938 Letters to the Editor
Fig. 1 Screenshot of the eRecord steroid-dependence ‘pop-up’.
first time on any given day. A single, daily alert per user was chosen, as early experience with eRecord suggested that users develop ‘pop-up fatigue’ and tend to close-down (unread) alerts that appear too often. We then began to log all our steroid-dependent patients attending (or who had attended) endocrinology clinics in our institution, by collating a list from the clinical coding department and then triangulating with individual physician databases. After confirming them as steroid-dependent, using information derived from their most recent electronic endocrinology letter, an alert was added for each patient by accessing their eRecord directly. The on-screen alert will therefore act much like the emergency card, but with the added advantage that we will be able to track good and poor practice with regard to steroid prescribing within our hospital and offer re-education to professional groups if and when poor practice is identified. This is an ongoing initiative, with alerts being set up for new patients individually as they present for the first time and we continue to cross-check that logging has been performed when regular patients attend clinic or the endocrine investigation unit. Although this exercise was modestly time-consuming initially, we felt it to be a departmental imperative to take advantage of a platform with the potential for improving safety and outcomes for our steroid-dependent patients on admission to hospital in the future. We hope to encourage departments with significant numbers of iatrogenically steroid-dependent patients, such as the respiratory medicine and rheumatology departments, to use the same approach for their patients who cannot be weaned off long-term steroids. We believe that a combined approach, encompassing structured and ongoing patient and clinician education, in addition to alert devices, both physical and electronic, is what is ultimately needed, throughout Europe and the rest of the world, to improve safety for patients who are steroid-dependent.
Anna L. Mitchell*, Catherine Napier†, Muhammad Asam*, Naveen Siddaramaiah*, Andrew Heed‡, Margaret Morris*, Margaret Miller*, Petros Perros*, R Andy James*, Stephen G. Ball*, Simon H.S. Pearce*,† and Richard Quinton*,† *Department of Endocrinology, Newcastle-upon-Tyne Hospitals Foundation NHS Trust, †Institute of Genetic Medicine, Newcastle University and ‡Pharmacy eRecord Programme, Newcastle-uponTyne Hospitals Foundation NHS Trust, Newcastle-upon-Tyne, UK E-mail: [email protected] doi: 10.1111/cen.12457
References 1 Quinkler, M., Hahner, S., Johannsson, G. et al. (2014) Saving lives of patients with adrenal insufficiency: a pan-European initiative? Clinical Endocrinology, 80, 319–321. 2 Wass, J.A. & Arlt, W. (2012) How to avoid precipitating an acute adrenal crisis. BMJ, 345, e6333.
Fibroblast growth factor-21: a metabolic regulator or something more? Dear Editor, We appreciate the article ‘Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction’ written by Hindricks and colleagues1 and read it with great interest. They aimed to investigate whether FGF-21 serum concentrations increase with deteriorating renal function in chronic kidney disease (CKD) and are increased in acute renal dysfunction after nephrectomy. It was the first study that covered the whole spectrum of CKD stages and demonstrated that circulating FGF-21 is increased in both chronic and acute kidney diseases. These findings may likely contribute to the understanding © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 936–942
Letters to the Editor 939 of the in vivo physiology of FGF-21 and its clinical application. In terms of daily practice, this subject is very relevant and justifies the emphasis given. Fibroblast growth factor 21 is an endocrine factor, secreted mainly by the liver, with beneficial effects on glucose and lipid homeostasis. In this context, FGF-21 have been shown to be elevated in subjects with impaired glucose tolerance, type 2 diabetes mellitus (DM), adverse lipid profiles, obesity, metabolic syndrome, hypertension and coronary heart disease. Elevated serum FGF-21 levels were also associated with carotid atherosclerosis in humans, independent of established risk factors including adverse lipid profiles and C-reactive protein.2 On the basis of these findings, it has been suggested that raised FGF-21 levels may occur in compensation to metabolic disturbances or tissue resistance. Furthermore, other studies have reported high levels of serum FGF-21 in individuals with poorer renal function.1 In harmony with this, the current findings supported the hypothesis that renal excretion is a major route to eliminate FGF-21 from circulation. We agree with the authors that markers of renal function should be included in studies on FGF-21 physiology. However, the physiological role of FGF-21 in kidney diseases as well as its benefit in daily practice is still unclear. Indeed, only a few articles in the literature have addressed this issue. From this viewpoint, the authors reported that none of the previous studies had included a sample of more than 250 patients. Interestingly, there was a previous report conducted by Crasto et al.3 that involved a large sample size of 744 adults from the Baltimore Longitudinal Study of Aging. Crasto et al. found a consistent relationship of serum FGF-21 with renal function and CKD, even after adjustment for DM. As high FGF-21 levels are associated with abnormal glucose metabolism, the inclusion of fasting glucose or DM in the multivariate regression analysis of the study population 1 may have been useful. According to the authors, the estimated glomerular filtration rate (GFR) remained a strong independent and negative predictor of FGF-21 levels in the cohort of 499 patients. However, to achieve these results, the authors used a cross-sectional approach in the study population 1. In addition, FGF-21 levels were significantly different between the five CKD stages.1 Of note, the GFR was estimated by the MDRD formula, and all patients were classified into CKD according to KDOQI guidelines. Notwithstanding, a new version of CKD guidelines, developed by KDIGO, recommends the CKD-EPI equation to estimate GFR, especially in patients with increased risk for CKD progression.4 Diabetes mellitus is a major cause of CKD in the world, and glucose control should be part of a multifactorial intervention strategy in individuals with CKD and DM. It is also known that lipotoxicity is the whole point of the pathogenesis of diabetic nephropathy. In the present study, when the authors divided the patients according to DM status, circulating median FGF-21 was significantly higher in patients with DM in comparison with non-DM.1 Recently, Kim et al.5 administered recombinant FGF21 to db/db mice and observed its effects in renal functional and morphological changes. The exogenous administration of FGF21 improved dyslipidaemia as well as metabolic abnormalities. © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 936–942
Additionally, the FGF-21 treatment decreased urinary albumin excretion as well as structural changes and oxidative stress in the kidney.5 In keeping with this, Zhang et al.6 investigated the renal protective function of FGF-21 under lipotoxic and diabetic conditions, and the possible protective mechanism. They observed that FGF-21 administration can significantly prevent lipotoxicity- and diabetes-induced early-stage renal apoptosis, hypertrophy and dysfunction. Moreover, FGF-21 treatment prevented renal lipid accumulation and subsequent inflammation, oxidative damage and fibrotic effect.6 FGF-21 has been recently pointed out as an early indicator of subclinical diabetic nephropathy. In patients with overt diabetic nephropathy, high FGF-21 levels are explained by the decline in renal function. On the other hand, raised FGF-21 in early diabetic nephropathy might reflect a defensive response of the organism to counteract metabolic disturbances such as hyperinsulinaemia and dyslipidaemia.2 In summary, we suggest FGF-21 as a clinically useful biomarker for the early diagnosis of diabetic nephropathy. Although FGF-21 is a potential candidate for therapeutic application against diabetic nephropathy, its clinical use still warrants further investigation. Other accurate renal markers or even gold standard measurements of GFR should also be used to investigate the feasible role of FGF-21 in kidney disease and its related comorbidities.
Conflicting interests Nothing to declare.
Financial disclosure Nothing to declare. Jo~ao Victor Salgado* and Bernardete Jorge Salgado† *Kidney Disease Prevention Centre, Department of Physiological Sciences, Federal University of Maranh~ao, †Endocrinology and Metabolism Service, Department of Physiological Sciences, Federal University of Maranh~ao, S~ao Luıs, Brazil E-mail: [email protected] doi: 10.1111/cen.12516
References 1 Hindricks, J., Ebert T., Bachmann, A. et al. (2014) Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction. Clinical Endocrinology 80, 918–924. 2 Woo, Y.C., Xu, A., Wang, Y. et al. (2013) Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. Clinical endocrinology, 78, 489–496. 3 Crasto, C., Semba RD., Sun K., Ferrucci L. (2012) Serum fibroblast growth factor 21 is associated with renal function and chronic kidney disease in community-dwelling adults. Journal of the American Geriatrics Society, 60, 792–793. 4 Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2013) KDIGO 2012 Clinical Practice Guideline for
940 Letters to the Editor the Evaluation and Management of Chronic Kidney Disease. Kidney International, 3, 1–150. 5 Kim, H.W., Lee, J.E., Cha, J.J. et al. (2013) Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology, 154, 3366–3376. 6 Zhang, C., Shao, M., Yang, H. et al. (2013) Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation. PLoS ONE, 8, e82275.
Protracted hypocalcaemia following a single dose of denosumab in humoral hypercalcaemia of malignancy due to PTHrP-secreting neuroendocrine tumour Dear Editors, Management of humoral hypercalcaemia of malignancy (HHM) refractory to bisphosphonates, or where their use is contraindicated, can be challenging. We present a case of PTHrP-secreting metastatic pancreatic neuroendocrine tumour (NET) with recurrent hypercalcaemic crises and renal failure. The challenges of
(a)
(c)
managing hypercalcaemia in the presence of kidney disease are highlighted in this case. A 38-year-old man presented with severe hypercalcaemia (calcium 450 M, normal 212–263 M) and renal failure requiring haemodialysis. His medical history was significant for primary hyperparathyroidism, managed successfully with removal of two hyperplastic parathyroid glands 14 years prior. HHM was confirmed by undetectable serum PTH level (
Fig. 1 Screenshot of the eRecord steroid-dependence ‘pop-up’.
first time on any given day. A single, daily alert per user was chosen, as early experience with eRecord suggested that users develop ‘pop-up fatigue’ and tend to close-down (unread) alerts that appear too often. We then began to log all our steroid-dependent patients attending (or who had attended) endocrinology clinics in our institution, by collating a list from the clinical coding department and then triangulating with individual physician databases. After confirming them as steroid-dependent, using information derived from their most recent electronic endocrinology letter, an alert was added for each patient by accessing their eRecord directly. The on-screen alert will therefore act much like the emergency card, but with the added advantage that we will be able to track good and poor practice with regard to steroid prescribing within our hospital and offer re-education to professional groups if and when poor practice is identified. This is an ongoing initiative, with alerts being set up for new patients individually as they present for the first time and we continue to cross-check that logging has been performed when regular patients attend clinic or the endocrine investigation unit. Although this exercise was modestly time-consuming initially, we felt it to be a departmental imperative to take advantage of a platform with the potential for improving safety and outcomes for our steroid-dependent patients on admission to hospital in the future. We hope to encourage departments with significant numbers of iatrogenically steroid-dependent patients, such as the respiratory medicine and rheumatology departments, to use the same approach for their patients who cannot be weaned off long-term steroids. We believe that a combined approach, encompassing structured and ongoing patient and clinician education, in addition to alert devices, both physical and electronic, is what is ultimately needed, throughout Europe and the rest of the world, to improve safety for patients who are steroid-dependent.
Anna L. Mitchell*, Catherine Napier†, Muhammad Asam*, Naveen Siddaramaiah*, Andrew Heed‡, Margaret Morris*, Margaret Miller*, Petros Perros*, R Andy James*, Stephen G. Ball*, Simon H.S. Pearce*,† and Richard Quinton*,† *Department of Endocrinology, Newcastle-upon-Tyne Hospitals Foundation NHS Trust, †Institute of Genetic Medicine, Newcastle University and ‡Pharmacy eRecord Programme, Newcastle-uponTyne Hospitals Foundation NHS Trust, Newcastle-upon-Tyne, UK E-mail: [email protected] doi: 10.1111/cen.12457
References 1 Quinkler, M., Hahner, S., Johannsson, G. et al. (2014) Saving lives of patients with adrenal insufficiency: a pan-European initiative? Clinical Endocrinology, 80, 319–321. 2 Wass, J.A. & Arlt, W. (2012) How to avoid precipitating an acute adrenal crisis. BMJ, 345, e6333.
Fibroblast growth factor-21: a metabolic regulator or something more? Dear Editor, We appreciate the article ‘Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction’ written by Hindricks and colleagues1 and read it with great interest. They aimed to investigate whether FGF-21 serum concentrations increase with deteriorating renal function in chronic kidney disease (CKD) and are increased in acute renal dysfunction after nephrectomy. It was the first study that covered the whole spectrum of CKD stages and demonstrated that circulating FGF-21 is increased in both chronic and acute kidney diseases. These findings may likely contribute to the understanding © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 936–942
Letters to the Editor 939 of the in vivo physiology of FGF-21 and its clinical application. In terms of daily practice, this subject is very relevant and justifies the emphasis given. Fibroblast growth factor 21 is an endocrine factor, secreted mainly by the liver, with beneficial effects on glucose and lipid homeostasis. In this context, FGF-21 have been shown to be elevated in subjects with impaired glucose tolerance, type 2 diabetes mellitus (DM), adverse lipid profiles, obesity, metabolic syndrome, hypertension and coronary heart disease. Elevated serum FGF-21 levels were also associated with carotid atherosclerosis in humans, independent of established risk factors including adverse lipid profiles and C-reactive protein.2 On the basis of these findings, it has been suggested that raised FGF-21 levels may occur in compensation to metabolic disturbances or tissue resistance. Furthermore, other studies have reported high levels of serum FGF-21 in individuals with poorer renal function.1 In harmony with this, the current findings supported the hypothesis that renal excretion is a major route to eliminate FGF-21 from circulation. We agree with the authors that markers of renal function should be included in studies on FGF-21 physiology. However, the physiological role of FGF-21 in kidney diseases as well as its benefit in daily practice is still unclear. Indeed, only a few articles in the literature have addressed this issue. From this viewpoint, the authors reported that none of the previous studies had included a sample of more than 250 patients. Interestingly, there was a previous report conducted by Crasto et al.3 that involved a large sample size of 744 adults from the Baltimore Longitudinal Study of Aging. Crasto et al. found a consistent relationship of serum FGF-21 with renal function and CKD, even after adjustment for DM. As high FGF-21 levels are associated with abnormal glucose metabolism, the inclusion of fasting glucose or DM in the multivariate regression analysis of the study population 1 may have been useful. According to the authors, the estimated glomerular filtration rate (GFR) remained a strong independent and negative predictor of FGF-21 levels in the cohort of 499 patients. However, to achieve these results, the authors used a cross-sectional approach in the study population 1. In addition, FGF-21 levels were significantly different between the five CKD stages.1 Of note, the GFR was estimated by the MDRD formula, and all patients were classified into CKD according to KDOQI guidelines. Notwithstanding, a new version of CKD guidelines, developed by KDIGO, recommends the CKD-EPI equation to estimate GFR, especially in patients with increased risk for CKD progression.4 Diabetes mellitus is a major cause of CKD in the world, and glucose control should be part of a multifactorial intervention strategy in individuals with CKD and DM. It is also known that lipotoxicity is the whole point of the pathogenesis of diabetic nephropathy. In the present study, when the authors divided the patients according to DM status, circulating median FGF-21 was significantly higher in patients with DM in comparison with non-DM.1 Recently, Kim et al.5 administered recombinant FGF21 to db/db mice and observed its effects in renal functional and morphological changes. The exogenous administration of FGF21 improved dyslipidaemia as well as metabolic abnormalities. © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 936–942
Additionally, the FGF-21 treatment decreased urinary albumin excretion as well as structural changes and oxidative stress in the kidney.5 In keeping with this, Zhang et al.6 investigated the renal protective function of FGF-21 under lipotoxic and diabetic conditions, and the possible protective mechanism. They observed that FGF-21 administration can significantly prevent lipotoxicity- and diabetes-induced early-stage renal apoptosis, hypertrophy and dysfunction. Moreover, FGF-21 treatment prevented renal lipid accumulation and subsequent inflammation, oxidative damage and fibrotic effect.6 FGF-21 has been recently pointed out as an early indicator of subclinical diabetic nephropathy. In patients with overt diabetic nephropathy, high FGF-21 levels are explained by the decline in renal function. On the other hand, raised FGF-21 in early diabetic nephropathy might reflect a defensive response of the organism to counteract metabolic disturbances such as hyperinsulinaemia and dyslipidaemia.2 In summary, we suggest FGF-21 as a clinically useful biomarker for the early diagnosis of diabetic nephropathy. Although FGF-21 is a potential candidate for therapeutic application against diabetic nephropathy, its clinical use still warrants further investigation. Other accurate renal markers or even gold standard measurements of GFR should also be used to investigate the feasible role of FGF-21 in kidney disease and its related comorbidities.
Conflicting interests Nothing to declare.
Financial disclosure Nothing to declare. Jo~ao Victor Salgado* and Bernardete Jorge Salgado† *Kidney Disease Prevention Centre, Department of Physiological Sciences, Federal University of Maranh~ao, †Endocrinology and Metabolism Service, Department of Physiological Sciences, Federal University of Maranh~ao, S~ao Luıs, Brazil E-mail: [email protected] doi: 10.1111/cen.12516
References 1 Hindricks, J., Ebert T., Bachmann, A. et al. (2014) Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction. Clinical Endocrinology 80, 918–924. 2 Woo, Y.C., Xu, A., Wang, Y. et al. (2013) Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. Clinical endocrinology, 78, 489–496. 3 Crasto, C., Semba RD., Sun K., Ferrucci L. (2012) Serum fibroblast growth factor 21 is associated with renal function and chronic kidney disease in community-dwelling adults. Journal of the American Geriatrics Society, 60, 792–793. 4 Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2013) KDIGO 2012 Clinical Practice Guideline for
940 Letters to the Editor the Evaluation and Management of Chronic Kidney Disease. Kidney International, 3, 1–150. 5 Kim, H.W., Lee, J.E., Cha, J.J. et al. (2013) Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology, 154, 3366–3376. 6 Zhang, C., Shao, M., Yang, H. et al. (2013) Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation. PLoS ONE, 8, e82275.
Protracted hypocalcaemia following a single dose of denosumab in humoral hypercalcaemia of malignancy due to PTHrP-secreting neuroendocrine tumour Dear Editors, Management of humoral hypercalcaemia of malignancy (HHM) refractory to bisphosphonates, or where their use is contraindicated, can be challenging. We present a case of PTHrP-secreting metastatic pancreatic neuroendocrine tumour (NET) with recurrent hypercalcaemic crises and renal failure. The challenges of
(a)
(c)
managing hypercalcaemia in the presence of kidney disease are highlighted in this case. A 38-year-old man presented with severe hypercalcaemia (calcium 450 M, normal 212–263 M) and renal failure requiring haemodialysis. His medical history was significant for primary hyperparathyroidism, managed successfully with removal of two hyperplastic parathyroid glands 14 years prior. HHM was confirmed by undetectable serum PTH level (
