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Prevalence of renal abnormality in pediatric intestinal failure
Journal of Pediatric Surgery xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Prevalence of renal abnormality in pediatric intestinal failure☆ Christina Kosar a, Nicole De Silva a, Yaron Avitzur a,b, Karen Steinberg a, Glenda Courtney-Martin a, Kathryn Chambers a, Kevin Fitzgerald a, Elizabeth Harvey a,c, Paul W. Wales a,d,⁎ a
Group for Improvement of Intestinal Function and Treatment (GIFT), The Hospital for Sick Children, University of Toronto, Canada Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Canada Division of Nephrology, The Hospital for Sick Children, University of Toronto, Canada d Division of General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, Canada b c
a r t i c l e
i n f o
Article history: Received 24 January 2016 Accepted 7 February 2016 Available online xxxx Key words: Pediatric Intestinal failure Renal abnormality Parenteral nutrition
a b s t r a c t Background: Outcomes of children with intestinal failure have improved over the last decade. However, with improved survival, other co-morbidities have become evident. The goal of our study was to evaluate the presence of renal nephrocalcinosis or increased echogenicity in a cohort of patients with pediatric intestinal failure (PIF). Methods: A cross-sectional prevalence design was performed in PIF patients followed by our intestinal rehabilitation program between 2013 and 2014. Renal function was evaluated using serum creatinine and urea, urine oxalate, creatinine, calcium, and calcium/creatinine ratios. Renal ultrasounds were performed to assess for echogenicity. Data was collected on intestinal failure related factors and nutritional intake. Data was analyzed using medians and Mann–Whitney U or proportions and chi square. Results: Fifty-four patients (median age 48 months; 33 males (61%) were studied. Twenty-two patients (41%) had increased echogenicity or nephrocalcinosis on ultrasound. There were no differences in serum Creatinine or urea, but patients with nephrocalcinosis had statistically different calcium:creatinine ratio (1.69 vs 0.74; p = 0.043), urine oxalate (108 vs 219; p = 0.06), and serum phosphate (1.55 vs 1.75; p = 0.044). Patients with echogenicity had a shorter colonic remnant (25 cm vs 31 cm; p = 0.01), a history of longer PN exposure (928 vs 483 days; p = 0.05), percent PN calories (37 vs 0; p = 0.05), PN h/day (13 vs 0; p = 0.05), but no difference in PN Ca/phosphate/magnesium content (mmol/kg). Conclusion: A large proportion of PIF patients have increased echogenicity/nephrocalcinosis on ultrasound that is associated with prolonged PN exposure. This has implications for long-term management. Regular surveillance is required, and further study is warranted to determine specific risk factors. © 2016 Elsevier Inc. All rights reserved.
Pediatric intestinal failure (PIF) is defined as the inability of the gastrointestinal tract to sustain life without supplementation with parenteral nutrition (PN) [1]. The most common cause of intestinal failure (IF) is short bowel syndrome (SBS) with an overall incidence of 22.1 per 1000 neonatal intensive care admissions and 24.5 per 100,000 live births [2]. Mortality rates within PIF are estimated to be around 30% [3–5], but vary greatly depending on age at diagnosis and underlying disease. Introduction of multidisciplinary teams and novel therapies have resulted in improved outcomes, but children with IF remain at
Abbreviations: IF, intestinal failure; PN, parenteral nutrition; SBS, short bowel syndrome; PIF, pediatric intestinal failure; GFR, glomerular filtration rate; CKD, chronic kidney disease; ITx, intestinal transplant; eGFR, estimated glomerular filtration rate; TFI, total fluid intake; IQR, interquartile range; RR, relative risk; US, ultrasound; SB, small bowel; LB, large bowel; cm, centimeter. ☆ Level of Evidence: 3. ⁎ Corresponding author at: The Hospital for Sick Children, Rm 1526, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada. Tel.: +1 416 813 7654x201490; fax: +1 416 813 7477. E-mail address: [email protected] (P.W. Wales).
risk for multiple co-morbidities, including liver dysfunction, electrolyte imbalance, metabolic bone disease, and infectious complications [2–5]. Patients with irreversible IF require PN for maintenance of fluid, electrolyte and protein-energy balance. Patients require long-term PN until intestinal adaptation occurs or serious complications arise necessitating intestinal transplantation [3,4]. Renal dysfunction was first reported by Moukarzel et al. in 1991 in children receiving long-term PN. They reported a decrease in glomerular filtration rate (GFR) but were unable to identify a contributing mechanism [6]. Reports in adult patients on long-term PN have suggested that 50% of patients had decreased renal function characterized by a decreased GFR or progressive decrease of GFR [7–9]. A recent retrospective crosssectional study compared the prevalence of chronic kidney disease (CKD) between adults on PN versus intestinal transplant (ITx). It found that while ITx patients have a significant risk for developing CKD, patients on long-term PN showed an annual estimated GFR (eGFR) decline of 2.8% and after a median duration of 7 years of PN a prevalence of mild CRF in 21.2% [10]. The mechanism for the decline in renal impairment has not been identified in previous studies [8–10].
http://dx.doi.org/10.1016/j.jpedsurg.2016.02.025 0022-3468/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Kosar C, et al, Prevalence of renal abnormality in pediatric intestinal failure, J Pediatr Surg (2016), http://dx.doi.org/ 10.1016/j.jpedsurg.2016.02.025
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C. Kosar et al. / Journal of Pediatric Surgery xxx (2016) xxx–xxx
It is well recognized that creatinine is a poor marker for renal function, especially in the early stages of renal damage. Increased echogenicity of the renal parenchyma on renal ultrasound is a nonspecific finding but is usually indicative of renal parenchymal disease, outside the newborn period where the kidneys are routinely echogenic. The causes of increased renal echogenicity are multiple and include glomerular disease, tubular disorders and interstitial inflammation, and nephrocalcinosis. Findings of increased echogenicity on ultrasound (US) though nonspecific are an important finding and may signify the presence of renal disease [11,12]. Nephrocalcinosis is defined as mineral precipitates within the renal parenchyma [13]. The formation of nephrocalcinosis is often a result of an imbalance between stonepromoting and stone-inhibiting factors and is often multifactorial. Factors that can lead to the promotion of nephrocalcinosis include acidosis, medications such as diuretics and vitamin D supplementation, hyperoxaluria, PN, fat malabsorption, episodes of dehydration [14,15]; all of which exist in PIF patients. An index child with PIF was noted to have severe nephrocalcinosis, and several patients were reported to have abnormal renal echogenicity on renal ultrasound. This prompted us to look at renal function and the prevalence of nephrocalcinosis and/or abnormal renal echogenicity in our PIF population to try and identify risk factors for the later development of CKD in this cohort. The goals of our study were to evaluate the prevalence of renal abnormality in a cohort of pediatric patients with IF and identify factors associated with its development.
1. Methods We performed a retrospective cross-sectional prevalence study to determine the proportion of patients with nephrocalcinosis and/or abnormal renal echogenicity. Pediatric intestinal failure patients managed by our multi-disciplinary intestinal rehabilitation program at The Hospital for Sick Children in Toronto during 2013–2014 were potential candidates. Patients had a history of prolonged PN use but did not have to be on PN at the time of evaluation. Patients receive regular monitoring and follow-up for PN related complications which includes yearly vascular ultrasound, abdominal ultrasound and DEXA scans. Patients who did not receive an abdominal/renal ultrasound completed during the study period were excluded. In addition, patients with previous liver or intestinal transplantation were not included in analysis. Data was collected from the electronic patient chart. Demographic data collected included date of birth, gestational age (weeks), gender, etiology of IF, category of IF (SBS, mucosal enteropathy or primary dysmotility). Residual intestinal anatomy including both absolute length and percentage of expected length based on established norms [16] of both small and large bowel was recorded. In addition, presence of an ostomy and presence of the ileocecal valve were included. To quantify PN exposure, we collected total number of PN days, percentage of PN calorie support, number of PN infusion hours per day, and total fluid intake (TFI) per kilogram per day. PN composition was also collected and included amount of prescribed acetate, calcium, phosphate and magnesium. Laboratory values collected included spot urinary calcium, chloride, creatinine, sodium, citrate, and oxalate. Serum biochemistry data included creatinine, ionized calcium, phosphate, urea, 25-hydroxy vitamin D level and serum blood gas. Based on urine biochemical values, calculations were completed to determine the calcium:creatinine ratio, calcium:citrate ratio and citrate:creatinine ratio. Radiology results for abdominal/renal ultrasounds were collected to determine the presence of nephrocalcinosis or echogenicity. Kidney length was also recorded. All laboratory results had to be drawn within two months of the completion of the renal ultrasound to be included in the analysis. All data collection was completed by two clinical nurse practitioners with extensive clinical experience. Reference ranges for renal values
were obtained from several sources to provide parameters and age ranges [17–20]. Patients were stratified based on the presence of nephrocalcinosis or increased echogenicity on renal ultrasound. Baseline and outcome data were compared using appropriate summary statistics. Continuous variables were presented as medians with interquartile range (IQR) as the data was not normally distributed after review of frequency histograms. Data was analyzed using the Mann–Whitney U test. Categorical variables were presented as frequencies and proportions and statistical testing was performed with the chi square. Relative risks (RR) were included as a measure of association. An alpha-value of 0.05 was considered statistically significant. IBM SPSS Statistics 22 (2013) was used for the analyses. 2. Results During the study enrollment period, fifty-six patients met inclusion criteria with a median age of 48 months and 35 patients were male (57%). Of the participants 24 (43%) had increased echogenicity or nephrocalcinosis on US compared to 32 participants without radiographic evidence of renal abnormality. Table 1 displays the patient characteristics based on presence of echogenicity and nephrocalcinosis at the time of ultrasound. The majority of patients had SBS (73.9% for nephrocalcinosis/echogenicity and 81.3% for no-nephrocalcinosis/echogenicity, respectively). Residual small bowel length did not differ significantly between the two groups; however, the colonic remnant was significantly shorter in the group with renal impairment (p = 0.001). PIF patients with renal abnormality on US were also more likely to have a stoma (70.8% vs 45.2%; p = 0.05; RR = 1.9, 95% CI 1.0–3.7). Table 2 illustrates the impact of PN exposure and composition on development of nephrocalcinosis/echogenicity. The total exposure to PN in days was significantly more in PIF patients with nephrocalcinosis/ echogenicity (928 vs 500; p = 0.05), as was the percentage of total calorie delivery in the form of PN (37% vs 0%; p = 0.05) and PN TFI [in ml/ kg/day] (103 vs 21; p = 0.05). The number of PN infusion hours per day was not significantly different between the two groups (13 vs 4; p = 0.102). The number of PIF patients receiving PN at the time of renal US was higher in the nephrocalcinosis/echogenicity group (70.8% vs 43.8%; p = 0.044) with a relative risk of 2.0 (95% CI 1.0–3.9). Parenteral nutrition composition was compared between the two groups for calcium, phosphate, magnesium and acetate (mmol/kg/day). The composition of the parenteral nutrition did not vary between the two groups. Serum and urine biochemistry results for the two groups are displayed in Table 3. At the time of measurement urinary calcium was Table 1 Patient characteristics. Nephrocalcinosis/ echogenicity (n = 24) Age (months) Male (%) Gestational Age (weeks) IF Category (%) SBS Enteropathy Dysmotility Residual SB length (cm) Residual SB % Residual LB length (cm) Residual LB % Stoma Present (%) On PN at time of US (%)
Normal
Pvalue
(n = 32)
48 (21–82) 17 (70.8) 35 (32–40)
27 (16–62) 18 (56.3) 35 (33–38)
17 (73.9) 1 (4.3) 5 (21.7) 45 (25–100) 27 (14–66) 25 (15–35) 50 (30–90) 17 (70.8) 17 (70.8)
26 (81.3) 3 (9.4) 3 (9.4) 64 (19–133) 45 (15–100) 33 (30–40) 100 (75–100) 14 (45.2) 14 (43.8)
0.362 0.403 0.811 0.373
0.519 0.361 0.007 0.001 0.05 0.04
Values are medians with interquartile ranges. % represents frequencies and percentages. IF = intestinal failure; SBS = short bowel syndrome; SB = small bowel; LB = large bowel; PN = parenteral nutrition; US = ultrasound.
Please cite this article as: Kosar C, et al, Prevalence of renal abnormality in pediatric intestinal failure, J Pediatr Surg (2016), http://dx.doi.org/ 10.1016/j.jpedsurg.2016.02.025
C. Kosar et al. / Journal of Pediatric Surgery xxx (2016) xxx–xxx
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Table 2 Parenteral nutrition exposure.
PN days Proportion of PN support (%) PN hours daily PN TFI (cc/kg/day)
Nephrocalcinosis/echogenicity (n = 24)
Normal (n = 32)
P-value
928 (408–1613) 37 (0–100) 13 (10–15) 103 (53–131)
500 (149–921) 0 (0–49) 4 (0–13) 21 (0–118)
0.05 0.05 0.102 0.05
Values are medians with interquartile ranges. % represents frequencies and percentages. PN = Parenteral nutrition; TFI = Total fluid intake.
increased compared to the group with normal renal function (2.51 vs 1.62; p = 0.027). The nephrocalcinosis/echogenicity group also had an elevated calcium:creatinine ratio (1.47 vs 0.71; p = 0.014). Urinary oxalate excretion was also decreased in patients with nephrocalcinosis/echogenicity (108 vs 228; p = 0.044), as was serum phosphate levels (1.56 vs 1.74; p = 0.035); however the oxalate:creatinine ratio was not significantly different (75.6 vs 98.4; p = 0.326). Additional renal parameters were calculated including calcium:citrate ratio, citrate:creatinine ratio but these were not found to be statistically significant between the two groups. 3. Discussion Premature babies are at particular risk with nephrocalcinosis present in 7–41% of babies with gestational age b 32 weeks. Many of these patients will demonstrate spontaneous resolution in the first few years of life [13]. While numerous studies have shown an increased risk for developing CKD in intestinal transplant patients [10,21–26], there is increasing awareness of renal impairment in patients requiring long-term PN. However, most of the research completed to date has been on the adult IF population [7–10]. With the improved survival rates of PIF patients, there is an increased awareness of morbidity related to prolonged PN exposure. Our results indicate that PIF patients with prolonged PN exposure, presence of a stoma and shorter colonic remnant are at increased risk of developing renal impairment. The causes of renal impairment in PIF patients on long-term PN continues to be largely unexplained. Previous studies have consistently been unable to identify an underlying etiology [6–10]. While PN exposure and shorter colonic remnant were statistically significant for the development of nephrocalcinosis/echogenicity in our study, age, gestational age, category of IF and small bowel residual length did not contribute. There was also limited indication from standard laboratory
results (ie, urea or creatinine) that would predict patients at risk for developing nephrocalcinosis or abnormal renal echogenicity, which may be a harbinger of later CKD. Previous studies have suggested that septic events and hypovolemia related to chronic dehydration [7,9] may contribute to the development of renal dysfunction within adults on longterm PN. Low urinary citrate excretion has been thought to be a major risk factor for calcium stone formation. Citrate has an inhibitory effect on the formation of calcium stones in several ways. Urinary citrate excretion is influenced by acid–base status which can lead to reduced urinary citrate values due to an increased reabsorption of citrate. While we did not find a statistical difference in our two study populations, majority of patients evaluated in this study had samples taken in the morning, shortly after completing their PN cycle at which point they are in their most hydrated state. It is also important to note that all patients were supplemented with acetate and were not in an acidotic state. It would be valuable information to also obtain urine results prior to PN hook-up to determine if the results are significantly impacted in relation to hydration status. In addition, although citrate levels were not different between groups, 70% of nephrocalcinosis patients and 52% of normal patients had a calcium:citrate ratio greater than 1.6 mmol/mmol which is the threshold to identify patients at risk of stone formation [19]. Prolonged PN exposure was a significant risk for the development of echogenicity and/or nephrocalcinosis. This took the form of total PN days, proportion of total calories delivered as PN and total fluid intake infused in PN (cc/kg/day). While cyclical dehydration may be a long term risk factor to the kidney, heavy metal contamination continues to be an ongoing issue particularly with contamination of Aluminum. Aluminum can accumulate in bone, liver, brain, spleen, kidney, parathyroid gland and other tissues in the body [27]. Our group recently published a study of 27 PIF patients on long-term PN demonstrating plasma Aluminum concentrations to be significantly higher than the
Table 3 Patient biochemistry.
Serum creatinine Serum urea Serum phosphate Serum calcium Urine oxalate Urine citrate Calcium: creatinine ratio (mol/mol) Calcium: citrate ratio (mmol/mmol) Calcium: citrate N1.6 mmol/mmol (%) Citrate: creatinine ratio (mmol/mmol) Oxalate: creatinine ratio (mmol/mmol) Serum pH Serum bicarbonate
Nephrocalcinosis/echogenicity (n = 24)
Normal (n = 32)
P-value
28 (20–35) 4.95 (4.40–7.08) 1.56 (1.41–1.77) 1.27 (1.25–1.35) 108 (84–256) 0.90 (0.50–2.10)
23 (17–33) 4.90 (3.93–5.58) 1.74 (1.59–1.89) 1.29 (1.26–1.33) 228 (113–441) 0.80 (0.35–1.90)
0.324 0.584 0.035 0.885 0.044 0.476
1.47 (0.75–2.30)
0.71 (0.24–1.73)
0.014
1.80 (1.19–5.40) 16 (69.6)
1.54 (0.74–3.30) 13 (52.0)
0.445 0.214
0.63 (0.32–1.08)
0.44 (0.12–0.88)
0.317
75.6 (52.4–116.5) 7.38 (7.34–7.39) 26 (24–27)
98.4 (54.8–135.1) 7.37 (7.36–7.39) 25 (23–27)
0.326 0.905 0.334
Values are medians with interquartile ranges. % represents frequencies and percentages.
Please cite this article as: Kosar C, et al, Prevalence of renal abnormality in pediatric intestinal failure, J Pediatr Surg (2016), http://dx.doi.org/ 10.1016/j.jpedsurg.2016.02.025
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control group participants (1195 ± 710 vs 142 ± 63 nmol/L; p b 0.0001). In the subgroup of patients who had analysis of their PN solution, aluminum intake was found to be 3-fold greater than the Food and Drug Administration upper level of recommended intake [28]. Aluminum is buffered into the bone and may cause calcium to leech out of the bone, where it will then need to be excreted renally, contributing to the hypercalciuria. The finding that patients with impaired renal function had a shorter colonic remnant contradicts previous findings that patients with ileal resection (as little as 20-30 cm) and a residual colon are at risk for hyperoxaluria. This is because fatty acids undigested in the ileum enter the colon and bind to calcium. Typically, calcium binds to oxalate in the stool and it is excreted. If calcium binds to fatty acids, oxalate is reabsorbed in the colon and will bind with calcium in the serum leading to calcium oxalate stones [29]. In addition, there may also be increased colonic permeability due to colitis caused by unabsorbed bile salts and fatty acids [30]. It may be that a shorter colon remnant translates into larger fluid stool losses and the need for increased volume requirements, as shown in the PN TFI delivery. Patients with a shorter residual colon are also more likely to have a reduced transit time resulting in poor absorption, as well as higher fluid requirements. Also, there is likely higher losses of bicarbonate in the stool that contribute to acidosis and/or hypocitraturia. The major limitation of our study was the retrospective design. We were able to determine the prevalence of renal abnormality within our PIF population, but were not able to compare changes over time. The majority of previous literature has been completed in the adult IF population which evaluated GFR and have also been retrospective or cross-sectional in design [7–10]. Although we were able to determine parenteral calcium, phosphate and protein delivery in our patients, enteral intake of calcium, phosphate and protein, while desirable to ascertain, was not possible in a retrospective study. Due to the small sample size in our study, it is quite possible we were under powered to detect subtle differences in laboratory results between the two groups. Moving forward, it would also be valuable to look at markers of renal tubular function in future studies (beta 2 microglobulin to creatinine ratio), as well as, obtaining urine and blood samples at various time points in the patients PN cycle to determine if their hydration status has an impact on results and outcomes. In summary a large proportion of PIF patients have abnormal echogenicity/nephrocalcinosis on ultrasound that is associated with prolonged PN exposure. This has implications for long-term management. The long term implication of this renal abnormality is unknown and the cause likely multifactorial. However, regular radiographic surveillance is recommended, since routine laboratory monitoring is not reliable in predicting who is at risk, as patients are able to maintain normal serum creatinine and urea levels. Further study is warranted to determine specific risk factors. It is also important to monitor these patients to determine which proportion of patients with echogenicity and/or nephrocalcinosis go on to develop renal impairment. References [1] Goulet O, Ruemmele F, Lacaille F, et al. Irreversible intestinal failure. J Pediatr Gastroenterol Nut 2004;38:250–69.
[2] Wales PW, de Silva N, Kim J, et al. Neonatal short bowel syndrome: populationbased estimates of incidence and mortality rates. J Pediatr Surg 2004;39:609–95. [3] Diamond IR, de Silva N, Pencharz PB, et al. Neonatal short bowel syndrome outcomes after the establishment of the first Canadian multidisciplinary intestinal rehabilitation program: preliminary experience. J Pediatr Surg 2007;42:806–11. [4] Squires RH, Duggan C, Teitelbaum DH, et al. Natural history of pediatric intestinal failure: initial report from the pediatric intestinal failure consortium. J Pediatr 2012;161(4):723–8. [5] Hess RA, Welch KB, Brown PI, et al. Survival outcomes of pediatric intestinal failure patients: analysis of factors contributing to improved survival over the past two decades. J Surg Res 2001. [6] Moukarzel AA, Ament ME, Buchman A, et al. Renal function of children receiving long-term parenteral nutrition. J Pediatr 1991;119:864–8. [7] Buchman AL, Moukarzel A, Ament ME, et al. Serious renal impairment is associated with long-term parenteral nutrition. JPEN Parenter Enteral Nutr 1993;17:438–44. [8] Boncompain-Gerard M, Robert D, Fouque D, et al. Renal function and urinary excretion of electrolytes in patients receiving cyclic parenteral nutrition. JPEN J Parenter Enteral Nutr 2000;24:234–9. [9] Lauverjat M, Hadj-Aissa A, Vanhems P, et al. Chronic dehydration may impair renal function in patients with chronic intestinal failure on long-term parenteral nutrition. Clin Nutr 2006;25:75–81. [10] Pironi L, Lauro A, Soverini V, et al. Renal function in patients on long-term home parenteral nutrition and in intestinal transplant recipients. Nutrition 2014;30:1011–4. [11] Kraus RA, Gaisie G, Young LW. Increased renal parenchymal echogenicity: causes in pediatric patients. Radiographics 1990;10(6):1009–18. [12] Faubel S, Patel NU, Lockhart ME, et al. Renal relevant radiology: use of ultrasonography in patients with AKI. Clin J Am Soc Nephrol 2014;9(2):382–94. [13] Schell-Feith EA, Kist-van Holthe JE, van Zweiten PH, et al. Preterm neonates with nephrocalcinosis: natural course and renal function. Pediatr Nephrol 2003;18: 1102–8. [14] Schell-Feith EA, Kist-van Holthe JE, van der Heijden AJ. Nephrocalcinosis in perterm neonates. Pediatr Nephrol 2010;25:221–30. [15] Giapros V, Tsoni C, Challa A, et al. Renal function and kidney length in preterm infants with nephrocalcinosis: a longitudinal study. Pediatr Nephrol 2011;26: 1873–80. [16] Strujis MC, Diamond IR, de Silva N, et al. Establishing norms for intestinal length in children. J Pediatr Surg 2009;44(5):933–8. [17] Bernd H, Leumann E, Milliner DS, et al. Chapter 33: Urolithiasis and nephrocalcinosis in childhood. In: Geary DF, editor. Comprehensive Pediatric Nephrology. Mosby Elsevier; 2008. p. 506. [18] Matos V, van Melle G, Boulat O, et al. Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. J Pediatr 1997;131:252–7. [19] Srivastava T, Winston MJ, Auron A, et al. Urine calcium/citrate ratio in children with hypercalciuric stones. Pediatr Res 2009;66:85–90. [20] Kirejczyk JK, Porowski T, Konstantynowicz J, et al. Urinary citrate excretion in healthy children depends on age and gender. Pediatr Nephrol 2014;29(9):1575–82. [21] Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931–40. [22] Watson MJ, Venick RS, Kaldas F, et al. Renal function impacts outcomes after intestinal transplantation. Transplantation 2008;86(1):117–22. [23] Ueno T, Kato T, Gaynor J, et al. Renal function after pediatric intestinal transplant. Transplant Proc 2006;38:1759–61. [24] Suzuki M, Mujtaba MA, Sharfuddin AA, et al. Risk factors for native kidney dysfunction in patients with abdominal multivisceral/small bowel transplantation. Clin Transplant 2012;26:E351–8. [25] Boyer O, Noto C, De Serre NP, et al. Renal function and histology in children after small bowel transplantation. Pediatr Transplant 2013;17:65–72. [26] Ueno T, Kato T, Gaynor J, et al. Renal dysfunction following adult intestinal transplant under tacrolimus-based immunosuppressioin. Transplant Proc 2006;38: 1762–4. [27] Klein GL. Aluminum contamination of parenteral nutrition solutions and its impact on the pediatric patient. Nutr Clin Pract 2003;18:302–7. [28] Courtney-Martin G, Kosar C, Campbell A, et al. Plasma aluminum concentrations in pediatric patients receiving long-term parenteral nutrition. J Parenter Enteral Nutr 2015;39(5):578–85. [29] Smith LH, Fromm H, Fofmann AF. Aquired hyperoxaluria, nephrolithiasis, and intestinal disease. description of a syndrome. N Engl J Med 1972;286:1371–5. [30] Dobbins JW, Binder HJ. Effect of bile salts and fatty acids on the colonic absorption of oxalate. Gastroenterology 1976;70:1096–100.
Please cite this article as: Kosar C, et al, Prevalence of renal abnormality in pediatric intestinal failure, J Pediatr Surg (2016), http://dx.doi.org/ 10.1016/j.jpedsurg.2016.02.025
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Prevalence of renal abnormality in pediatric intestinal failure☆ Christina Kosar a, Nicole De Silva a, Yaron Avitzur a,b, Karen Steinberg a, Glenda Courtney-Martin a, Kathryn Chambers a, Kevin Fitzgerald a, Elizabeth Harvey a,c, Paul W. Wales a,d,⁎ a
Group for Improvement of Intestinal Function and Treatment (GIFT), The Hospital for Sick Children, University of Toronto, Canada Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Canada Division of Nephrology, The Hospital for Sick Children, University of Toronto, Canada d Division of General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, Canada b c
a r t i c l e
i n f o
Article history: Received 24 January 2016 Accepted 7 February 2016 Available online xxxx Key words: Pediatric Intestinal failure Renal abnormality Parenteral nutrition
a b s t r a c t Background: Outcomes of children with intestinal failure have improved over the last decade. However, with improved survival, other co-morbidities have become evident. The goal of our study was to evaluate the presence of renal nephrocalcinosis or increased echogenicity in a cohort of patients with pediatric intestinal failure (PIF). Methods: A cross-sectional prevalence design was performed in PIF patients followed by our intestinal rehabilitation program between 2013 and 2014. Renal function was evaluated using serum creatinine and urea, urine oxalate, creatinine, calcium, and calcium/creatinine ratios. Renal ultrasounds were performed to assess for echogenicity. Data was collected on intestinal failure related factors and nutritional intake. Data was analyzed using medians and Mann–Whitney U or proportions and chi square. Results: Fifty-four patients (median age 48 months; 33 males (61%) were studied. Twenty-two patients (41%) had increased echogenicity or nephrocalcinosis on ultrasound. There were no differences in serum Creatinine or urea, but patients with nephrocalcinosis had statistically different calcium:creatinine ratio (1.69 vs 0.74; p = 0.043), urine oxalate (108 vs 219; p = 0.06), and serum phosphate (1.55 vs 1.75; p = 0.044). Patients with echogenicity had a shorter colonic remnant (25 cm vs 31 cm; p = 0.01), a history of longer PN exposure (928 vs 483 days; p = 0.05), percent PN calories (37 vs 0; p = 0.05), PN h/day (13 vs 0; p = 0.05), but no difference in PN Ca/phosphate/magnesium content (mmol/kg). Conclusion: A large proportion of PIF patients have increased echogenicity/nephrocalcinosis on ultrasound that is associated with prolonged PN exposure. This has implications for long-term management. Regular surveillance is required, and further study is warranted to determine specific risk factors. © 2016 Elsevier Inc. All rights reserved.
Pediatric intestinal failure (PIF) is defined as the inability of the gastrointestinal tract to sustain life without supplementation with parenteral nutrition (PN) [1]. The most common cause of intestinal failure (IF) is short bowel syndrome (SBS) with an overall incidence of 22.1 per 1000 neonatal intensive care admissions and 24.5 per 100,000 live births [2]. Mortality rates within PIF are estimated to be around 30% [3–5], but vary greatly depending on age at diagnosis and underlying disease. Introduction of multidisciplinary teams and novel therapies have resulted in improved outcomes, but children with IF remain at
Abbreviations: IF, intestinal failure; PN, parenteral nutrition; SBS, short bowel syndrome; PIF, pediatric intestinal failure; GFR, glomerular filtration rate; CKD, chronic kidney disease; ITx, intestinal transplant; eGFR, estimated glomerular filtration rate; TFI, total fluid intake; IQR, interquartile range; RR, relative risk; US, ultrasound; SB, small bowel; LB, large bowel; cm, centimeter. ☆ Level of Evidence: 3. ⁎ Corresponding author at: The Hospital for Sick Children, Rm 1526, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada. Tel.: +1 416 813 7654x201490; fax: +1 416 813 7477. E-mail address: [email protected] (P.W. Wales).
risk for multiple co-morbidities, including liver dysfunction, electrolyte imbalance, metabolic bone disease, and infectious complications [2–5]. Patients with irreversible IF require PN for maintenance of fluid, electrolyte and protein-energy balance. Patients require long-term PN until intestinal adaptation occurs or serious complications arise necessitating intestinal transplantation [3,4]. Renal dysfunction was first reported by Moukarzel et al. in 1991 in children receiving long-term PN. They reported a decrease in glomerular filtration rate (GFR) but were unable to identify a contributing mechanism [6]. Reports in adult patients on long-term PN have suggested that 50% of patients had decreased renal function characterized by a decreased GFR or progressive decrease of GFR [7–9]. A recent retrospective crosssectional study compared the prevalence of chronic kidney disease (CKD) between adults on PN versus intestinal transplant (ITx). It found that while ITx patients have a significant risk for developing CKD, patients on long-term PN showed an annual estimated GFR (eGFR) decline of 2.8% and after a median duration of 7 years of PN a prevalence of mild CRF in 21.2% [10]. The mechanism for the decline in renal impairment has not been identified in previous studies [8–10].
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Please cite this article as: Kosar C, et al, Prevalence of renal abnormality in pediatric intestinal failure, J Pediatr Surg (2016), http://dx.doi.org/ 10.1016/j.jpedsurg.2016.02.025
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It is well recognized that creatinine is a poor marker for renal function, especially in the early stages of renal damage. Increased echogenicity of the renal parenchyma on renal ultrasound is a nonspecific finding but is usually indicative of renal parenchymal disease, outside the newborn period where the kidneys are routinely echogenic. The causes of increased renal echogenicity are multiple and include glomerular disease, tubular disorders and interstitial inflammation, and nephrocalcinosis. Findings of increased echogenicity on ultrasound (US) though nonspecific are an important finding and may signify the presence of renal disease [11,12]. Nephrocalcinosis is defined as mineral precipitates within the renal parenchyma [13]. The formation of nephrocalcinosis is often a result of an imbalance between stonepromoting and stone-inhibiting factors and is often multifactorial. Factors that can lead to the promotion of nephrocalcinosis include acidosis, medications such as diuretics and vitamin D supplementation, hyperoxaluria, PN, fat malabsorption, episodes of dehydration [14,15]; all of which exist in PIF patients. An index child with PIF was noted to have severe nephrocalcinosis, and several patients were reported to have abnormal renal echogenicity on renal ultrasound. This prompted us to look at renal function and the prevalence of nephrocalcinosis and/or abnormal renal echogenicity in our PIF population to try and identify risk factors for the later development of CKD in this cohort. The goals of our study were to evaluate the prevalence of renal abnormality in a cohort of pediatric patients with IF and identify factors associated with its development.
1. Methods We performed a retrospective cross-sectional prevalence study to determine the proportion of patients with nephrocalcinosis and/or abnormal renal echogenicity. Pediatric intestinal failure patients managed by our multi-disciplinary intestinal rehabilitation program at The Hospital for Sick Children in Toronto during 2013–2014 were potential candidates. Patients had a history of prolonged PN use but did not have to be on PN at the time of evaluation. Patients receive regular monitoring and follow-up for PN related complications which includes yearly vascular ultrasound, abdominal ultrasound and DEXA scans. Patients who did not receive an abdominal/renal ultrasound completed during the study period were excluded. In addition, patients with previous liver or intestinal transplantation were not included in analysis. Data was collected from the electronic patient chart. Demographic data collected included date of birth, gestational age (weeks), gender, etiology of IF, category of IF (SBS, mucosal enteropathy or primary dysmotility). Residual intestinal anatomy including both absolute length and percentage of expected length based on established norms [16] of both small and large bowel was recorded. In addition, presence of an ostomy and presence of the ileocecal valve were included. To quantify PN exposure, we collected total number of PN days, percentage of PN calorie support, number of PN infusion hours per day, and total fluid intake (TFI) per kilogram per day. PN composition was also collected and included amount of prescribed acetate, calcium, phosphate and magnesium. Laboratory values collected included spot urinary calcium, chloride, creatinine, sodium, citrate, and oxalate. Serum biochemistry data included creatinine, ionized calcium, phosphate, urea, 25-hydroxy vitamin D level and serum blood gas. Based on urine biochemical values, calculations were completed to determine the calcium:creatinine ratio, calcium:citrate ratio and citrate:creatinine ratio. Radiology results for abdominal/renal ultrasounds were collected to determine the presence of nephrocalcinosis or echogenicity. Kidney length was also recorded. All laboratory results had to be drawn within two months of the completion of the renal ultrasound to be included in the analysis. All data collection was completed by two clinical nurse practitioners with extensive clinical experience. Reference ranges for renal values
were obtained from several sources to provide parameters and age ranges [17–20]. Patients were stratified based on the presence of nephrocalcinosis or increased echogenicity on renal ultrasound. Baseline and outcome data were compared using appropriate summary statistics. Continuous variables were presented as medians with interquartile range (IQR) as the data was not normally distributed after review of frequency histograms. Data was analyzed using the Mann–Whitney U test. Categorical variables were presented as frequencies and proportions and statistical testing was performed with the chi square. Relative risks (RR) were included as a measure of association. An alpha-value of 0.05 was considered statistically significant. IBM SPSS Statistics 22 (2013) was used for the analyses. 2. Results During the study enrollment period, fifty-six patients met inclusion criteria with a median age of 48 months and 35 patients were male (57%). Of the participants 24 (43%) had increased echogenicity or nephrocalcinosis on US compared to 32 participants without radiographic evidence of renal abnormality. Table 1 displays the patient characteristics based on presence of echogenicity and nephrocalcinosis at the time of ultrasound. The majority of patients had SBS (73.9% for nephrocalcinosis/echogenicity and 81.3% for no-nephrocalcinosis/echogenicity, respectively). Residual small bowel length did not differ significantly between the two groups; however, the colonic remnant was significantly shorter in the group with renal impairment (p = 0.001). PIF patients with renal abnormality on US were also more likely to have a stoma (70.8% vs 45.2%; p = 0.05; RR = 1.9, 95% CI 1.0–3.7). Table 2 illustrates the impact of PN exposure and composition on development of nephrocalcinosis/echogenicity. The total exposure to PN in days was significantly more in PIF patients with nephrocalcinosis/ echogenicity (928 vs 500; p = 0.05), as was the percentage of total calorie delivery in the form of PN (37% vs 0%; p = 0.05) and PN TFI [in ml/ kg/day] (103 vs 21; p = 0.05). The number of PN infusion hours per day was not significantly different between the two groups (13 vs 4; p = 0.102). The number of PIF patients receiving PN at the time of renal US was higher in the nephrocalcinosis/echogenicity group (70.8% vs 43.8%; p = 0.044) with a relative risk of 2.0 (95% CI 1.0–3.9). Parenteral nutrition composition was compared between the two groups for calcium, phosphate, magnesium and acetate (mmol/kg/day). The composition of the parenteral nutrition did not vary between the two groups. Serum and urine biochemistry results for the two groups are displayed in Table 3. At the time of measurement urinary calcium was Table 1 Patient characteristics. Nephrocalcinosis/ echogenicity (n = 24) Age (months) Male (%) Gestational Age (weeks) IF Category (%) SBS Enteropathy Dysmotility Residual SB length (cm) Residual SB % Residual LB length (cm) Residual LB % Stoma Present (%) On PN at time of US (%)
Normal
Pvalue
(n = 32)
48 (21–82) 17 (70.8) 35 (32–40)
27 (16–62) 18 (56.3) 35 (33–38)
17 (73.9) 1 (4.3) 5 (21.7) 45 (25–100) 27 (14–66) 25 (15–35) 50 (30–90) 17 (70.8) 17 (70.8)
26 (81.3) 3 (9.4) 3 (9.4) 64 (19–133) 45 (15–100) 33 (30–40) 100 (75–100) 14 (45.2) 14 (43.8)
0.362 0.403 0.811 0.373
0.519 0.361 0.007 0.001 0.05 0.04
Values are medians with interquartile ranges. % represents frequencies and percentages. IF = intestinal failure; SBS = short bowel syndrome; SB = small bowel; LB = large bowel; PN = parenteral nutrition; US = ultrasound.
Please cite this article as: Kosar C, et al, Prevalence of renal abnormality in pediatric intestinal failure, J Pediatr Surg (2016), http://dx.doi.org/ 10.1016/j.jpedsurg.2016.02.025
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Table 2 Parenteral nutrition exposure.
PN days Proportion of PN support (%) PN hours daily PN TFI (cc/kg/day)
Nephrocalcinosis/echogenicity (n = 24)
Normal (n = 32)
P-value
928 (408–1613) 37 (0–100) 13 (10–15) 103 (53–131)
500 (149–921) 0 (0–49) 4 (0–13) 21 (0–118)
0.05 0.05 0.102 0.05
Values are medians with interquartile ranges. % represents frequencies and percentages. PN = Parenteral nutrition; TFI = Total fluid intake.
increased compared to the group with normal renal function (2.51 vs 1.62; p = 0.027). The nephrocalcinosis/echogenicity group also had an elevated calcium:creatinine ratio (1.47 vs 0.71; p = 0.014). Urinary oxalate excretion was also decreased in patients with nephrocalcinosis/echogenicity (108 vs 228; p = 0.044), as was serum phosphate levels (1.56 vs 1.74; p = 0.035); however the oxalate:creatinine ratio was not significantly different (75.6 vs 98.4; p = 0.326). Additional renal parameters were calculated including calcium:citrate ratio, citrate:creatinine ratio but these were not found to be statistically significant between the two groups. 3. Discussion Premature babies are at particular risk with nephrocalcinosis present in 7–41% of babies with gestational age b 32 weeks. Many of these patients will demonstrate spontaneous resolution in the first few years of life [13]. While numerous studies have shown an increased risk for developing CKD in intestinal transplant patients [10,21–26], there is increasing awareness of renal impairment in patients requiring long-term PN. However, most of the research completed to date has been on the adult IF population [7–10]. With the improved survival rates of PIF patients, there is an increased awareness of morbidity related to prolonged PN exposure. Our results indicate that PIF patients with prolonged PN exposure, presence of a stoma and shorter colonic remnant are at increased risk of developing renal impairment. The causes of renal impairment in PIF patients on long-term PN continues to be largely unexplained. Previous studies have consistently been unable to identify an underlying etiology [6–10]. While PN exposure and shorter colonic remnant were statistically significant for the development of nephrocalcinosis/echogenicity in our study, age, gestational age, category of IF and small bowel residual length did not contribute. There was also limited indication from standard laboratory
results (ie, urea or creatinine) that would predict patients at risk for developing nephrocalcinosis or abnormal renal echogenicity, which may be a harbinger of later CKD. Previous studies have suggested that septic events and hypovolemia related to chronic dehydration [7,9] may contribute to the development of renal dysfunction within adults on longterm PN. Low urinary citrate excretion has been thought to be a major risk factor for calcium stone formation. Citrate has an inhibitory effect on the formation of calcium stones in several ways. Urinary citrate excretion is influenced by acid–base status which can lead to reduced urinary citrate values due to an increased reabsorption of citrate. While we did not find a statistical difference in our two study populations, majority of patients evaluated in this study had samples taken in the morning, shortly after completing their PN cycle at which point they are in their most hydrated state. It is also important to note that all patients were supplemented with acetate and were not in an acidotic state. It would be valuable information to also obtain urine results prior to PN hook-up to determine if the results are significantly impacted in relation to hydration status. In addition, although citrate levels were not different between groups, 70% of nephrocalcinosis patients and 52% of normal patients had a calcium:citrate ratio greater than 1.6 mmol/mmol which is the threshold to identify patients at risk of stone formation [19]. Prolonged PN exposure was a significant risk for the development of echogenicity and/or nephrocalcinosis. This took the form of total PN days, proportion of total calories delivered as PN and total fluid intake infused in PN (cc/kg/day). While cyclical dehydration may be a long term risk factor to the kidney, heavy metal contamination continues to be an ongoing issue particularly with contamination of Aluminum. Aluminum can accumulate in bone, liver, brain, spleen, kidney, parathyroid gland and other tissues in the body [27]. Our group recently published a study of 27 PIF patients on long-term PN demonstrating plasma Aluminum concentrations to be significantly higher than the
Table 3 Patient biochemistry.
Serum creatinine Serum urea Serum phosphate Serum calcium Urine oxalate Urine citrate Calcium: creatinine ratio (mol/mol) Calcium: citrate ratio (mmol/mmol) Calcium: citrate N1.6 mmol/mmol (%) Citrate: creatinine ratio (mmol/mmol) Oxalate: creatinine ratio (mmol/mmol) Serum pH Serum bicarbonate
Nephrocalcinosis/echogenicity (n = 24)
Normal (n = 32)
P-value
28 (20–35) 4.95 (4.40–7.08) 1.56 (1.41–1.77) 1.27 (1.25–1.35) 108 (84–256) 0.90 (0.50–2.10)
23 (17–33) 4.90 (3.93–5.58) 1.74 (1.59–1.89) 1.29 (1.26–1.33) 228 (113–441) 0.80 (0.35–1.90)
0.324 0.584 0.035 0.885 0.044 0.476
1.47 (0.75–2.30)
0.71 (0.24–1.73)
0.014
1.80 (1.19–5.40) 16 (69.6)
1.54 (0.74–3.30) 13 (52.0)
0.445 0.214
0.63 (0.32–1.08)
0.44 (0.12–0.88)
0.317
75.6 (52.4–116.5) 7.38 (7.34–7.39) 26 (24–27)
98.4 (54.8–135.1) 7.37 (7.36–7.39) 25 (23–27)
0.326 0.905 0.334
Values are medians with interquartile ranges. % represents frequencies and percentages.
Please cite this article as: Kosar C, et al, Prevalence of renal abnormality in pediatric intestinal failure, J Pediatr Surg (2016), http://dx.doi.org/ 10.1016/j.jpedsurg.2016.02.025
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control group participants (1195 ± 710 vs 142 ± 63 nmol/L; p b 0.0001). In the subgroup of patients who had analysis of their PN solution, aluminum intake was found to be 3-fold greater than the Food and Drug Administration upper level of recommended intake [28]. Aluminum is buffered into the bone and may cause calcium to leech out of the bone, where it will then need to be excreted renally, contributing to the hypercalciuria. The finding that patients with impaired renal function had a shorter colonic remnant contradicts previous findings that patients with ileal resection (as little as 20-30 cm) and a residual colon are at risk for hyperoxaluria. This is because fatty acids undigested in the ileum enter the colon and bind to calcium. Typically, calcium binds to oxalate in the stool and it is excreted. If calcium binds to fatty acids, oxalate is reabsorbed in the colon and will bind with calcium in the serum leading to calcium oxalate stones [29]. In addition, there may also be increased colonic permeability due to colitis caused by unabsorbed bile salts and fatty acids [30]. It may be that a shorter colon remnant translates into larger fluid stool losses and the need for increased volume requirements, as shown in the PN TFI delivery. Patients with a shorter residual colon are also more likely to have a reduced transit time resulting in poor absorption, as well as higher fluid requirements. Also, there is likely higher losses of bicarbonate in the stool that contribute to acidosis and/or hypocitraturia. The major limitation of our study was the retrospective design. We were able to determine the prevalence of renal abnormality within our PIF population, but were not able to compare changes over time. The majority of previous literature has been completed in the adult IF population which evaluated GFR and have also been retrospective or cross-sectional in design [7–10]. Although we were able to determine parenteral calcium, phosphate and protein delivery in our patients, enteral intake of calcium, phosphate and protein, while desirable to ascertain, was not possible in a retrospective study. Due to the small sample size in our study, it is quite possible we were under powered to detect subtle differences in laboratory results between the two groups. Moving forward, it would also be valuable to look at markers of renal tubular function in future studies (beta 2 microglobulin to creatinine ratio), as well as, obtaining urine and blood samples at various time points in the patients PN cycle to determine if their hydration status has an impact on results and outcomes. In summary a large proportion of PIF patients have abnormal echogenicity/nephrocalcinosis on ultrasound that is associated with prolonged PN exposure. This has implications for long-term management. The long term implication of this renal abnormality is unknown and the cause likely multifactorial. However, regular radiographic surveillance is recommended, since routine laboratory monitoring is not reliable in predicting who is at risk, as patients are able to maintain normal serum creatinine and urea levels. Further study is warranted to determine specific risk factors. It is also important to monitor these patients to determine which proportion of patients with echogenicity and/or nephrocalcinosis go on to develop renal impairment. References [1] Goulet O, Ruemmele F, Lacaille F, et al. Irreversible intestinal failure. J Pediatr Gastroenterol Nut 2004;38:250–69.
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Please cite this article as: Kosar C, et al, Prevalence of renal abnormality in pediatric intestinal failure, J Pediatr Surg (2016), http://dx.doi.org/ 10.1016/j.jpedsurg.2016.02.025