Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal disease and can be symptomatic

Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal... Background: Heterozygous mutations in the HNF1B gene are the most common monogenic cause of developmental kidney disease. Extrarenal phenotypes frequently occur, including diabetes mellitus and pancreatic hypoplasia; the latter is associated with subclinical exocrine dysfunction. We measured faecal elastase-1 in patients with HNF1B-associated disease regardless of diabetes status and assessed the degree of symptoms associated with pancreatic exocrine deficiency. Methods: Faecal elastase-1 was measured in 29 patients with a known HNF1B mutation. We defined a low faecal elastase-1 concentration based on the 2.5 percentile of 99 healthy control individuals (410 mg/g stool). Symptoms related to pancreatic exocrine dysfunction were assessed and a subset of the HNF1B cohort (n ¼ 6) underwent pancreatic imaging. Results: Faecal elastase-1 was below the 2.5 percentile of the control cohort in 18/29 (62%) patients with HNF1B-associated renal disease. A total of 8/29 (28%) had a measurement suggestive of exocrine pancreatic insufficiency at <200 mg/g stool; of these, 3 suffered with abdominal pain, loose stools and/or unintentional weight loss. All three experienced symptomatic improvement and weight gain after commencing pancreatic enzyme replacement therapy. Faecal elastase-1 was low in 7/15 (47%) HNF1B patients without diabetes compared with 11/14 (79%) of those with diabetes (P ¼ 0.1). Conclusions: Faecal elastase-1 deficiency is a common feature of HNF1B-associated renal disease even when diabetes is not present and pancreatic exocrine deficiency may be more symptomatic than previously suggested. Faecal elastase-1 should be measured in all patients with known HNF1B-associated disease complaining of chronic abdominal pain, loose stools or unintentional weight loss. The discovery of a low faecal elastase-1 concentration in individuals with developmental kidney disease of uncertain cause should prompt referral for HNF1B genetic testing. Key words: developmental kidney disease, diabetes mellitus, faecal elastase, HNF1B, pancreatic hypoplasia Received: August 2, 2017. Editorial decision: November 22, 2017 V The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 454 | R.L. Clissold et al. one case of symptomatic pancreatic exocrine insufficiency requir- Introduction ing treatment in HNF1B-associated disease has been described in Hepatocyte nuclear factor 1b (HNF1B) is a transcription factor theliteraturetodate [21]. In this study, our aims were to measure with important roles in the development of the kidney, pan- faecal elastase-1 in patients with HNF1B-associated disease regard- creas, liver and genital tract [1]. Heterozygous mutations of the less of diabetes status and assess the degree of symptoms associ- HNF1B gene are the most common known monogenic cause of ated with pancreatic exocrine deficiency. developmental kidney disease [2–4]. Despite this single genetic aetiology, the phenotype of HNF1B-associated renal disease is Materials and methods very variable (Box 1). Biochemical abnormalities, including hypomagnesaemia and hyperuricaemia, are also frequently Recruitment and genetic analysis seen [5, 6]. HNF1B-associated disease is a multisystem disorder Participants with HNF1B-associated disease were recruited from 31 and extrarenal phenotypic features include young-onset diabe- January 2013 to 10 October 2015 from three sites in the UK (adult tes mellitus, pancreatic hypoplasia, abnormal liver function renal and diabetes units at the Royal Devon and Exeter Hospital; tests and genital tract malformations [7–12]. Genetic changes paediatric renal units at Great Ormond Street Hospital for Children comprise either HNF1B intragenic mutations (one-half of and Evelina London Children’s Hospital), as previously described patients) or an approximate 1.3-Mb deletion at chromosome [22]. Inclusion criteria included the presence of either an HNF1B 17q12, which includes the entire HNF1B gene [13, 14]. Both may intragenic mutation or whole-gene deletion on genetic testing per- arise spontaneously, which means there is often no family his- formed due to underlying renal abnormalities or diabetes and cur- tory of renal disease or diabetes [15–17]. In view of the clinical rent age 4 years. Informed written consent was obtained from all heterogeneity of the condition and frequent absence of a family adult participants and parents of child participants, with assent history, diagnosis can be challenging and it is likely that many from those <16 years of age. The study was conducted in agree- cases remain undetected. ment with the Declaration of Helsinki principles and approved by a regional ethics committee (National Research Ethics Service Box 1. The variable phenotype of HNF1B-associated Committee South West—Frenchay). A total of 29 patients from 20 unrelated families with HNF1B-associated disease participated. renal disease Mutation screening was performed by sequencing of coding exons Bilateral hyperechogenic kidneys with normal or and exon–intron boundaries together with gene dosage assess- slightly increased size on antenatal ultrasonography ment by multiplex ligation–dependent probe amplification as pre- Renal cysts (including cystic dysplasia and multicystic viously described [14, 17]. dysplastic kindney) Faecal elastase-1 was also measured in a cohort of healthy Single kidney controls in order to define a low faecal elastase-1 concentration Renal hypoplasia based on the 2.5 percentile. Healthy controls were recruited Horseshoe kidney from 4 March 2015 to 19 August 2016 from two sites in the UK Duplex kidney (National Institute for Health Research Exeter Clinical Research Isolated bilateral hydronephrosis and hydroureter Facility at the Royal Devon and Exeter Hospital; Oxford Centre Collecting system abnormality (usually in conjunction for Diabetes, Endocrinology and Metabolism at the Oxford with other renal structural abnormality) University Hospitals National Health Service Foundation Trust). Inclusion criteria included age 16–75 years, ethnicity reflective of local demographics and capacity to consent. Informed writ- Imaging of the pancreas in HNF1B-associated disease with ten consent was obtained from all participants. The study was either computed tomography (CT) or magnetic resonance imag- conducted in agreement with the Declaration of Helsinki princi- ing (MRI) has shown less tissue corresponding to the body and ples and approved by a regional ethics committee (South tail of the pancreas, with a slightly atrophic head [8, 9]. This is West—Frenchay Research Ethics Committee). A total of 99 indi- consistent with agenesis of the dorsal pancreas, the embryonic viduals participated. The median age of this cohort was 61.7 structure that gives rise to the pancreatic body, tail and a small years [interquartile range (IQR) 52.8–66.3]. A total of 39/99 (39%) section of the head. Pancreatic exocrine hypersecretion has was male and all were of White ethnicity. The median faecal been observed in patients with HNF1B-associated disease using elastase-1 concentration was 1580 mg/g stool (IQR 1000–2000). secretin-stimulated MRI and rapid endoscopic secretin stimula- The 2.5 percentile for faecal elastase-1 in this cohort was a con- tion tests; this is likely to be a compensatory mechanism for centration of 410 mg/g stool (Supplementary data, Figure S1). reduced pancreatic volume and provides further evidence that There was only a weak association between increasing age and the small pancreas seen on imaging is due to hypoplasia rather lower faecal elastase-1 concentrations with a Spearman’s q of than atrophy [18]. A report of 20 foetal autopsy cases with 0.2, (P ¼ 0.02) (Supplementary data, Figure S2). HNF1B mutations described pancreatic agenesis in 2/20 and hypoplasia in 13/20 [19]. Clinical evaluation Pancreatic hypoplasia in HNF1B-associated disease has been associated with subclinical pancreatic exocrine insufficiency. Relevant medical details, including symptoms related to pan- This has mainly been studied in small series of patients with creatic exocrine dysfunction (abdominal pain, loose stools HNF1B mutations and diabetes using indirect tests of pancreatic and unintentional weight loss), were documented using a function, usually faecal elastase-1 measurement in stool [8, 9, standardized assessment of medical records and participant/ 20]. Lower exocrine pancreatic function involving both ductal parent interview. Diabetes was diagnosed either according and acinar cells has been confirmed in direct testing with rapid to World Health Organization guidelines or on the basis of endoscopic secretin tests and secretin-stimulated MRI in seven established treatment with oral hypoglycaemic agents/insulin. individuals with HNF1B mutations [18]. To our knowledge, only In order to measure endogenous insulin production, the Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Exocrine pancreatic dysfunction in HNF1B disease | 455 urinary C-peptide creatinine ratio (UCPCR) was measured on a post-prandial urine sample taken approximately 2 h after a meal stimulus [23]. Faecal elastase-1 concentration was assessed by enzyme- linked immunosorbent assay on a single spot stool sample at the Royal Cornwall Hospital; healthy control samples were tested using a 10 dilution to obtain an absolute value for faecal elastase-1, as the majority of samples were expected to have a result greater than the 500 mg/g detection limit of the assay. Faecal elastase-1 <200 mg/g is considered abnormal, with meas- urements of 100–200 mg/g suggestive of moderate to mild pancre- atic exocrine insufficiency and measurements <100 mg/g suggestive of severe insufficiency [24]. Previous imaging results from CT or MRI were reviewed to look for pancreas abnormalities. All patients with HNF1B-associated disease were also invited to undergo pancreatic MRI using a 1.5-T Philips Intera system utiliz- Fig. 1. Bar chart showing the percentage of individuals with HNF1B-associated ing three-dimensional gradient echo and spin echo sequences, disease with faecal elastase-1 (FE-1) measurements <100 mg/g stool (suggestive with and without fat suppression, at a range of orientations. of severe pancreatic exocrine insufficiency), 100–200 mg/g stool (moderate to Images were subsequently reviewed and reported by a consultant mild insufficiency), 200–500 mg/g stool and >500 mg/g stool. The dotted red line radiologist in order to assess pancreatic structure and ensure indicates that 3/99 (3%) healthy controls had an FE-1 measurement of 200–500 mg/g stool whereas in the remainder it was >500 mg/g stool. there were no incidental findings of clinical concern. participants: one was reported to show diffuse pancreatic atro- Statistical analysis phy with calcification of the head and body plus common bile Qualitative variables were described with percentages and duct dilatation, whereas the other three demonstrated absence quantitative variables with median and IQR. Differences or atrophy of the body and tail of the pancreas only. All four between groups were assessed using the Fisher exact test for patients had been diagnosed with diabetes and faecal elastase- categorical variables and the Mann–Whitney U test for conti- 1 measurements ranged from 31 to 280 mg/g stool. Two of six nuous variables. Correlations were tested by Spearman’s q. individuals had scans reported within normal limits. One of A P-value <0.05 was considered to be statistically significant. All these patients was a 20-year-old male without evidence of dia- analyses were carried out using StataSE (version 14; StataCorp, betes and a normal faecal elastase-1 result of 432 mg/g stool. The College Station, TX, USA) and GraphPad statistical software other patient was a 65-year-old female who had been diagnosed (GraphPad Software, La Jolla, CA, USA). with new-onset diabetes after transplantation at the age of 62 years and had a faecal elastase-1 result >500 mg/g stool. Results Markedly low faecal elastase-1 levels are more common Participant characteristics in HNF1B-associated disease when diabetes is present The median age of individuals with HNF1B-associated renal Faecal elastase-1 measurements were compared in individuals disease was 25 years (IQR 14–44) and 13/29 (45%) were male. The with HNF1B-associated disease according to diabetes status. Only majority of the cohort was White, with just 1/29 (3%) being of 1/15 (7%) of those without diabetes had a markedly low faecal mixed ethnicity. A total of 14/29 (48%) had diabetes. elastase-1 measurement (<200 mg/g stool) compared to 7/14 (50%) of those with diabetes (P ¼ 0.01) (Figure 2). Overall, faecal Exocrine pancreatic deficiency is common in HNF1B- elastase-1 levels were low in 7/15 (47%) HNF1B patients without associated disease and can be symptomatic diabetes compared with 11/14 (79%) of those with diabetes (P ¼ 0.1). There was only a weak association between increasing dura- Faecal elastase-1 was low (below the 2.5 percentile of the con- tion of diabetes and lower faecal elastase-1 concentrations, with trol cohort) in 18/29 (62%) patients with HNF1B-associated renal a Spearman’s q of 0.3 (P ¼ 0.4) (Supplementary data,Figure S3). disease. In all, 8/29 (28%) had a faecal elastase-1 concentration The two groups were different with respect to many clinical suggestive of exocrine pancreatic insufficiency at <200 mg/g characteristics (Table 2). The median age of the cohort without stool (Figure 1); in 4/29 (14%) the measurement was <100 mg/g diabetes was 14 years (IQR 9–19) compared to 43.5 years (IQR 34– stool, in keeping with severe deficiency. 55) in the group with diabetes (P ¼ 0.0005). In those patients A total of 3/8 individuals with a faecal elastase-1 measure- with more severe pancreatic disease, endogenous insulin secre- ment <200 mg/g stool suffered with abdominal pain, loose stools tion assessed by the UCP:Cr ratio was lower than in those with- and/or unintentional weight loss. All reported symptomatic out diabetes [median UCP:Cr ratio 1.1 nmol/mmol (IQR 0.6–1.5) improvement and weight gain after commencing pancreatic compared to 2.1 nmol/mmol (1.4–5.6), respectively; P ¼ 0.04]. enzyme replacement therapy. In all three cases it had taken several months for symptoms to be attributed to faecal elastase deficiency and for treatment to be commenced (Table 1). Discussion We have demonstrated that faecal elastase-1 deficiency is com- Individuals with low faecal elastase-1 levels have radio- mon in HNF1B-associated renal disease and exocrine pancreatic logical evidence of pancreatic hypoplasia dysfunction may be more symptomatic than previously pub- In all, 6/29 participants underwent pancreatic imaging with lished. This has important implications for the screening and either CT or MRI. Abnormalities were detected in four of six treatment of these patients. In all, three of eight individuals in Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 456 | R.L. Clissold et al. Table 1. Details of symptomatic faecal elastase deficiency in three individuals with HNF1B-associated renal disease Pancreatic insufficiency Age at study FE-1, Age at entry mg/g diagnosis Patient (years) Sex Genetic abnormality Diabetes status stool (years) Details 2 36 Female Mutation Diagnosed at age 20 90 39 FE-1 measured by renal team after (c.982_986delCCTCT) years, on insulin several months of abdominal pain and diarrhoea; resolution of symp- toms and weight gain after treat- ment commenced 3 61 Female Deletion Haemoglobin A1c of 56 31 63 Known pancreatic atrophy and calcifi- (c.1-?_1674þ? del) mmol/mol identified cation from previous imaging for at age 59 years but abdominal pain under surgical no treatment team. FE-1 measured by gastroen- commenced terology after referral with several months of abdominal pain, loose stools and weight loss; improve- ment in symptoms and 6-kg weight gain after pancreatic enzyme replacement therapy commenced 18 43 Female Deletion Diagnosed at age 107 43 Referred to gastroenterology with (c.1-?_1674þ? del) 32 years, on insulin abdominal pain, diarrhoea (with occasional blood mixed in) and weight loss; colonoscopy performed and found to be normal. FE-1 meas- ured by research team; commenced on pancreatic enzyme replacement therapy with symptomatic improvement del, deletion; FE-1, faecal elastase-1. Fig. 2. Bar charts showing the percentage of individuals with HNF1B-associated disease according to diabetes status with faecal elastase-1 (FE-1) measurements (A) either below or above the 2.5 percentile of a healthy control cohort and (B) <100 mg/g stool (suggestive of severe pancreatic exocrine insufficiency), 100–200 mg/g stool (moderate to mild insufficiency), 200–500 mg/g stool and >500 mg/g stool. this study with a faecal elastase-1 measurement <200 mg/g stool symptomatic improvement with weight gain once treatment had abdominal pain, loose stools and weight loss. The only pub- with pancreatic enzyme replacement therapy was commenced. lished report of symptomatic pancreatic insufficiency in This highlights how difficult it can be to diagnose pancreatic HNF1B-associated disease involved the identification of diabe- insufficiency and how prompt treatment benefits patients. tes and a small pancreas on imaging in an individual 5 years of Clinicians should have a low threshold for arranging pancreatic age; pancreatic enzyme replacement therapy became necessary function testing for individuals with known HNF1B-associated from the age of 16 years and lead to a normalization of body disease, even when subtle symptoms such as mild abdominal mass index [21]. There was a significant delay in attributing discomfort and bloating are present. symptoms to pancreatic insufficiency in the three cases identi- This is the largest series of faecal elastase-1 measurements fied in this article, and one of the patients even underwent a in individuals with HNF1B-associated renal disease recruited colonoscopy before the correct diagnosis was made. All showed irrespective of diabetes status; previous reports of faecal Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Exocrine pancreatic dysfunction in HNF1B disease | 457 Table 2. Characteristics of individuals with HNF1B-associated disease according to diabetes status Feature HNF1B-associated disease, no DM (n ¼ 15) HNF1B-associated disease with DM (n ¼ 14) P-value Age (years), median (IQR) 14 (9–19) 43.5 (34–55) 0.0005 Sex, n (%) Male 9 (60), Female 6 (40) Male 4 (29), Female 10 (71) 0.1 Genetic abnormality, n (%) Mut 9 (60), del 6 (40) Mut 7 (50), del 7 (50) 0.7 BMI (kg/m ), median (IQR) 20 (18–27) 23 (20–25) 0.1 Creatinine (mmol/L), median (IQR) 79 (55–115) 116 (90–144) 0.03 HbA1c (mmol/mol), median (IQR) 39 (37–42) 60 (55–74) 0.0005 UCP:Cr ratio (nmol/mmol), median (IQR) 2.1 (1.4–5.6) 1.1 (0.6–1.5) 0.04 del, deletion; DM, diabetes mellitus; mut, mutation. elastase deficiency in association with an HNF1B mutation have years to help select individuals who would benefit from screen- usually been from smaller series of patients with diabetes or ing: the HNF1B score designed by Faguer et al. [28] and adapted prediabetes [8, 9, 18, 20]. Tjora et al. [18] included one patient criteria for HNF1B analysis proposed by Raaijmakers et al. [29]. with an HNF1B mutation and normal glucose tolerance in their However, faecal elastase was not systematically assessed in study of exocrine pancreatic function using direct testing; this either of these studies. It is cheap and easy to measure, requir- individual was 38 years old with normal pancreas anatomy on ing only a single spot stool sample. Given that low faecal imaging and a faecal elastase-1 measurement of 312 mg/g stool. elastase-1 concentrations were seen in 18/29 (62%) patients An earlier study from the same group recruited an affected 6- with HNF1B-associated renal disease in this study, it would be year-old girl with no pancreatic body and tail identified on interesting to test the role of faecal elastase-1 as a biomarker for imaging and a faecal elastase-1 concentration of 131 mg/g stool; HNF1B-associated disease in a large cohort of individuals with she had developed impaired glucose tolerance when studied congenital anomalies of the kidneys and urinary tract. In the again at the age of 8 years [9, 18]. We included 15 HNF1B interim, we suggest that the finding of a low faecal elastase patients without diabetes in this study; 7/15 (47%) had a low fae- measurement in individuals with developmental kidney dis- cal elastase-1 measurement but only 1/15 (7%) had a measure- ease of uncertain cause should prompt referral for HNF1B ment of <200 mg/g stool. We would hypothesize that pancreatic genetic testing. insufficiency and diabetes in HNF1B-associated disease are associated, as they are secondary to reduced exocrine and endo- crine cells as a result of pancreatic hypoplasia. However, cau- Conclusion tion must be applied when interpreting the results between the HNF1B cohorts with and without diabetes, as any differences In summary, faecal elastase-1 deficiency is an important feature may reflect the discrepancy in age between the two groups. It of HNF1B-associated renal disease even when diabetes is not would be very interesting in future work to follow a cohort of present. Faecal elastase-1 should be measured in all individuals paediatric patients with HNF1B mutations over time using serial with an HNF1B mutation complaining of abdominal pain, loose indirect pancreatic function testing and imaging to see if these stools or unintentional weight loss. The role of faecal elastase-1 non-invasive tests can be used to predict who will develop dia- as a biomarker for HNF1B-associated disease requires further betes and exocrine insufficiency and at what age. investigation. Several limitations were associated with this work. The cohort of healthy controls used to define the lower limit of the Acknowledgements normal range for faecal elastase-1 were older; the median age was 61.7 years (IQR 52.8–66.3) compared to 24.5 years (IQR 14–44) We would like to thank Professor Tim Frayling from the in the individuals with HNF1B-associated renal disease. University of Exeter for the use of the faecal elastase-1 However, faecal elastase concentrations decline with age, so results from a local cohort of healthy controls and Professor defining a cut-off for faecal elastase-1 using the 2.5 percentile of Ingfrid Haldorsen from Haukeland University Hospital for a younger control cohort may have yielded an even greater advice on pancreatic MRI. value than the 410 mg/g stool used in this study [25]. The median faecal elastase-1 measurement of 1580 mg/g stool (IQR 1000– 2000) in our local control cohort is higher than values reported Funding for healthy controls in other studies [25–27]. This may reflect assay differences between laboratories but, as we have defined R.C. is supported by a Medical Research Council Clinical low faecal elastase-1 as measurements that fall below the 2.5 Training Fellowship (grant reference number MR/J011630/1). percentile of a local healthy control group, this make our results B.S. and A.H. are core members of the National Institute for generalizable. Furthermore, we found that our local cut-off of Health Research Exeter Clinical Research Facility. A.H. is a 410 mg/g stool correlated with the presence or absence of pan- National Institute for Health Research Senior Investigator. creatic hypoplasia on radiological imaging. Finally, our small S.E. and A.H. are supported by a Wellcome Trust Senior sample size of 29 individuals with HNF1B-associated disease Investigator award. means we may have been underpowered to make definitive comments on the comparison of patients with and without diabetes. Supplementary data There is no consensus as to when HNF1B genetic testing should be performed. Two tools have been developed in recent Supplementary data are available at ckj online. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 458 | R.L. Clissold et al. 15. Decramer S, Parant O, Beaufils S et al. Anomalies of the TCF2 References gene are the main cause of fetal bilateral hyperechogenic 1. Coffinier C, Barra J, Babinet C et al. Expression of the vHNF1/ kidneys. J Am Soc Nephrol 2007; 18: 923–933 HNF1b homeoprotein gene during mouse organogenesis. 16. Ulinski T, Lescure S, Beaufils S et al. Renal phenotypes Mech Dev 1999; 89: 211–233 related to hepatocyte nuclear factor-1b (TCF2) mutations in 2. Weber S, Moriniere V, Knuppel T et al. Prevalence of muta- a pediatric cohort. J Am Soc Nephrol 2006; 17: 497–503 tions in renal developmental genes in children with renal 17. 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Clissold RL, Shaw-Smith C, Turnpenny P et al. Chromosome 2001; 68: 219–224 17q12 microdeletions but not intragenic HNF1B mutations 8. Bellanne´-Chantelot C, Chauveau D, Gautier J-F et al. Clinical link developmental kidney disease and psychiatric disorder. spectrum associated with hepatocyte nuclear factor-1b Kidney Int 2016; 90: 203–211 mutations. Ann Intern Med 2004; 140: 510–517 23. Besser REJ, Ludvigsson J, Jones AG et al. Urine C-peptide crea- 9. Haldorsen IS, Vesterhus M, Rder H et al. Lack of pancreatic tinine ratio is a noninvasive alternative to the mixed-meal body and tail in HNF1B mutation carriers. Diabetic Med 2008; tolerance test in children and adults with type 1 diabetes. 25: 782–787 Diabetes Care 2011; 34: 607–609 10. Iwasaki N, Ogata M, Tomonaga O et al. Liver and kidney func- 24. Loser C, Mollgaard A, Folsch UR et al. Faecal elastase 1: a tion in Japanese patients with maturity-onset diabetes of novel, highly sensitive, and specific tubeless pancreatic the young. 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Hum Mol Genet 1999; 8: 2001–2008 tase levels in feces as a marker of exocrine pancreatic function in patients with diabetes mellitus. Lab Med 2016; 47: 140–148 13. Bellanne´-Chantelot C, Clauin S, Chauveau D et al. Large genomic rearrangements in the hepatocyte nuclear factor- 28. Faguer S, Chassaing N, Bandin F et al. The HNF1B score is a simple tool to select patients for HNF1B gene analysis. 1b (TCF2) gene are the most frequent cause of maturity- onset diabetes of the young type 5. Diabetes 2005; 54: Kidney Int 2014; 86: 1007–1015 29. Raaijmakers A, Corveleyn A, Devriendt K et al. Criteria for 3126–3132 HNF1B analysis in patients with congenital abnormalities of 14. Edghill EL, Oram RA, Owens M et al. Hepatocyte nuclear factor-1b gene deletions—a common cause of renal disease. kidney and urinary tract. Nephrol Dial Transplant 2015; 30: Nephrol Dial Transplant 2008; 23: 627–635 835–842 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal disease and can be symptomatic

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Abstract

Background: Heterozygous mutations in the HNF1B gene are the most common monogenic cause of developmental kidney disease. Extrarenal phenotypes frequently occur, including diabetes mellitus and pancreatic hypoplasia; the latter is associated with subclinical exocrine dysfunction. We measured faecal elastase-1 in patients with HNF1B-associated disease regardless of diabetes status and assessed the degree of symptoms associated with pancreatic exocrine deficiency. Methods: Faecal elastase-1 was measured in 29 patients with a known HNF1B mutation. We defined a low faecal elastase-1 concentration based on the 2.5 percentile of 99 healthy control individuals (410 mg/g stool). Symptoms related to pancreatic exocrine dysfunction were assessed and a subset of the HNF1B cohort (n ¼ 6) underwent pancreatic imaging. Results: Faecal elastase-1 was below the 2.5 percentile of the control cohort in 18/29 (62%) patients with HNF1B-associated renal disease. A total of 8/29 (28%) had a measurement suggestive of exocrine pancreatic insufficiency at <200 mg/g stool; of these, 3 suffered with abdominal pain, loose stools and/or unintentional weight loss. All three experienced symptomatic improvement and weight gain after commencing pancreatic enzyme replacement therapy. Faecal elastase-1 was low in 7/15 (47%) HNF1B patients without diabetes compared with 11/14 (79%) of those with diabetes (P ¼ 0.1). Conclusions: Faecal elastase-1 deficiency is a common feature of HNF1B-associated renal disease even when diabetes is not present and pancreatic exocrine deficiency may be more symptomatic than previously suggested. Faecal elastase-1 should be measured in all patients with known HNF1B-associated disease complaining of chronic abdominal pain, loose stools or unintentional weight loss. The discovery of a low faecal elastase-1 concentration in individuals with developmental kidney disease of uncertain cause should prompt referral for HNF1B genetic testing. Key words: developmental kidney disease, diabetes mellitus, faecal elastase, HNF1B, pancreatic hypoplasia Received: August 2, 2017. Editorial decision: November 22, 2017 V The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 454 | R.L. Clissold et al. one case of symptomatic pancreatic exocrine insufficiency requir- Introduction ing treatment in HNF1B-associated disease has been described in Hepatocyte nuclear factor 1b (HNF1B) is a transcription factor theliteraturetodate [21]. In this study, our aims were to measure with important roles in the development of the kidney, pan- faecal elastase-1 in patients with HNF1B-associated disease regard- creas, liver and genital tract [1]. Heterozygous mutations of the less of diabetes status and assess the degree of symptoms associ- HNF1B gene are the most common known monogenic cause of ated with pancreatic exocrine deficiency. developmental kidney disease [2–4]. Despite this single genetic aetiology, the phenotype of HNF1B-associated renal disease is Materials and methods very variable (Box 1). Biochemical abnormalities, including hypomagnesaemia and hyperuricaemia, are also frequently Recruitment and genetic analysis seen [5, 6]. HNF1B-associated disease is a multisystem disorder Participants with HNF1B-associated disease were recruited from 31 and extrarenal phenotypic features include young-onset diabe- January 2013 to 10 October 2015 from three sites in the UK (adult tes mellitus, pancreatic hypoplasia, abnormal liver function renal and diabetes units at the Royal Devon and Exeter Hospital; tests and genital tract malformations [7–12]. Genetic changes paediatric renal units at Great Ormond Street Hospital for Children comprise either HNF1B intragenic mutations (one-half of and Evelina London Children’s Hospital), as previously described patients) or an approximate 1.3-Mb deletion at chromosome [22]. Inclusion criteria included the presence of either an HNF1B 17q12, which includes the entire HNF1B gene [13, 14]. Both may intragenic mutation or whole-gene deletion on genetic testing per- arise spontaneously, which means there is often no family his- formed due to underlying renal abnormalities or diabetes and cur- tory of renal disease or diabetes [15–17]. In view of the clinical rent age 4 years. Informed written consent was obtained from all heterogeneity of the condition and frequent absence of a family adult participants and parents of child participants, with assent history, diagnosis can be challenging and it is likely that many from those <16 years of age. The study was conducted in agree- cases remain undetected. ment with the Declaration of Helsinki principles and approved by a regional ethics committee (National Research Ethics Service Box 1. The variable phenotype of HNF1B-associated Committee South West—Frenchay). A total of 29 patients from 20 unrelated families with HNF1B-associated disease participated. renal disease Mutation screening was performed by sequencing of coding exons Bilateral hyperechogenic kidneys with normal or and exon–intron boundaries together with gene dosage assess- slightly increased size on antenatal ultrasonography ment by multiplex ligation–dependent probe amplification as pre- Renal cysts (including cystic dysplasia and multicystic viously described [14, 17]. dysplastic kindney) Faecal elastase-1 was also measured in a cohort of healthy Single kidney controls in order to define a low faecal elastase-1 concentration Renal hypoplasia based on the 2.5 percentile. Healthy controls were recruited Horseshoe kidney from 4 March 2015 to 19 August 2016 from two sites in the UK Duplex kidney (National Institute for Health Research Exeter Clinical Research Isolated bilateral hydronephrosis and hydroureter Facility at the Royal Devon and Exeter Hospital; Oxford Centre Collecting system abnormality (usually in conjunction for Diabetes, Endocrinology and Metabolism at the Oxford with other renal structural abnormality) University Hospitals National Health Service Foundation Trust). Inclusion criteria included age 16–75 years, ethnicity reflective of local demographics and capacity to consent. Informed writ- Imaging of the pancreas in HNF1B-associated disease with ten consent was obtained from all participants. The study was either computed tomography (CT) or magnetic resonance imag- conducted in agreement with the Declaration of Helsinki princi- ing (MRI) has shown less tissue corresponding to the body and ples and approved by a regional ethics committee (South tail of the pancreas, with a slightly atrophic head [8, 9]. This is West—Frenchay Research Ethics Committee). A total of 99 indi- consistent with agenesis of the dorsal pancreas, the embryonic viduals participated. The median age of this cohort was 61.7 structure that gives rise to the pancreatic body, tail and a small years [interquartile range (IQR) 52.8–66.3]. A total of 39/99 (39%) section of the head. Pancreatic exocrine hypersecretion has was male and all were of White ethnicity. The median faecal been observed in patients with HNF1B-associated disease using elastase-1 concentration was 1580 mg/g stool (IQR 1000–2000). secretin-stimulated MRI and rapid endoscopic secretin stimula- The 2.5 percentile for faecal elastase-1 in this cohort was a con- tion tests; this is likely to be a compensatory mechanism for centration of 410 mg/g stool (Supplementary data, Figure S1). reduced pancreatic volume and provides further evidence that There was only a weak association between increasing age and the small pancreas seen on imaging is due to hypoplasia rather lower faecal elastase-1 concentrations with a Spearman’s q of than atrophy [18]. A report of 20 foetal autopsy cases with 0.2, (P ¼ 0.02) (Supplementary data, Figure S2). HNF1B mutations described pancreatic agenesis in 2/20 and hypoplasia in 13/20 [19]. Clinical evaluation Pancreatic hypoplasia in HNF1B-associated disease has been associated with subclinical pancreatic exocrine insufficiency. Relevant medical details, including symptoms related to pan- This has mainly been studied in small series of patients with creatic exocrine dysfunction (abdominal pain, loose stools HNF1B mutations and diabetes using indirect tests of pancreatic and unintentional weight loss), were documented using a function, usually faecal elastase-1 measurement in stool [8, 9, standardized assessment of medical records and participant/ 20]. Lower exocrine pancreatic function involving both ductal parent interview. Diabetes was diagnosed either according and acinar cells has been confirmed in direct testing with rapid to World Health Organization guidelines or on the basis of endoscopic secretin tests and secretin-stimulated MRI in seven established treatment with oral hypoglycaemic agents/insulin. individuals with HNF1B mutations [18]. To our knowledge, only In order to measure endogenous insulin production, the Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Exocrine pancreatic dysfunction in HNF1B disease | 455 urinary C-peptide creatinine ratio (UCPCR) was measured on a post-prandial urine sample taken approximately 2 h after a meal stimulus [23]. Faecal elastase-1 concentration was assessed by enzyme- linked immunosorbent assay on a single spot stool sample at the Royal Cornwall Hospital; healthy control samples were tested using a 10 dilution to obtain an absolute value for faecal elastase-1, as the majority of samples were expected to have a result greater than the 500 mg/g detection limit of the assay. Faecal elastase-1 <200 mg/g is considered abnormal, with meas- urements of 100–200 mg/g suggestive of moderate to mild pancre- atic exocrine insufficiency and measurements <100 mg/g suggestive of severe insufficiency [24]. Previous imaging results from CT or MRI were reviewed to look for pancreas abnormalities. All patients with HNF1B-associated disease were also invited to undergo pancreatic MRI using a 1.5-T Philips Intera system utiliz- Fig. 1. Bar chart showing the percentage of individuals with HNF1B-associated ing three-dimensional gradient echo and spin echo sequences, disease with faecal elastase-1 (FE-1) measurements <100 mg/g stool (suggestive with and without fat suppression, at a range of orientations. of severe pancreatic exocrine insufficiency), 100–200 mg/g stool (moderate to Images were subsequently reviewed and reported by a consultant mild insufficiency), 200–500 mg/g stool and >500 mg/g stool. The dotted red line radiologist in order to assess pancreatic structure and ensure indicates that 3/99 (3%) healthy controls had an FE-1 measurement of 200–500 mg/g stool whereas in the remainder it was >500 mg/g stool. there were no incidental findings of clinical concern. participants: one was reported to show diffuse pancreatic atro- Statistical analysis phy with calcification of the head and body plus common bile Qualitative variables were described with percentages and duct dilatation, whereas the other three demonstrated absence quantitative variables with median and IQR. Differences or atrophy of the body and tail of the pancreas only. All four between groups were assessed using the Fisher exact test for patients had been diagnosed with diabetes and faecal elastase- categorical variables and the Mann–Whitney U test for conti- 1 measurements ranged from 31 to 280 mg/g stool. Two of six nuous variables. Correlations were tested by Spearman’s q. individuals had scans reported within normal limits. One of A P-value <0.05 was considered to be statistically significant. All these patients was a 20-year-old male without evidence of dia- analyses were carried out using StataSE (version 14; StataCorp, betes and a normal faecal elastase-1 result of 432 mg/g stool. The College Station, TX, USA) and GraphPad statistical software other patient was a 65-year-old female who had been diagnosed (GraphPad Software, La Jolla, CA, USA). with new-onset diabetes after transplantation at the age of 62 years and had a faecal elastase-1 result >500 mg/g stool. Results Markedly low faecal elastase-1 levels are more common Participant characteristics in HNF1B-associated disease when diabetes is present The median age of individuals with HNF1B-associated renal Faecal elastase-1 measurements were compared in individuals disease was 25 years (IQR 14–44) and 13/29 (45%) were male. The with HNF1B-associated disease according to diabetes status. Only majority of the cohort was White, with just 1/29 (3%) being of 1/15 (7%) of those without diabetes had a markedly low faecal mixed ethnicity. A total of 14/29 (48%) had diabetes. elastase-1 measurement (<200 mg/g stool) compared to 7/14 (50%) of those with diabetes (P ¼ 0.01) (Figure 2). Overall, faecal Exocrine pancreatic deficiency is common in HNF1B- elastase-1 levels were low in 7/15 (47%) HNF1B patients without associated disease and can be symptomatic diabetes compared with 11/14 (79%) of those with diabetes (P ¼ 0.1). There was only a weak association between increasing dura- Faecal elastase-1 was low (below the 2.5 percentile of the con- tion of diabetes and lower faecal elastase-1 concentrations, with trol cohort) in 18/29 (62%) patients with HNF1B-associated renal a Spearman’s q of 0.3 (P ¼ 0.4) (Supplementary data,Figure S3). disease. In all, 8/29 (28%) had a faecal elastase-1 concentration The two groups were different with respect to many clinical suggestive of exocrine pancreatic insufficiency at <200 mg/g characteristics (Table 2). The median age of the cohort without stool (Figure 1); in 4/29 (14%) the measurement was <100 mg/g diabetes was 14 years (IQR 9–19) compared to 43.5 years (IQR 34– stool, in keeping with severe deficiency. 55) in the group with diabetes (P ¼ 0.0005). In those patients A total of 3/8 individuals with a faecal elastase-1 measure- with more severe pancreatic disease, endogenous insulin secre- ment <200 mg/g stool suffered with abdominal pain, loose stools tion assessed by the UCP:Cr ratio was lower than in those with- and/or unintentional weight loss. All reported symptomatic out diabetes [median UCP:Cr ratio 1.1 nmol/mmol (IQR 0.6–1.5) improvement and weight gain after commencing pancreatic compared to 2.1 nmol/mmol (1.4–5.6), respectively; P ¼ 0.04]. enzyme replacement therapy. In all three cases it had taken several months for symptoms to be attributed to faecal elastase deficiency and for treatment to be commenced (Table 1). Discussion We have demonstrated that faecal elastase-1 deficiency is com- Individuals with low faecal elastase-1 levels have radio- mon in HNF1B-associated renal disease and exocrine pancreatic logical evidence of pancreatic hypoplasia dysfunction may be more symptomatic than previously pub- In all, 6/29 participants underwent pancreatic imaging with lished. This has important implications for the screening and either CT or MRI. Abnormalities were detected in four of six treatment of these patients. In all, three of eight individuals in Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 456 | R.L. Clissold et al. Table 1. Details of symptomatic faecal elastase deficiency in three individuals with HNF1B-associated renal disease Pancreatic insufficiency Age at study FE-1, Age at entry mg/g diagnosis Patient (years) Sex Genetic abnormality Diabetes status stool (years) Details 2 36 Female Mutation Diagnosed at age 20 90 39 FE-1 measured by renal team after (c.982_986delCCTCT) years, on insulin several months of abdominal pain and diarrhoea; resolution of symp- toms and weight gain after treat- ment commenced 3 61 Female Deletion Haemoglobin A1c of 56 31 63 Known pancreatic atrophy and calcifi- (c.1-?_1674þ? del) mmol/mol identified cation from previous imaging for at age 59 years but abdominal pain under surgical no treatment team. FE-1 measured by gastroen- commenced terology after referral with several months of abdominal pain, loose stools and weight loss; improve- ment in symptoms and 6-kg weight gain after pancreatic enzyme replacement therapy commenced 18 43 Female Deletion Diagnosed at age 107 43 Referred to gastroenterology with (c.1-?_1674þ? del) 32 years, on insulin abdominal pain, diarrhoea (with occasional blood mixed in) and weight loss; colonoscopy performed and found to be normal. FE-1 meas- ured by research team; commenced on pancreatic enzyme replacement therapy with symptomatic improvement del, deletion; FE-1, faecal elastase-1. Fig. 2. Bar charts showing the percentage of individuals with HNF1B-associated disease according to diabetes status with faecal elastase-1 (FE-1) measurements (A) either below or above the 2.5 percentile of a healthy control cohort and (B) <100 mg/g stool (suggestive of severe pancreatic exocrine insufficiency), 100–200 mg/g stool (moderate to mild insufficiency), 200–500 mg/g stool and >500 mg/g stool. this study with a faecal elastase-1 measurement <200 mg/g stool symptomatic improvement with weight gain once treatment had abdominal pain, loose stools and weight loss. The only pub- with pancreatic enzyme replacement therapy was commenced. lished report of symptomatic pancreatic insufficiency in This highlights how difficult it can be to diagnose pancreatic HNF1B-associated disease involved the identification of diabe- insufficiency and how prompt treatment benefits patients. tes and a small pancreas on imaging in an individual 5 years of Clinicians should have a low threshold for arranging pancreatic age; pancreatic enzyme replacement therapy became necessary function testing for individuals with known HNF1B-associated from the age of 16 years and lead to a normalization of body disease, even when subtle symptoms such as mild abdominal mass index [21]. There was a significant delay in attributing discomfort and bloating are present. symptoms to pancreatic insufficiency in the three cases identi- This is the largest series of faecal elastase-1 measurements fied in this article, and one of the patients even underwent a in individuals with HNF1B-associated renal disease recruited colonoscopy before the correct diagnosis was made. All showed irrespective of diabetes status; previous reports of faecal Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Exocrine pancreatic dysfunction in HNF1B disease | 457 Table 2. Characteristics of individuals with HNF1B-associated disease according to diabetes status Feature HNF1B-associated disease, no DM (n ¼ 15) HNF1B-associated disease with DM (n ¼ 14) P-value Age (years), median (IQR) 14 (9–19) 43.5 (34–55) 0.0005 Sex, n (%) Male 9 (60), Female 6 (40) Male 4 (29), Female 10 (71) 0.1 Genetic abnormality, n (%) Mut 9 (60), del 6 (40) Mut 7 (50), del 7 (50) 0.7 BMI (kg/m ), median (IQR) 20 (18–27) 23 (20–25) 0.1 Creatinine (mmol/L), median (IQR) 79 (55–115) 116 (90–144) 0.03 HbA1c (mmol/mol), median (IQR) 39 (37–42) 60 (55–74) 0.0005 UCP:Cr ratio (nmol/mmol), median (IQR) 2.1 (1.4–5.6) 1.1 (0.6–1.5) 0.04 del, deletion; DM, diabetes mellitus; mut, mutation. elastase deficiency in association with an HNF1B mutation have years to help select individuals who would benefit from screen- usually been from smaller series of patients with diabetes or ing: the HNF1B score designed by Faguer et al. [28] and adapted prediabetes [8, 9, 18, 20]. Tjora et al. [18] included one patient criteria for HNF1B analysis proposed by Raaijmakers et al. [29]. with an HNF1B mutation and normal glucose tolerance in their However, faecal elastase was not systematically assessed in study of exocrine pancreatic function using direct testing; this either of these studies. It is cheap and easy to measure, requir- individual was 38 years old with normal pancreas anatomy on ing only a single spot stool sample. Given that low faecal imaging and a faecal elastase-1 measurement of 312 mg/g stool. elastase-1 concentrations were seen in 18/29 (62%) patients An earlier study from the same group recruited an affected 6- with HNF1B-associated renal disease in this study, it would be year-old girl with no pancreatic body and tail identified on interesting to test the role of faecal elastase-1 as a biomarker for imaging and a faecal elastase-1 concentration of 131 mg/g stool; HNF1B-associated disease in a large cohort of individuals with she had developed impaired glucose tolerance when studied congenital anomalies of the kidneys and urinary tract. In the again at the age of 8 years [9, 18]. We included 15 HNF1B interim, we suggest that the finding of a low faecal elastase patients without diabetes in this study; 7/15 (47%) had a low fae- measurement in individuals with developmental kidney dis- cal elastase-1 measurement but only 1/15 (7%) had a measure- ease of uncertain cause should prompt referral for HNF1B ment of <200 mg/g stool. We would hypothesize that pancreatic genetic testing. insufficiency and diabetes in HNF1B-associated disease are associated, as they are secondary to reduced exocrine and endo- crine cells as a result of pancreatic hypoplasia. However, cau- Conclusion tion must be applied when interpreting the results between the HNF1B cohorts with and without diabetes, as any differences In summary, faecal elastase-1 deficiency is an important feature may reflect the discrepancy in age between the two groups. It of HNF1B-associated renal disease even when diabetes is not would be very interesting in future work to follow a cohort of present. Faecal elastase-1 should be measured in all individuals paediatric patients with HNF1B mutations over time using serial with an HNF1B mutation complaining of abdominal pain, loose indirect pancreatic function testing and imaging to see if these stools or unintentional weight loss. The role of faecal elastase-1 non-invasive tests can be used to predict who will develop dia- as a biomarker for HNF1B-associated disease requires further betes and exocrine insufficiency and at what age. investigation. Several limitations were associated with this work. The cohort of healthy controls used to define the lower limit of the Acknowledgements normal range for faecal elastase-1 were older; the median age was 61.7 years (IQR 52.8–66.3) compared to 24.5 years (IQR 14–44) We would like to thank Professor Tim Frayling from the in the individuals with HNF1B-associated renal disease. University of Exeter for the use of the faecal elastase-1 However, faecal elastase concentrations decline with age, so results from a local cohort of healthy controls and Professor defining a cut-off for faecal elastase-1 using the 2.5 percentile of Ingfrid Haldorsen from Haukeland University Hospital for a younger control cohort may have yielded an even greater advice on pancreatic MRI. value than the 410 mg/g stool used in this study [25]. The median faecal elastase-1 measurement of 1580 mg/g stool (IQR 1000– 2000) in our local control cohort is higher than values reported Funding for healthy controls in other studies [25–27]. This may reflect assay differences between laboratories but, as we have defined R.C. is supported by a Medical Research Council Clinical low faecal elastase-1 as measurements that fall below the 2.5 Training Fellowship (grant reference number MR/J011630/1). percentile of a local healthy control group, this make our results B.S. and A.H. are core members of the National Institute for generalizable. Furthermore, we found that our local cut-off of Health Research Exeter Clinical Research Facility. A.H. is a 410 mg/g stool correlated with the presence or absence of pan- National Institute for Health Research Senior Investigator. creatic hypoplasia on radiological imaging. Finally, our small S.E. and A.H. are supported by a Wellcome Trust Senior sample size of 29 individuals with HNF1B-associated disease Investigator award. means we may have been underpowered to make definitive comments on the comparison of patients with and without diabetes. Supplementary data There is no consensus as to when HNF1B genetic testing should be performed. Two tools have been developed in recent Supplementary data are available at ckj online. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018 458 | R.L. Clissold et al. 15. Decramer S, Parant O, Beaufils S et al. Anomalies of the TCF2 References gene are the main cause of fetal bilateral hyperechogenic 1. Coffinier C, Barra J, Babinet C et al. Expression of the vHNF1/ kidneys. J Am Soc Nephrol 2007; 18: 923–933 HNF1b homeoprotein gene during mouse organogenesis. 16. Ulinski T, Lescure S, Beaufils S et al. Renal phenotypes Mech Dev 1999; 89: 211–233 related to hepatocyte nuclear factor-1b (TCF2) mutations in 2. Weber S, Moriniere V, Knuppel T et al. Prevalence of muta- a pediatric cohort. J Am Soc Nephrol 2006; 17: 497–503 tions in renal developmental genes in children with renal 17. 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Nephrol Dial Transplant 2015; 30: Nephrol Dial Transplant 2008; 23: 627–635 835–842 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/453/4830060 by Ed 'DeepDyve' Gillespie user on 07 August 2018

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Clinical Kidney JournalOxford University Press

Published: Aug 1, 2018

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