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Comprehensive nutritional assessment in short bowel syndrome with chronic renal failure on teduglutide therapy: a case report
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Comprehensive nutritional assessment in short bowel syndrome with chronic renal failure on teduglutide therapy: a case report Valeria Borioli RD , Emanuele Cereda MD, PhD , Federica Lobascio MD , Caterina Mengoli MD , Marilisa Caraccia RD , Anna Pagani MD , Nicola Aronico , Paolo Pedrazzoli MD , Antonio Disabatino MD, PhD , Riccardo Caccialanza MD PII: DOI: Reference:
S0899-9007(20)30003-4 https://doi.org/10.1016/j.nut.2020.110720 NUT 110720
To appear in:
Nutrition
Received date: Revised date: Accepted date:
6 May 2019 24 October 2019 30 December 2019
Please cite this article as: Valeria Borioli RD , Emanuele Cereda MD, PhD , Federica Lobascio MD , Caterina Mengoli MD , Marilisa Caraccia RD , Anna Pagani MD , Nicola Aronico , Paolo Pedrazzoli MD , Antonio Disabatino MD, PhD , Riccardo Caccialanza MD , Comprehensive nutritional assessment in short bowel syndrome with chronic renal failure on teduglutide therapy: a case report, Nutrition (2020), doi: https://doi.org/10.1016/j.nut.2020.110720
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
HIGLIGHTS Teduglutide allows reduction of PN requirements and complications in SBS patients. There is no standardized protocol for PN-dependent SBS patients under teduglutide. BIVA could be proposed for appropriate management of SBS patients under teduglutide.
Comprehensive nutritional assessment in short bowel syndrome with chronic renal failure on teduglutide therapy: a case report Running head: Nutritional assessment in SBS under teduglutide
Valeria Borioli RD1, Emanuele Cereda MD PhD1, Federica Lobascio MD1, Caterina Mengoli MD2, Marilisa Caraccia RD1, Anna Pagani3 MD, Nicola Aronico2, Paolo Pedrazzoli3 MD, Antonio Disabatino MD PhD2, and Riccardo Caccialanza MD1* 1
Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
2
First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy. 3
Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo and Department of Internal Medicine, University of Pavia, Pavia, Italy. * Corresponding author: Riccardo Caccialanza MD, Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo Viale Golgi 19, 27100 Pavia, Italy (Tel.: +39 0382 501615; Fax: + 39 0382 502801) E-mail: [email protected]
ABSTRACT We report the case of a 62-years old woman with short bowel syndrome (SBS) and chronic renal failure, successfully treated with teduglutide, who underwent comprehensive systematic nutritional assessment including bioelectrical impedance vectorial analysis (BIVA). The patient did not tolerate the attempt of gradual suspension of parenteral nutrition (PN), bumping into the worsening of nutritional status and renal function. Then, she was declared eligible for teduglutide, a glucagon-like peptide 2 analogue, which stimulates structural and functional intestinal adaptation and increases nutrient and fluid absorption. To date, there is no standardized nutritional management protocol for PN-dependent SBS patients treated with teduglutide. We here report our first 1-year follow-up data. The patient underwent comprehensive systematic nutritional assessment initially every two weeks, then monthly. It included handgrip strength (HG), blood tests (particularly serum creatinine, estimated glomerular filtration rate, urea, electrolytes, micronutrients, serum albumin), fluid intake, urine output, quality of life (QoL) evaluation and BIVA, which estimates fat-free mass (FFM) and measures phase angle (PhA) and hydration status. At treatment initiation, the patient was on PN 3 days a week. After 3 months, she was weaned off PN. At 1 year, weight and serum albumin were reduced (-7.5 kg, -0.6 g/dL, respectively), FFM, PhA and HG slightly decreased, hydration status and renal function were preserved and QoL subtly improved. No relevant clinical complications or metabolic imbalances occurred. The inclusion of BIVA in the comprehensive systematic nutritional assessment of SBS patients treated with teduglutide could be proposed for appropriate and safe management, particularly in the presence of renal impairment.
KEY WORDS: bioimpedance vectorial analysis, nutritional assessment, parenteral nutrition, short bowel syndrome, teduglutide.
INTRODUCTION Short bowel syndrome (SBS) is a rare and disabling disease, which leads to the reduction in gut function, below the minimum necessary for the absorption of macronutrients, water and electrolytes 1. In adults, SBS is the most frequent cause of chronic intestinal failure (CIF). CIF often results from extended intestinal resection frequently caused by Crohn’s disease, mesenteric ischemia, intestinal cancer, volvulus, but it can also be caused by other conditions that decrease absorptive capacity in the absence of resection, including radiation enteritis, chronic intestinal pseudo-obstruction, and congenital villus atrophy 1. Patients with SBS experience a variety of symptoms affecting quality of life (QoL), including asthenia, weight loss, severe diarrhea, which leads to development of protein-calorie malnutrition and dehydration, because the patients are unable to maintain fluid, electrolyte, micronutrient, calorie and protein balance with normal oral diet 1. Intravenous supplementation to provide fluid and nutrient support is the primary treatment for SBS 2, but permanent dependence on PN may decrease survival and QoL 1. In order to reduce the dependence on PN, the European guidelines on CIF in adults recommend to consider the use of growth factors and to evaluate their efficacy according to standardized protocols 2. Glucagone-like peptide-2 (GLP-2) is a hormone secreted in response to nutrients ingestion by entero-endocrine cells, primarily located in the terminal ileum and colon. GLP-2 is involved in regulation, growth and maintenance of intestinal epithelium function, and it has also been associated with intestinal adaptation after surgical resection 3. Teduglutide, a recent attractive therapeutic agent, is a GLP-2 analogue, with a longer half-life (2 hours) than native GLP2, which is produced in Escherichia Coli cells by recombinant DNA technology 4. As for native GLP2, its biologic effects involve structural and functional intestinal adaptation, as it increases intestinal blood flow, the height of villi and the depth of crypts, thus enhancing intestinal nutrient
and fluid absorption 4. Teduglutide was declared orphan drug for SBS by the Food and Drug Administration in 2000 and approved in 2012 for the treatment of adult patient with SBS who are dependent on parenteral support 5. This approval was based on an extensive clinical program, especially on two trials addressing short-term and long-term safety and efficacy of teduglutide (0.05mg/kg/day) in reducing PN requirements (volume/frequency of infusions) and associated complications
6,7
. Common treatment-related complications are abdominal pain, catheter sepsis,
and decreased weight (25-35%). Nonetheless, approximately 20-30% of patients experience problems with fluid balance (dehydration/fluid overload) 7. Indeed, PN in SBS is a life-saving treatment, but when it becomes a permanent or long-term intervention it is frequently associated with decreased QoL and can lead to dangerous complications, including catheter-related bloodstream infections and sepsis 2. The risk of PNrelated mortality increases with PN dependence duration 2. A major issue in daily practice is the availability of accurate and non-invasive technologies to evaluate and monitor the nutritional and hydration status of SBS patient. The use of measured bioelectrical parameters, such as phase angle (PhA), using bioelectrical impedance vectorial analysis (BIVA), was demonstrated to reliably reflect cell integrity and energy balance in patients with chronic diseases
8,9
. In addition, BIVA appears to be a feasible procedure to evaluate body
composition, since it is independent of body weight and allows the assessment of hydration status, which can be easily and reliably monitored in several clinical conditions 8. Several studies showed that BIVA can predict outcomes and prognosis in different stage of kidney disease 10, heart failure 11, cancer and other chronic diseases 12. To date, there is no standardized nutritional management protocol for PN-dependent SBS patients treated with teduglutide and BIVA has not been applied in their clinical management, yet.
Here, we present the case of a PN-dependent SBS woman with chronic renal failure, successfully treated with teduglutide, who underwent comprehensive systematic nutritional assessment including BIVA.
CASE REPORT The patient is a 62-year-old, Caucasian woman who underwent a sub-total gastrectomy for gastric adenocarcinoma in January 2003, followed by adjuvant chemotherapy (CT), ended in July 2003. At the end of CT, she reported a weight ranging from 53 kg to 55 kg (body mass index [BMI] 22.122.9 kg/m2). Her usual weight was 62 kg (BMI 25.8 kg/m2). In August 2008, she was hospitalized for severe generalized peritonitis with septic shock and total jejunal-ileal necrosis caused by volvulus on the Roux loop; she was then subjected to total jejunalileal resection with a jejun-caecal anastomosis. X-ray gastroduodenal esophagus transit exam showed a residual tract of the small bowel of about 100-140 cm. When she was referred to our Unit, body weight was 49.5 kg (BMI 20.6 kg/m2). She was following a very low-fiber diet with sufficient protein-calorie estimated intake; general conditions were fair and no particular metabolic abnormalities were recorded, with exception of mild hypokalaemia, hypomagnesemia and hyposideremia and vitamin B12 deficiency. We supplemented the patient with oral electrolytes, iron and vitamin B12, and started the follow-up, which was set initially every month, then every 3-4 months. For about 6 years, the patient was in good health and nutritional conditions, and she was simultaneously followed by the Gastroenterology Unit and the Oncology Unit of our Hospital. Suddenly, in December 2014, she was admitted to our Nephrology Unit for severe hypokalemia, acute renal failure and acute worsening of nutritional status, associated with a prolonged lung infection in the previous 3 weeks. Body weight at admission was 36.5 kg (BMI 15.2 kg/m2).
After nutritional assessment, a central venous catheter (CVC, Groshong type) was placed in order to start a daily HPN with three-in-one solution and a volume of 1000 mL (1000 kcal, amino-acids 57 g, glucose 110 g, lipids 40 g). After discharge (weight 38 kg; BMI 15.8 kg/m2), the patient continued the follow-up every 2 months. Renal function remained stable and in May 2015 weight was 53.5 kg (BMI 22.3 kg/m2). Then, we decided to decrease HPN administration to 3 times a week with the same three-in-one bag, till full suspension in December 2015 (weight 55.5 kg, BMI 23.1 Kg/m2). Five months later, worsening of patient’s clinical conditions occurred: we registered a weight loss of 5.5 kg and a new outbreak of renal failure (creatinine 1.18 mg/dl; estimated glomerular filtration rate [eGFR] 51 mL/min/1.73m). Our Nephrologists contextually diagnosed chronic kidney disease G3a. We restarted HPN for 3 times a week. Then, the patient was followed-up until April 2017, with no significant changes in her clinical conditions; weight was around 54 kg (BMI 22.5 kg/m2) and kidney function was stable (creatinine 1.06 mg/dl; eGFR 57 mL/min/1.73m). Nutritional assessment showed an average food intake of 1600-1700 Kcal/die and liquid intake of 2000 mL/day. She reported chronic diarrhea (6-7 surges/day) and random gastrointestinal symptoms, including postprandial nausea and vomiting. She underwent colonoscopy on March 2017, and no pathological signs were detected. The patient was declared eligible for treatment with teduglutide; the therapy was started on July 2017 (weight 56 kg; BMI 23.3 kg/m2) at an initial dose of 0.025mg/kg/day, due to the previously attested presence of renal impairment. After 2 months, kidney function was stable and the dose was increased to 0.05 mg/kg/day. During treatment, the patient underwent weekly home monitoring by nursing staff, who checked fluid balance, compliance to treatment and the occurrence of any side effect.
Furthermore, the patient underwent comprehensive nutritional assessment initially every two weeks for the first 8 months, then monthly, including handgrip strength (HG) measured by digital dynamometry (DynEx™, Akern/MD Systems), food and liquid intake (24 h recall), blood tests (including serum creatinine, eGFR, urea, electrolytes, micronutrients and serum albumin), urine output, and BIVA (NutriLAB, Akern/RJL), which estimates fat-free mass (FFM) and measures PhA and hydration status (total body water [TBW], extracellular water [ECW], hydration index). In addition, QoL was assessed by the 36-Item Short Form Health Survey (SF-36) every 3 months. At baseline, the patient was on HPN 3 days a week. After 3 months, the patient was weaned off PN. Diarrhea was reduced to 2-4 surges/day and gastrointestinal symptoms slightly improved during the follow-up. Compliance to treatment was very good and no serious or clinically significant side effects, such as fluid or metabolic imbalances, were reported throughout the entire observation period. The clinical and instrumental follow-up data are reported in Table 1, while BIVA results are depicted in Figure 1. After 1-year follow-up, weight and serum albumin were reduced (-7.5 kg, 0.6 g/dL, respectively), average food and fluid intake, and urine output did not significantly change, FFM, PhA and handgrip strength slightly decreased, hydration status and renal function were preserved, while the physical component score (PCS) of QoL improved. Treatment and follow-up are still ongoing.
DISCUSSION This report shows the efficacy of comprehensive systematic nutritional assessment including BIVA, muscle strength and QoL evaluation, in the clinical management of a SBS patient with concomitant renal impairment successfully treated with teduglutide.
The natural adaptive response of the bowel to resection is a crucial event in SBS 2. In our patient intestinal adaptation after surgery had not been enough to fully restore the absorptive function of the residual bowel, to allow nutritional autonomy and fluid balance, and to prevent renal failure. The patient did not tolerate the attempt of gradual PN weaning made seven years after SBS’s diagnosis, which resulted in the worsening of clinical conditions, the outbreak of acute renal failure and the necessity to restart HPN. Indeed, permanent dependence on HPN would have been necessary, along with the associated increased risk of complications. The chance to start teduglutide treatment has determined a different evolution of patient’s clinical history: quick weaning off parenteral support was achieved along with the preservation of renal function, while the risk of CVC related infections was definitively avoided. The European guidelines on CIF in adults recommend the evaluation of the efficacy of growth factor treatment according to standardized protocols measuring fluids, electrolytes and, whenever possible, energy balance 2. However, to date there is no standardized nutritional management protocol for PNdependent SBS patient treated with teduglutide. In this perspective, our case could serve as example of safe and appropriate practice. Weight loss was in line with that observed in other clinical studies 13, final-current weight was similar to that post-surgery at first referral in 2008, and BMI was still in the range of normality. Interestingly, FFM, PhA and HG only slightly decreased, indicating a quite modest reduction in muscle mass and strength. This observation is consistent with the significant improvement of PCS of QoL, which would have been hardly possible in the presence of significant nutritional status deterioration. In particular, the 7-point increase in the PCS score at 12 months (range: 0 [worst possible health state] - 100 [best possible health state]; 50 = mean score of the US general
population) was above the estimated minimal clinically important difference in this patient population, according to the one-mean standard error change method 14,15. Overall, despite weight loss and the associated moderate decrease of muscle mass, we can argue for a positive risk-benefit ratio of the intervention. Accurate fluid management is crucial in SBS, particularly in the presence of renal impairment. Teduglutide treatment implies rapid fluid shift, which could be associated with serious side effect due to fluid retention
5-7
. In our case, BIVA was very feasible and effective in monitoring fluid
balance. Moreover, vector shifts on the BIVA graph reflected renal function changes. BIVA allowed also the monitoring of body composition parameters, which are essential for the accuracy of nutritional status assessment and resulted in line with HG data.
CONCLUSION This case showed that the inclusion of BIVA in the comprehensive systematic nutritional assessment of SBS patients treated with teduglutide could be proposed for appropriate and safe management, particularly in the presence of renal impairment. Furthermore, it remarks the importance of the management of teduglutide treatment by multidisciplinary teams with specific skills and experience in SBS.
CONFLICT OF INTEREST No conflicts of interest and funding sources have to be declared by the authors.
ACKNOWLEDGMENTS The patient gave informed consent for her data to be anonymously used for scientific scope according to the policy of our Institution. No conflicts of interest and funding sources have to be declared.
REFERENCES 1. Storch KJ. Overview of short bowel syndrome: clinical features, pathophysiology, impact, and management. JPEN J Parenter Enteral Nutr. 2014;38:5S-7S 2. Pironi L, Arends J, Bozzetti F, Cuerda C, Gillanders L, Jeppesen PB, et el. ESPEN guidelines on chronic intestinal failure in adults. Clinical Nutrition 2016;35:247-307 3. Jeppenes PB, Sanguinetti EL, Buchman, A Howard L, Scolapio JS, Ziegler TR, et al. Teduglutide, a (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut. 2005;54:1224-1231 4. Jeppenes PB. Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome. Ther Adv Gastroenterol. 2012;5: 159-171 5. Kochar B, Long MD, Shelton E, Young L, Farraye FA, Yajnik V, et al. Safety and efficacy of Teduglutide (Gattex) in patients with Crohn’s desease and need for parental support due to short bowel syndrome-associated intestinal failure. J Clin Gastroenterol 2017;51:508-511 6. Jeppesen P, Pertkiewicz M, Messing B, Iyer K, Seidner DL, O'keefe SJ, et al. Teduglutide Reduces Need for Parenteral Support Among Patients With Short Bowel Syndrome With Intestinal Failure. Gastroenterology 2012; 143:1473-1481 7. Schwartz L, O'Keefe SJ, Fujioka K, Gabe SM, Lamprecht G, Pape UF, et al. Long-Term Teduglutide for the Treatment of Patients with Intestinal Failure Associated With Short Bowel Syndrome. Clinical and Translational Gastroenterology 2016;7:e142 8. Norman K, Stobäus N, Pirlich M, Bosy-Westphal A. Bioelectrical phase angle and impedance vector analysis--clinical relevance and applicability of impedance parameters. Clin Nutr. 2012;31:854-61
9. Caccialanza R, Cereda E, Klersy C, Bonardi C, Cappello S, Quarleri L, et al. Phase angle and handgrip strength are sensitive early markers of energy intake in hypophagic, non-surgical patients at nutritional risk, with contraindications to enteral nutrition. Nutrients. 2015; 7:1828-40 10. Shin JH, Kim CR, Park KH, Hwang JH, Kim SH. Predicting clinical outcomes using phase angle as assessed by bioelectrical impedance analysis in maintenance hemodialysis patients. Nutrition. 2017;41:7-13 11. Alves FD, Souza GC, Aliti GB, Rabelo-Silva ER, Clausell N, Biolo A. Dynamic changes in bioelectrical impedance vector analysis and phase angle in acute decompensated heart failure. Nutrition. 2015;31:84-9 12. Garlini LM, Alves FD, Ceretta LB, Perry IS, Souza GC, Clausell NO. Phase angle and mortality: a systematic review. Eur J Clin Nutr. 2019;73:495-508 13. Schoeler M, Klag T, Wendler J, Bernhard S, Adolph M, Kirschniak A, et al. GLP-2 analog teduglutide significantly reduces need for parenteral nutrition and stool frequency in a real-life setting. Therap Adv Gastroenterol. 2018;11:1-11 14. Coteur G, Feagan B, Keininger DL, Kosinski M. Evaluation of the meaningfulness of healthrelated quality of life improvements as assessed by the SF-36 and the EQ-5D VAS in patients with active Crohn's disease. Aliment Pharmacol Ther. 2009; 29:1032-41 15. Jeppesen PB, Lund P, Gottschalck IB, Nielsen HB, Holst JJ, Mortensen J, et al. Short bowel patients treated for two years with glucagon-like peptide 2 (GLP-2): compliance, safety, and effects on quality of life. Gastroenterol Res Pract. 2009; 2009:425759.
Table 1. Quarterly clinical and instrumental data.
Time 0
Month 3
Month 6
Month 9 Month 12
Weight (kg)
56
55
53.5
50.5
48.5
BMI (kg/m2)
23.3
22.9
22.3
21
20.2
FFM (kg)
39
38
39.3
37.3
37.3
TBW (L)
28.6
27.6
28.8
27.4
27.4
ECW (L)
15,1
13,2
15,6
14,6
15
Hydration index (%)
73,4
72,7
73,6
73,3
73,5
PhA (°)
4.7
5.6
5
4.6
4.4
23
24.5
22.2
22.3
20.1
Creatinine (mg/dL)
1
1.12
1.04
0.94
0.94
eGFR (mL/min/1.73 m)
61
53
58
66
66
Urea (mg/dL)
35
53
51
16
30
Albumin (g/dL)
3.4
3.3
2.9
3.1
2.7
PCS
48
50
53
52
55
MCS
51
49
50
50
51
Anthropometry
BIVA
Muscle
Handgrip (kg)
strength
Blood tests
SF-36
Abbreviations: BIVA: bioelectrical impedance vectorial analysis; SF-36: 36-Item Short Form Health Survey; BMI: body mass index; FFM: fat-free mass; TBW: total body water; ECW: extracellular water; PhA: phase angle; eGFR: estimated glomerular filtration rate; PCS: SF-36 physical component score; MCS: SF-36 mental component score.
Figure 1. Quarterly bioimpedance vectorial analysis (BIVA) data.
Vector position at: 1 = treatment initiation; 2 = 3 months; 3 = 6 months; 4 = 9 months; 5 = 12 months. Interpretation: Phase angle expresses both changes in the amount as well as the quality of soft tissue mass (i.e., cell membrane permeability and soft tissue hydration). It can be directly calculated from R and Xc as arc‐tangent (Xc/R) × 180°/π. Therefore, it is on the one hand dependent on the capacitive behavior of tissues (Xc) associated with cellularity, cell size, and integrity of the cell membrane, and on the other hand on its pure resistive behavior (R), mainly dependent on tissue hydration. BIVA uses the impedance vector Z components, resistance (R) and reactance (Xc) that are obtained at 50 kHz and normalized by the height of the subject (R/H Xc/H). R/H and Xc/H of each patient can be plotted in the R/H-Xc/H graph that is drawn from a healthy reference population using the 50%, 75% and 95% tolerance ellipses. The vector displacements on the R/H-Xc/H graph allow evaluated changes in hydration status (vertical axis: ascent = decrease; descent = increase) and more or less body cell mass (horizontal axis: right shift = decrease; left shift = increase).
Comprehensive nutritional assessment in short bowel syndrome with chronic renal failure on teduglutide therapy: a case report Valeria Borioli RD , Emanuele Cereda MD, PhD , Federica Lobascio MD , Caterina Mengoli MD , Marilisa Caraccia RD , Anna Pagani MD , Nicola Aronico , Paolo Pedrazzoli MD , Antonio Disabatino MD, PhD , Riccardo Caccialanza MD PII: DOI: Reference:
S0899-9007(20)30003-4 https://doi.org/10.1016/j.nut.2020.110720 NUT 110720
To appear in:
Nutrition
Received date: Revised date: Accepted date:
6 May 2019 24 October 2019 30 December 2019
Please cite this article as: Valeria Borioli RD , Emanuele Cereda MD, PhD , Federica Lobascio MD , Caterina Mengoli MD , Marilisa Caraccia RD , Anna Pagani MD , Nicola Aronico , Paolo Pedrazzoli MD , Antonio Disabatino MD, PhD , Riccardo Caccialanza MD , Comprehensive nutritional assessment in short bowel syndrome with chronic renal failure on teduglutide therapy: a case report, Nutrition (2020), doi: https://doi.org/10.1016/j.nut.2020.110720
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
HIGLIGHTS Teduglutide allows reduction of PN requirements and complications in SBS patients. There is no standardized protocol for PN-dependent SBS patients under teduglutide. BIVA could be proposed for appropriate management of SBS patients under teduglutide.
Comprehensive nutritional assessment in short bowel syndrome with chronic renal failure on teduglutide therapy: a case report Running head: Nutritional assessment in SBS under teduglutide
Valeria Borioli RD1, Emanuele Cereda MD PhD1, Federica Lobascio MD1, Caterina Mengoli MD2, Marilisa Caraccia RD1, Anna Pagani3 MD, Nicola Aronico2, Paolo Pedrazzoli3 MD, Antonio Disabatino MD PhD2, and Riccardo Caccialanza MD1* 1
Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
2
First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy. 3
Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo and Department of Internal Medicine, University of Pavia, Pavia, Italy. * Corresponding author: Riccardo Caccialanza MD, Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo Viale Golgi 19, 27100 Pavia, Italy (Tel.: +39 0382 501615; Fax: + 39 0382 502801) E-mail: [email protected]
ABSTRACT We report the case of a 62-years old woman with short bowel syndrome (SBS) and chronic renal failure, successfully treated with teduglutide, who underwent comprehensive systematic nutritional assessment including bioelectrical impedance vectorial analysis (BIVA). The patient did not tolerate the attempt of gradual suspension of parenteral nutrition (PN), bumping into the worsening of nutritional status and renal function. Then, she was declared eligible for teduglutide, a glucagon-like peptide 2 analogue, which stimulates structural and functional intestinal adaptation and increases nutrient and fluid absorption. To date, there is no standardized nutritional management protocol for PN-dependent SBS patients treated with teduglutide. We here report our first 1-year follow-up data. The patient underwent comprehensive systematic nutritional assessment initially every two weeks, then monthly. It included handgrip strength (HG), blood tests (particularly serum creatinine, estimated glomerular filtration rate, urea, electrolytes, micronutrients, serum albumin), fluid intake, urine output, quality of life (QoL) evaluation and BIVA, which estimates fat-free mass (FFM) and measures phase angle (PhA) and hydration status. At treatment initiation, the patient was on PN 3 days a week. After 3 months, she was weaned off PN. At 1 year, weight and serum albumin were reduced (-7.5 kg, -0.6 g/dL, respectively), FFM, PhA and HG slightly decreased, hydration status and renal function were preserved and QoL subtly improved. No relevant clinical complications or metabolic imbalances occurred. The inclusion of BIVA in the comprehensive systematic nutritional assessment of SBS patients treated with teduglutide could be proposed for appropriate and safe management, particularly in the presence of renal impairment.
KEY WORDS: bioimpedance vectorial analysis, nutritional assessment, parenteral nutrition, short bowel syndrome, teduglutide.
INTRODUCTION Short bowel syndrome (SBS) is a rare and disabling disease, which leads to the reduction in gut function, below the minimum necessary for the absorption of macronutrients, water and electrolytes 1. In adults, SBS is the most frequent cause of chronic intestinal failure (CIF). CIF often results from extended intestinal resection frequently caused by Crohn’s disease, mesenteric ischemia, intestinal cancer, volvulus, but it can also be caused by other conditions that decrease absorptive capacity in the absence of resection, including radiation enteritis, chronic intestinal pseudo-obstruction, and congenital villus atrophy 1. Patients with SBS experience a variety of symptoms affecting quality of life (QoL), including asthenia, weight loss, severe diarrhea, which leads to development of protein-calorie malnutrition and dehydration, because the patients are unable to maintain fluid, electrolyte, micronutrient, calorie and protein balance with normal oral diet 1. Intravenous supplementation to provide fluid and nutrient support is the primary treatment for SBS 2, but permanent dependence on PN may decrease survival and QoL 1. In order to reduce the dependence on PN, the European guidelines on CIF in adults recommend to consider the use of growth factors and to evaluate their efficacy according to standardized protocols 2. Glucagone-like peptide-2 (GLP-2) is a hormone secreted in response to nutrients ingestion by entero-endocrine cells, primarily located in the terminal ileum and colon. GLP-2 is involved in regulation, growth and maintenance of intestinal epithelium function, and it has also been associated with intestinal adaptation after surgical resection 3. Teduglutide, a recent attractive therapeutic agent, is a GLP-2 analogue, with a longer half-life (2 hours) than native GLP2, which is produced in Escherichia Coli cells by recombinant DNA technology 4. As for native GLP2, its biologic effects involve structural and functional intestinal adaptation, as it increases intestinal blood flow, the height of villi and the depth of crypts, thus enhancing intestinal nutrient
and fluid absorption 4. Teduglutide was declared orphan drug for SBS by the Food and Drug Administration in 2000 and approved in 2012 for the treatment of adult patient with SBS who are dependent on parenteral support 5. This approval was based on an extensive clinical program, especially on two trials addressing short-term and long-term safety and efficacy of teduglutide (0.05mg/kg/day) in reducing PN requirements (volume/frequency of infusions) and associated complications
6,7
. Common treatment-related complications are abdominal pain, catheter sepsis,
and decreased weight (25-35%). Nonetheless, approximately 20-30% of patients experience problems with fluid balance (dehydration/fluid overload) 7. Indeed, PN in SBS is a life-saving treatment, but when it becomes a permanent or long-term intervention it is frequently associated with decreased QoL and can lead to dangerous complications, including catheter-related bloodstream infections and sepsis 2. The risk of PNrelated mortality increases with PN dependence duration 2. A major issue in daily practice is the availability of accurate and non-invasive technologies to evaluate and monitor the nutritional and hydration status of SBS patient. The use of measured bioelectrical parameters, such as phase angle (PhA), using bioelectrical impedance vectorial analysis (BIVA), was demonstrated to reliably reflect cell integrity and energy balance in patients with chronic diseases
8,9
. In addition, BIVA appears to be a feasible procedure to evaluate body
composition, since it is independent of body weight and allows the assessment of hydration status, which can be easily and reliably monitored in several clinical conditions 8. Several studies showed that BIVA can predict outcomes and prognosis in different stage of kidney disease 10, heart failure 11, cancer and other chronic diseases 12. To date, there is no standardized nutritional management protocol for PN-dependent SBS patients treated with teduglutide and BIVA has not been applied in their clinical management, yet.
Here, we present the case of a PN-dependent SBS woman with chronic renal failure, successfully treated with teduglutide, who underwent comprehensive systematic nutritional assessment including BIVA.
CASE REPORT The patient is a 62-year-old, Caucasian woman who underwent a sub-total gastrectomy for gastric adenocarcinoma in January 2003, followed by adjuvant chemotherapy (CT), ended in July 2003. At the end of CT, she reported a weight ranging from 53 kg to 55 kg (body mass index [BMI] 22.122.9 kg/m2). Her usual weight was 62 kg (BMI 25.8 kg/m2). In August 2008, she was hospitalized for severe generalized peritonitis with septic shock and total jejunal-ileal necrosis caused by volvulus on the Roux loop; she was then subjected to total jejunalileal resection with a jejun-caecal anastomosis. X-ray gastroduodenal esophagus transit exam showed a residual tract of the small bowel of about 100-140 cm. When she was referred to our Unit, body weight was 49.5 kg (BMI 20.6 kg/m2). She was following a very low-fiber diet with sufficient protein-calorie estimated intake; general conditions were fair and no particular metabolic abnormalities were recorded, with exception of mild hypokalaemia, hypomagnesemia and hyposideremia and vitamin B12 deficiency. We supplemented the patient with oral electrolytes, iron and vitamin B12, and started the follow-up, which was set initially every month, then every 3-4 months. For about 6 years, the patient was in good health and nutritional conditions, and she was simultaneously followed by the Gastroenterology Unit and the Oncology Unit of our Hospital. Suddenly, in December 2014, she was admitted to our Nephrology Unit for severe hypokalemia, acute renal failure and acute worsening of nutritional status, associated with a prolonged lung infection in the previous 3 weeks. Body weight at admission was 36.5 kg (BMI 15.2 kg/m2).
After nutritional assessment, a central venous catheter (CVC, Groshong type) was placed in order to start a daily HPN with three-in-one solution and a volume of 1000 mL (1000 kcal, amino-acids 57 g, glucose 110 g, lipids 40 g). After discharge (weight 38 kg; BMI 15.8 kg/m2), the patient continued the follow-up every 2 months. Renal function remained stable and in May 2015 weight was 53.5 kg (BMI 22.3 kg/m2). Then, we decided to decrease HPN administration to 3 times a week with the same three-in-one bag, till full suspension in December 2015 (weight 55.5 kg, BMI 23.1 Kg/m2). Five months later, worsening of patient’s clinical conditions occurred: we registered a weight loss of 5.5 kg and a new outbreak of renal failure (creatinine 1.18 mg/dl; estimated glomerular filtration rate [eGFR] 51 mL/min/1.73m). Our Nephrologists contextually diagnosed chronic kidney disease G3a. We restarted HPN for 3 times a week. Then, the patient was followed-up until April 2017, with no significant changes in her clinical conditions; weight was around 54 kg (BMI 22.5 kg/m2) and kidney function was stable (creatinine 1.06 mg/dl; eGFR 57 mL/min/1.73m). Nutritional assessment showed an average food intake of 1600-1700 Kcal/die and liquid intake of 2000 mL/day. She reported chronic diarrhea (6-7 surges/day) and random gastrointestinal symptoms, including postprandial nausea and vomiting. She underwent colonoscopy on March 2017, and no pathological signs were detected. The patient was declared eligible for treatment with teduglutide; the therapy was started on July 2017 (weight 56 kg; BMI 23.3 kg/m2) at an initial dose of 0.025mg/kg/day, due to the previously attested presence of renal impairment. After 2 months, kidney function was stable and the dose was increased to 0.05 mg/kg/day. During treatment, the patient underwent weekly home monitoring by nursing staff, who checked fluid balance, compliance to treatment and the occurrence of any side effect.
Furthermore, the patient underwent comprehensive nutritional assessment initially every two weeks for the first 8 months, then monthly, including handgrip strength (HG) measured by digital dynamometry (DynEx™, Akern/MD Systems), food and liquid intake (24 h recall), blood tests (including serum creatinine, eGFR, urea, electrolytes, micronutrients and serum albumin), urine output, and BIVA (NutriLAB, Akern/RJL), which estimates fat-free mass (FFM) and measures PhA and hydration status (total body water [TBW], extracellular water [ECW], hydration index). In addition, QoL was assessed by the 36-Item Short Form Health Survey (SF-36) every 3 months. At baseline, the patient was on HPN 3 days a week. After 3 months, the patient was weaned off PN. Diarrhea was reduced to 2-4 surges/day and gastrointestinal symptoms slightly improved during the follow-up. Compliance to treatment was very good and no serious or clinically significant side effects, such as fluid or metabolic imbalances, were reported throughout the entire observation period. The clinical and instrumental follow-up data are reported in Table 1, while BIVA results are depicted in Figure 1. After 1-year follow-up, weight and serum albumin were reduced (-7.5 kg, 0.6 g/dL, respectively), average food and fluid intake, and urine output did not significantly change, FFM, PhA and handgrip strength slightly decreased, hydration status and renal function were preserved, while the physical component score (PCS) of QoL improved. Treatment and follow-up are still ongoing.
DISCUSSION This report shows the efficacy of comprehensive systematic nutritional assessment including BIVA, muscle strength and QoL evaluation, in the clinical management of a SBS patient with concomitant renal impairment successfully treated with teduglutide.
The natural adaptive response of the bowel to resection is a crucial event in SBS 2. In our patient intestinal adaptation after surgery had not been enough to fully restore the absorptive function of the residual bowel, to allow nutritional autonomy and fluid balance, and to prevent renal failure. The patient did not tolerate the attempt of gradual PN weaning made seven years after SBS’s diagnosis, which resulted in the worsening of clinical conditions, the outbreak of acute renal failure and the necessity to restart HPN. Indeed, permanent dependence on HPN would have been necessary, along with the associated increased risk of complications. The chance to start teduglutide treatment has determined a different evolution of patient’s clinical history: quick weaning off parenteral support was achieved along with the preservation of renal function, while the risk of CVC related infections was definitively avoided. The European guidelines on CIF in adults recommend the evaluation of the efficacy of growth factor treatment according to standardized protocols measuring fluids, electrolytes and, whenever possible, energy balance 2. However, to date there is no standardized nutritional management protocol for PNdependent SBS patient treated with teduglutide. In this perspective, our case could serve as example of safe and appropriate practice. Weight loss was in line with that observed in other clinical studies 13, final-current weight was similar to that post-surgery at first referral in 2008, and BMI was still in the range of normality. Interestingly, FFM, PhA and HG only slightly decreased, indicating a quite modest reduction in muscle mass and strength. This observation is consistent with the significant improvement of PCS of QoL, which would have been hardly possible in the presence of significant nutritional status deterioration. In particular, the 7-point increase in the PCS score at 12 months (range: 0 [worst possible health state] - 100 [best possible health state]; 50 = mean score of the US general
population) was above the estimated minimal clinically important difference in this patient population, according to the one-mean standard error change method 14,15. Overall, despite weight loss and the associated moderate decrease of muscle mass, we can argue for a positive risk-benefit ratio of the intervention. Accurate fluid management is crucial in SBS, particularly in the presence of renal impairment. Teduglutide treatment implies rapid fluid shift, which could be associated with serious side effect due to fluid retention
5-7
. In our case, BIVA was very feasible and effective in monitoring fluid
balance. Moreover, vector shifts on the BIVA graph reflected renal function changes. BIVA allowed also the monitoring of body composition parameters, which are essential for the accuracy of nutritional status assessment and resulted in line with HG data.
CONCLUSION This case showed that the inclusion of BIVA in the comprehensive systematic nutritional assessment of SBS patients treated with teduglutide could be proposed for appropriate and safe management, particularly in the presence of renal impairment. Furthermore, it remarks the importance of the management of teduglutide treatment by multidisciplinary teams with specific skills and experience in SBS.
CONFLICT OF INTEREST No conflicts of interest and funding sources have to be declared by the authors.
ACKNOWLEDGMENTS The patient gave informed consent for her data to be anonymously used for scientific scope according to the policy of our Institution. No conflicts of interest and funding sources have to be declared.
REFERENCES 1. Storch KJ. Overview of short bowel syndrome: clinical features, pathophysiology, impact, and management. JPEN J Parenter Enteral Nutr. 2014;38:5S-7S 2. Pironi L, Arends J, Bozzetti F, Cuerda C, Gillanders L, Jeppesen PB, et el. ESPEN guidelines on chronic intestinal failure in adults. Clinical Nutrition 2016;35:247-307 3. Jeppenes PB, Sanguinetti EL, Buchman, A Howard L, Scolapio JS, Ziegler TR, et al. Teduglutide, a (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut. 2005;54:1224-1231 4. Jeppenes PB. Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome. Ther Adv Gastroenterol. 2012;5: 159-171 5. Kochar B, Long MD, Shelton E, Young L, Farraye FA, Yajnik V, et al. Safety and efficacy of Teduglutide (Gattex) in patients with Crohn’s desease and need for parental support due to short bowel syndrome-associated intestinal failure. J Clin Gastroenterol 2017;51:508-511 6. Jeppesen P, Pertkiewicz M, Messing B, Iyer K, Seidner DL, O'keefe SJ, et al. Teduglutide Reduces Need for Parenteral Support Among Patients With Short Bowel Syndrome With Intestinal Failure. Gastroenterology 2012; 143:1473-1481 7. Schwartz L, O'Keefe SJ, Fujioka K, Gabe SM, Lamprecht G, Pape UF, et al. Long-Term Teduglutide for the Treatment of Patients with Intestinal Failure Associated With Short Bowel Syndrome. Clinical and Translational Gastroenterology 2016;7:e142 8. Norman K, Stobäus N, Pirlich M, Bosy-Westphal A. Bioelectrical phase angle and impedance vector analysis--clinical relevance and applicability of impedance parameters. Clin Nutr. 2012;31:854-61
9. Caccialanza R, Cereda E, Klersy C, Bonardi C, Cappello S, Quarleri L, et al. Phase angle and handgrip strength are sensitive early markers of energy intake in hypophagic, non-surgical patients at nutritional risk, with contraindications to enteral nutrition. Nutrients. 2015; 7:1828-40 10. Shin JH, Kim CR, Park KH, Hwang JH, Kim SH. Predicting clinical outcomes using phase angle as assessed by bioelectrical impedance analysis in maintenance hemodialysis patients. Nutrition. 2017;41:7-13 11. Alves FD, Souza GC, Aliti GB, Rabelo-Silva ER, Clausell N, Biolo A. Dynamic changes in bioelectrical impedance vector analysis and phase angle in acute decompensated heart failure. Nutrition. 2015;31:84-9 12. Garlini LM, Alves FD, Ceretta LB, Perry IS, Souza GC, Clausell NO. Phase angle and mortality: a systematic review. Eur J Clin Nutr. 2019;73:495-508 13. Schoeler M, Klag T, Wendler J, Bernhard S, Adolph M, Kirschniak A, et al. GLP-2 analog teduglutide significantly reduces need for parenteral nutrition and stool frequency in a real-life setting. Therap Adv Gastroenterol. 2018;11:1-11 14. Coteur G, Feagan B, Keininger DL, Kosinski M. Evaluation of the meaningfulness of healthrelated quality of life improvements as assessed by the SF-36 and the EQ-5D VAS in patients with active Crohn's disease. Aliment Pharmacol Ther. 2009; 29:1032-41 15. Jeppesen PB, Lund P, Gottschalck IB, Nielsen HB, Holst JJ, Mortensen J, et al. Short bowel patients treated for two years with glucagon-like peptide 2 (GLP-2): compliance, safety, and effects on quality of life. Gastroenterol Res Pract. 2009; 2009:425759.
Table 1. Quarterly clinical and instrumental data.
Time 0
Month 3
Month 6
Month 9 Month 12
Weight (kg)
56
55
53.5
50.5
48.5
BMI (kg/m2)
23.3
22.9
22.3
21
20.2
FFM (kg)
39
38
39.3
37.3
37.3
TBW (L)
28.6
27.6
28.8
27.4
27.4
ECW (L)
15,1
13,2
15,6
14,6
15
Hydration index (%)
73,4
72,7
73,6
73,3
73,5
PhA (°)
4.7
5.6
5
4.6
4.4
23
24.5
22.2
22.3
20.1
Creatinine (mg/dL)
1
1.12
1.04
0.94
0.94
eGFR (mL/min/1.73 m)
61
53
58
66
66
Urea (mg/dL)
35
53
51
16
30
Albumin (g/dL)
3.4
3.3
2.9
3.1
2.7
PCS
48
50
53
52
55
MCS
51
49
50
50
51
Anthropometry
BIVA
Muscle
Handgrip (kg)
strength
Blood tests
SF-36
Abbreviations: BIVA: bioelectrical impedance vectorial analysis; SF-36: 36-Item Short Form Health Survey; BMI: body mass index; FFM: fat-free mass; TBW: total body water; ECW: extracellular water; PhA: phase angle; eGFR: estimated glomerular filtration rate; PCS: SF-36 physical component score; MCS: SF-36 mental component score.
Figure 1. Quarterly bioimpedance vectorial analysis (BIVA) data.
Vector position at: 1 = treatment initiation; 2 = 3 months; 3 = 6 months; 4 = 9 months; 5 = 12 months. Interpretation: Phase angle expresses both changes in the amount as well as the quality of soft tissue mass (i.e., cell membrane permeability and soft tissue hydration). It can be directly calculated from R and Xc as arc‐tangent (Xc/R) × 180°/π. Therefore, it is on the one hand dependent on the capacitive behavior of tissues (Xc) associated with cellularity, cell size, and integrity of the cell membrane, and on the other hand on its pure resistive behavior (R), mainly dependent on tissue hydration. BIVA uses the impedance vector Z components, resistance (R) and reactance (Xc) that are obtained at 50 kHz and normalized by the height of the subject (R/H Xc/H). R/H and Xc/H of each patient can be plotted in the R/H-Xc/H graph that is drawn from a healthy reference population using the 50%, 75% and 95% tolerance ellipses. The vector displacements on the R/H-Xc/H graph allow evaluated changes in hydration status (vertical axis: ascent = decrease; descent = increase) and more or less body cell mass (horizontal axis: right shift = decrease; left shift = increase).