the Hyponatremia Registry (9): patients with malignancy this article. were generally younger, were more often male and had higher levels of urine osmolality than patients with non- malignant disease. 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Journal

Endocrine Connections – Bioscientifica

Published: Jan 1, 2020

Keywords: hyponatremia

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