Long-term outcome in inherited nephrogenic diabetes insipidus

Long-term outcome in inherited nephrogenic diabetes insipidus Clinical Kidney Journal, 2018, 1–8 doi: 10.1093/ckj/sfy027 Original Article OR I G I N AL A R T I C L E Long-term outcome in inherited nephrogenic diabetes insipidus 1,2 3 3,4 5,6 Sonia Sharma , Emma Ashton , Daniela Iancu , Marie-Francoise Arthus , 1 1 1,4 5,6 Wesley Hayes , William van’t Hoff , Robert Kleta , Daniel G. Bichet and 1,4 Detlef Bockenhauer Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, 2 3 London, UK, Max Super Speciality Hospital & PSRI Hospital, New Delhi, India, North East Thames Regional Genetics Service Laboratories, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK, 4 5 Centre for Nephrology, University College London, London, UK, Departments of Medicine, Pharmacology and Physiology, Universite ´ de Montre ´ al, Montre ´ al, Que ´ bec, Canada and Unite ´ de recherche clinique, Centre de recherche et Service de ne ´ phrologie, Ho ˆ pital du Sacre ´ -Coeur de Montre ´ al, Que ´ bec, Canada Correspondence and offprint requests to: Detlef Bockenhauer; E-mail: d.bockenhauer@ucl.ac.uk ABSTRACT Background. Inherited nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by impaired urinary concentrating ability. Little clinical data on long-term outcome exists. Method. This was a single-centre retrospective medical record review of patients with a diagnosis of NDI followed between 1985 and 2017. We collected available data on growth, weight, school performance, complications and comorbidities. Results. We identified 36 patients with available data and a clinical diagnosis of NDI, which was genetically confirmed in 33 of them. Patients presented at a median age of 0.6 years and median length of follow-up was 9.5 years. Chief symptoms at presentation were faltering growth, vomiting/feeding concerns, polyuria/polydipsia, febrile illness and hypernatraemic dehydration. Median weight standard deviation scores (SDS) improved from 2.1 at presentation to 0.2 at last follow-up. In contrast, height SDS remained essentially unchanged at 1.1 at presentation and 0.9 at last follow-up. Most patients were treated with prostaglandin synthesis inhibitors and thiazides, yet weaned off during school age without an obvious change in urine output. Median estimated glomerular filtration rate at last follow-up was 81 mL/min/1.73 m . Urological complications were noted in 15 patients, constipation in 11 and learning difficulties in 5. Median age at resolution of nocturnal enuresis was 11 years. Estimated median daily fluid intake at median age of 13 years was 3800 mL/m . Conclusion. The overall prognosis in inherited NDI is favourable with regular treatment. As expected, most complications were related to polyuria. There is an apparent loss of efficacy of medications during school age. Our data inform the prognosis and management of patients with NDI. Keywords: AVPR2, AQP2, congenital nephrogenic diabetes insipidus, hypernatraemia, polyuria Received: 4.12.2017. Editorial decision: 22.2.2018 V C 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 Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| S. Sharma et al. Molecular details INTRODUCTION Twenty-six patients had mutations in AVPR2 (all boys) and Inherited nephrogenic diabetes insipidus (NDI) is a rare disorder seven in AQP2 (four boys, three girls) (Table 1). All were in- characterized by an insensitivity of the kidneys to arginine- herited in a recessive fashion. Mutations and selected clinical vasopressin (AVP) and a consequent inability to concentrate the details for some patients have been reported previously [9–12]. urine [1]. There are primary and secondary forms of inherited NDI [2]. In primary inherited NDI, we distinguish between an X- linked form, due to mutations in the gene encoding the vaso- Presenting features pressin type 2 receptor, namely arginine vasopressin receptor-2 Congenital NDI was diagnosed during the first year of life in (AVPR2) and an autosomal form, due to mutations in the gene 23 (69%) patients. The median age of diagnosis was 0.6 years encoding the water channel aquaporin2 (AQP2). In addition to (range 0.01–9). A family history of NDI was noted in 11 patients. NDI, patients with the X-linked form also have an impaired hae- One patient (23.2) had a prenatal diagnosis. Chief complaints at modynamic and coagulation response to AVPR2 stimulation [3]. time of admission were faltering growth, vomiting, polyuria/ Both forms are typically inherited in a recessive fashion, polydipsia and febrile illness with hypernatraemic dehydration although rare dominant cases have been described [4]. (Figure 1). Four (12%) were investigated due to a positive family Approximately 90% of cases are due to mutations in AVPR2 and history. to date more than 250 mutations have been described. As with Ten patients were treated for a different diagnosis before the most rare diseases, little long-term clinical data exists to inform establishment of NDI, most commonly gastroesophageal reflux management and prognosis. Previous reports have highlighted disease (n¼ 5). A pyloric web was diagnosed in one case (26), the potential complications of flow uropathy, behavioural based on vomiting and hypernatraemia, and surgically cor- abnormalities, such as attention deficit disorders as well as se- rected. One patient (19) was given an initial diagnosis of central vere developmental delay, sometimes associated with intracra- DI at his local hospital based on a partial response to 1-desa- nial calcifications [5–7]. Some of these, such as the mino-8-D-arginine vasopressin (DDAVP) (maximal urine osmo- developmental delay and the intracranial calcification, are con- lality 602 mOsm/kg), but was subsequently found to have a sidered preventable by appropriate treatment. Here we review clinical diagnosis of partial NDI, confirmed by genetic testing. the clinical course of patients in the tubulopathy clinic at Great Interestingly, a repeat DDAVP test at the age of 10 years showed Ormond Street Hospital (GOSH) for Children NHS Foundation no response to DDAVP. Two premature neonates (18, 20) were Trust. diagnosed in the neonatal intensive care unit based on polyuria. One patient (21) presented with global developmental delay and hypernatraemic dehydration at the age of 0.6 years. Magnetic MATERIALS AND METHODS resonance imaging of the brain had been performed in five pa- We performed a retrospective review of the medical records of tients. One patient (15) showed signs suggestive of myelinolysis patients with a clinical diagnosis of primary congenital NDI after experiencing severe acute hypernatraemia in the context who were followed in the specialized clinic for tubular disorders of treatment with 0.9% saline [12]. at GOSH between 1985 and 2017. We ascertained available mo- Median SDS or score and range for height at presentation lecular, as well as clinical data, including symptoms and age was 1.06 (4.94 to 1.9) and for weight: 2.1 (8.25 to 2.6). at presentation and last follow-up, family history, medical Weight for length (for children <3 years), SDS was 1.98 (7.5 to treatments, growth indicators, complications, comorbidities 2.3). and biochemical parameters (plasma sodium, creatinine and osmolality, as well as urine osmolality) at the time of presenta- Feeding tion and at last follow-up. Patients without genetic confirm- ation of the diagnosis were excluded from the main analysis to Treatment included input from a renal dietician and an osmotic maintain a clearly defined cohort. Standard deviation scores load<15 mOsm/kg was targeted. Tube feeding was performed (SDS) for anthropometric measures were calculated using in 34% (n¼ 12) of which 24% (n¼ 8) were fed via gastrostomy. growth charts based on National Health and Nutrition The indication for tube feeding was persistent growth failure in Examination Survey (NHANES), center for disease control (CDC)/ all (weight<0.4th percentile for age and no evidence of catch-up National Center for Health Statistics. Estimated glomerular fil- growth). Initially, a nasogastric tube was placed and, if tube tration rate (eGFR) was calculated with the Schwartz formula feeding was deemed necessary for several months, a gastros- modified for GOSH, using a k-value of 33 [8]. Statistical calcula- tomy was considered. Tube feeding was discontinued at a me- tions were performed using Microsoft Excel 2011 and GraphPad dian age of 2 years (range 2–4) once growth failure had resolved Prism software. and oral intake was deemed adequate. Medications RESULTS For drug treatment, all patients bar one (25) received thiazides Patients at diagnosis and 28 (84%) received an additional prostaglandin We identified 41 patients with a clinical diagnosis of NDI. Five synthesis inhibitor (PSI), mostly indomethacin (n¼ 25), or, alter- patients were excluded, due to untraceable records. The re- natively, celecoxib (n¼ 2) or ibuprofen (n¼ 1). PSI was discontin- maining 36 patients all had genetic testing performed and the ued in 10 (indomethacin in 9, ibuprofen in 1) because of diagnosis was confirmed in 33, of which 29 were male. Median perceived lack of efficacy at median age 12 years (range 4–16). In follow-up was 9.5 years (range 0.8–16.8) and median age at last addition, it was changed to celecoxib in one patient (15, at age follow-up was 11.9 years (range 0.8–17). 3 years) due to a gastrointestinal bleed and stopped in another Details of selected genetic and clinical data are presented in one (7.1) due to concerns over renal function associated with an Table 1. obstructive uropathy (at age 12 years). Five patients (2.3, 6, 7.2, Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Clinical outcomes in inherited NDI | 3 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 1. Clinical and molecular details of the 33 patients with identified causative mutations Genetic details Clinical details At presentation At last follow-up Plasma eGFR Uosm after eGFR Age osmolality (mL/min/ DDAVP Weight Height Age Weight Height (mL/min/ Remarks (complications/ 2 2 Nucleotide Protein Sex (years) (mOsm/kg) 1.73 m ) (mOsm/kg) SDS SDS (years) SDS SDS 1.73 m ) Meds comorbidities) Patients with mutations in AVPR2 1 c.851G>A p.(Trp284*) M 0.25 304 43 65 2.62 1.25 11.9 0.02 1.68 90 Indomethacin, thiazide Feeding difficulty, esophagitis 2.1 c.999dup p.(Ser334Leufs*23) M 0.016 300 44 73 0.44 0.51 15.3 1.03 1.16 76 Indomethacin, thiazide Transient hydronephrosis, large bladder, PVR, constipation 2.2 c.999dup p.(Ser334Leufs*23) M 0.021 310 34 53 0.84 0.89 16.7 0.34 0.53 75 Indomethacin, thiazide Hydronephrosis, constipation 2.3 c.999dup p.(Ser334Leufs*23) M 0.08 310 45 50 0.73 1.06 17 0.08 1.13 77 Indomethacin, thiazide ADHD, impaired concentration, mild hydronephrosis 2.4 c.999dup p.(Ser334Leufs*23) M 0.16 307 38 89 0.87 0.54 17 0.01 0.86 65 Indomethacin, thiazide Mild hydronephrosis, migraine 3 c.871C>T p.(Glu291*) M 0.83 304 54 111 0.91 0.76 16.3 0.29 0.89 79 Indomethacin, thiazide 4 c.27_54del p.(Val10Cysfs*18) M 0.3 301 43 129 3.01 0.86 14.1 1.49 0.92 76 Indomethacin, thiazide Transient hydronephrosis, growth hormone deficiency, impaired concentration 5 c.299del p.(Lys100Argfs*16) M 0.58 325 44 40 2.61 2.02 11.8 0.74 0.7 72 Indomethacin, thiazide Constipation 6 c.332T>C p.(Leu211Pro) M 0.66 354 34 197 4.08 3.19 14.2 1.11 2.4 106 Indomethacin, thiazide Constipation 7.1 c.262G>A p.(Val88Met) M 2 294 83 570 2.8 2.87 1 0.51 0.37 81 Indomethacin, thiazide Hydronephrosis, large bladder, PVR, constipation 7.2 c.262G>A p.(Val88Met) M 0.04 292 26 63 1.88 1.59 10 0.27 0.01 92 Indomethacin, thiazide ADHD, impaired concentration/ school performance 8 c.316C>T p.(Arg106Cys) M 2.9 294 140 173 1.78 1.56 17 0.31 0.97 85 Indomethacin, thiazide 9 c.809_810del p.(Val270Glyfs*86) M 0.5 319 69 173 3.38 2.25 10 0.19 0.66 95 Indomethacin, thiazide Mild hydronephrosis, constipation 10.1 c.316C>T p.(Arg106Cys) M 7 298 63 50 0.9 0.45 15 0.37 0.27 70 Indomethacin, thiazide Hydronephrosis, large bladder, PVR, PUV with left VUR 10.2 c.316C>T p.(Arg106Cys) M 9 N/A 89 220 1.39 0.62 14 0.82 0.78 80 Indomethacin, thiazides Hydronephrosis, constipation 11.1 c. (-1069_1007) p.? M 0.15 320 54 114 0.96 1.17 9 1.57 0.38 66 Indomethacin, thiazide del ins168 11.2 c.(-1069_1007) p.? M 0.5 328 41 179 2.66 0.33 5 0.92 0.68 67 Indomethacin, amiloride, ADHD, impaired concentration del ins168 thiazide 12 c.del970 p.(Ile324Serfs*112) M 8 298 69 55 2.6 1.59 17 0.92 1.42 56 Thiazide Hydronephrosis, single kidney, large bladder þ PVR 13 c.491G>A p.(W146X) M 1.83 277 103 44 2.55 2.13 15 0.7 0.23 86 Indomethacin, thiazide Large bladder, PVR, ADHD, dys- lexia mild hydronephrosis (continued) 4| S. Sharma et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 1. (Continued) Genetic details Clinical details At presentation At last follow-up Plasma eGFR Uosm after eGFR Age osmolality (mL/min/ DDAVP Weight Height Age Weight Height (mL/min/ Remarks (complications/ 2 2 Nucleotide Protein Sex (years) (mOsm/kg) 1.73 m ) (mOsm/kg) SDS SDS (years) SDS SDS 1.73 m ) Meds comorbidities) 14 c.357G>C p.(Glu119His) M 0.16 359 45 50 2.25 14 0.98 1.54 91 Indomethacin, thiazides 15 c.599G>A p.(Trp200*) M 1.66 290 102 147 1.98 1.02 3 1.64 1.3 114 Indomethacin, thiazide, Transient neurological impair- amiloride ment associated with acute hypernatraemia 16 c.604C>T p.(Arg202Cys) M 0.58 287 111 76 2.83 0.33 2.2 1.65 3.5 90 Amiloride, thiazide 17 c.(?-1) _(*1_?) p.? M 0.03 337 49 185 0.34 0.89 0.83 1.06 0.76 89 Celecoxib, thiazide del 18 c.348C>G p.(Lys116Asn) M 0.91 298 73 95 4.47 4.02 3.6 1.89 4.15 81 Indomethacin, thiazide, IUGR, necrotizing enterocolitis amiloride 19 c.830T>C p.(Val277Ala) M 8 338 41 73 2.2 1.9 16 2.3 2.1 83 Indomethacin, thiazide 20 c.332T>C p.(Leu111Pro) M 0.01 293 95 65 2.42 1.06 6.1 1.43 0.34 66 Celecoxib, thiazide, Rhomboencephalo-synapsis amiloride Patients with mutations in AQP2 21 c.377C>T p.(Thr126Met) M 0.58 354 62 95 2.8 2.97 13 0.23 0.9 60 Indomethacin, thiazide Global developmental delay 22 c.253C>T p.(Arg85*) M 3.6 304 85 177 1.49 1.86 17 3.06 1.39 81 Ibuprofen, thiazide Left hydronephrosis with 10% divided function, large blad- der, PVR 23.1 c.337C>T p.(Arg113Cys) F 0.33 340 45 158 2.83 2.23 7.9 2.58 2.85 67 Indomethacin, thiazide Constipation 23.2 c.337C>T p.(Arg113Cys) F0 280 52 114 2.55 1.33 3 2.75 1.72 97 Indomethacin, thiazide Constipation 24 c.211G>A p.(Val71Met) F 0.25 350 69 158 2.1 0.59 16 1.54 1.67 72 Indomethacin, thiazide Hydronephrosis 25 c.299G>T/ p.(Gly100Val)/ M 6.5 284 50 86 4.65 2.02 10.5 1.51 3.02 84 Celecoxib c.763C>T p.(Gln255*) 26 c.211G>A p.(Val71Met) M 1.75 295 107 100 8.25 4.94 5 1.92 1.32 129 Indomethacin, thiazide Mild hydronephrosis, constipation Shown are pertinent molecular and clinical details. Mutations in AQP2 are all homozygous, except for Patient 25, who is compound heterozygous. ‘?’ is standard genetic annotation for Unknown. Uosm, urine osmolality; PUV, posterior urethral valves; VUR, vesico-ureteric reflux; IUGR, intra-uterine growth retardation. Clinical outcomes in inherited NDI | 5 Biochemistries at last follow-up showed persistent NDI with a median (range) urine osmolality of 84 (31–215) mOsm/kg, but now with normal plasma values: median osmolality 292 (281– 307) mOsm/kg and sodium 143 (133–149) mmol/L. Growth Median SDS or z-score for weight (range) improved from: 2.1 (8.3 to 2.6) at presentation to 0.2 (2.8 to 3) at last follow-up (Table 2). In contrast, height SDS (range) remained essentially unchanged: 1.06 (4.94 to 1.9) at presentation and 0.9 (4.2 to 1.3) at last follow-up. Urological problems Urological complications were noted in 46% (n¼ 15) of patients. Nocturnal enuresis and incomplete voiding were the most com- mon concerns. Large bladder capacity and incomplete bladder emptying was noted in eight patients. During follow-up of mild- to-moderate severity, unilateral or bilateral hydronephosis was noticed in 14 patients and 7 of these had persistence of hydro- nephrosis and a large bladder capacity, whereas in 7 the dilata- tion was only mild and transient (Figure 2). Resolution of nocturnal enuresis was seen in 19 patients at a median age of FIGURE 1: Symptoms at initial presentation. Shown is the frequency of the chief 11.3 (range 5–16) years. Interestingly, one child (7.1) with partial complaints at presentation. NDI had resolution of nocturnal enuresis with desmopressin 20 and 25) switched from indomethacin to ibuprofen due to dif- therapy [9]. One patient (10.1) with hydronephrosis and multiple ficulties with medication availability. One patient (25) de- urinary tract infection was found to have posterior urethral veloped nausea after commencement of celecoxib and it was valves, and had a left nephroureterectomy and Mitrofanoff for- changed to ibuprofen. One patient (2.2) developed severe hydro- mation [10]. His brother (10.2) shared the diagnosis of NDI but nephrosis and a distended bladder with a volume of 1500 mL had no evidence of an obstructive uropathy. and post-void residual (PVR), which was noted for a first few months after stopping indomethacin. The drug was restarted Estimated glomerular filtration rate but without apparent change in urine volume and the hydro- Median eGFR at last follow-up was 81 (range 56–129) mL/min/ nephrosis persisted. The median daily dose of indomethacin at 1.73 m and was comparable between patients with AVPR2 and the time of discontinuation due to perceived lack of efficacy AQP2 mutations (Table 2). was available in eight patients and was 1.1 mg/kg (range 0.4– Fluid intake at last follow-up, as estimated by patients and/ 1.7). Those patients continuing indomethacin (n¼ 7) were pre- or family was available in 28 patients. Estimated median daily scribed at last follow-up a median daily dose of 1.4 mg/kg. fluid intake at a median age of 13 years was 3800 mL/m (range Similarly, thiazides were discontinued in eight patients at a 1600–9200). median age of 14 years (range 5–17). At this age, all eight were receiving bendroflumethiazide with a median daily dose of 0.08 mg/kg (range 0.06–0.11). In those continuing bendroflu- Constipation methiazide (n¼ 15), the median prescribed daily dose was Constipation remained a concern in our cohort in 11 patients. It 0.1 mg/kg. Urine output was not formally measured before and was often noted during the initial years with mild-to-moderate after stopping medications, but patients reported no apparent severity. Regular intake of laxatives was prescribed in most of change. these patients. Amiloride was given in four patients (Table 1) to maintain normokalaemia. Apart from these drugs, potassium chloride Intelligence and school performance was prescribed in 19% of patients. Other prescribed medications mostly included laxatives, antacids and prokinetics. Five pa- One patient (21) had severe global developmental delay already tients were able to stop all medications at median age of noted at his presentation at 7 months of age with faltering 14 years (12.56 3.8). growth and hypernatraemic (170 mmol/L) dehydration. Data on learning or behaviour problems were available in 5 (17.8%) out of 28 school-age children, who had been diagnosed with atten- tion-deficit hyperactivity disorder (ADHD) and/or learning diffi- Biochemistries culties and/or impaired concentration (Table 1). Biochemistries at presentation were consistent with the clinical No complaints on school performance were noted in the re- diagnosis of NDI: median (range) for urine osmolality was 86 cords of the remaining patients. (46–177) mOsm/kg, for plasma osmolality 303 (277–359) mOsm/kg and for plasma sodium 148 (133–177) mmol/L. Median eGFR at Genotype–phenotype correlation presentation was 54 mL/min/1.73 m (range 26–140). Interestingly, urine osmolality in patient 7.1 increased after We compared clinical parameters of the 26 patients with AVPR2 DDAVP to 570 mOsm/kg, consistent with a diagnosis of partial mutations to the 7 with AQP2 mutation. No significant differ- NDI [9]. ence was seen (see Table 2). Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| S. Sharma et al. Patients without genetic confirmation In three patients, no mutation in AVPR2 or AQP2 could be identi- fied: two male siblings and one female child presented at a median age of 0.16 (range 0.01–0.16) years. Further genetic analysis showed that both brothers had inherited the same X-chromosome from their mother. The girl, born to consanguin- eous parents, was homozygous at the AQP2 locus. Thus, it is pos- sible that these three patients have non-coding mutations in these genes, which were not assessed by the testing procedure in the laboratory. All three were unresponsive to intravenous DDAVP at presentation with median maximum osmolality of 97 (range 91–114) mOsm/kg, consistent with NDI. There were no clinical features that would suggest a diagnosis of secondary NDI [2, 13]. Median plasma sodium at presentation was 154 (150–157) mmol/L and osmolality 309 (307–317) mOsm/kg. Of specific inter- est was a spontaneous improvement of urinary concentrating ability in the two brothers, with a DDAVP test at 11 and 15 years of age showing a maximum urine osmolality of 536 and 752 mOsm/kg, respectively (Table 3). DISCUSSION We here report long-term clinical data on a single-centre cohort of patients with congenital NDI. Overall, our data show a favourable outcome: growth is in the normal range for the vast majority of patients, although median height at follow-up was slightly below the average at 0.9 SDS. Kidney function, as as- sessed by eGFR at last follow-up, was within chronic kidney dis- ease (CKD) Stages 1 or 2 in all except for Patient 12, who was born with a single kidney. Previous reports have highlighted the complications of NDI with regards to intellectual function [6, 14, 15]. Unfortunately, data on school performance were not systematically captured in the medical records and thus may be underestimated in our study, but intellectual and/or behavioural problems were noted in five patients (see Table 1), mostly in the form of a diagnosis of ADHD and/or impaired concentration and learning difficulties. This is considerably less than in a previous report where patients were systematically assessed and almost half had a diagnosis of ADHD and 70% a low score on short-term memory [5]. It has been debated whether ADHD is an intrinsic aspect of the disorder, as there are data suggesting at least temporary expression of AVPR2 in the brain, as well as an effect of AVP on learning and memory [16, 17]. Moreover, AVPR2 knock-out mice show altered expres- sion of genes in the hypothalamus [18]. Alternatively, ADHD and problems with concentration or memory may be secondary to the constant craving for water and the frequent need to void. In this context, it is interesting that we saw this complication only in patients with AVPR2. Yet, this difference in the proportion of patients with noted learning or behavioural problems was not statistically significant between AVPR2 and AQP2 (P¼ 0.2). Early reports on patients with NDI suggested severe intellec- tual impairment as an almost invariant feature of the disease, but subsequent observations indicate that this complication can be prevented in most by adequate treatment [5, 6, 15]. The latter is consistent with our observations here, as we saw severe global developmental delay in only one patient (21). Interestingly, while presenting with hypernatraemic dehydra- tion, his features were not substantially different from other pa- tients in this cohort. It is thus unclear whether for some reason this patient is more susceptible to brain damage, or whether his developmental delay is unrelated to the NDI. Brain imaging to assess for intracerebral calcifications had not been performed. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 2. Comparison between patient with AVPR2 and AQP2 mutations At presentation At last follow-up Median eGFR Median eGFR No. with Age of resolution No. with reported Median height Median weight (mL/min/ Median height Median weight (mL/min/ urological of nocturnal school/behavioural 2 2 Gene SDS (range) SDS (range) 1.73 m ) (range) SDS (range) SDS (range) 1.73 m ) (range) complication (%) enuresis complications AVPR2 1.0 (4 to 1.9) 1.9 (4.5 to 2.6) 51 (26–140) 0.7 (4.2 to 1.3) 0.3 (1.9 to 1.6) 80.5 (56–114) 10 (38.5) 10 (4–15) 5 AQP2 2.0 (4.9 to  0.6) 2.8 (8.3 to 1.5) 61 (45–107) 1.7 (3to 0.9) 1.5 (2.8 to 3) 81 (59.6–129) 5 (71) 12.4 (9.4–14) 0 Combined 1.1 (4.9 to 1.9) 2.1 (8.3 to 2.6) 54 (26–140) 0.9 (4.2 to 1.3) 0.2 (2.8 to 3) 81 (56–129) 15 (46) 11.3 (4–15) 5 Shown are selected data for patients with X-linked versus autosomal NDI. No significant differences were seen. Clinical outcomes in inherited NDI | 7 FIGURE 2: Examples of flow uropathy. Shown are ultrasound images detailing flow uropathy. (A) Marked hydronephrosis of single right kidney with loss of renal cortex in Patient 22 (at age 17 years). (B) Hydronephrosis, (C) Dilated bladder and ureter, (D) PVR in Patient 2.1 (all images at age 15 years). Hydronephrosis in this patient de- veloped after the age of 8 years. Table 3. Spontaneous improvement in urinary concentration in the two brothers without identified mutation Presentation Last follow-up Patient Age (months) Posm (mOsm/kg) Max Uosm after DDAVP Age (years) Posm (mOsm/kg) Max Uosm after DDAVP 28.1 1.5 317 114 15.3 298 536 28.2 0.1 309 91 11.5 285 752 Shown are data on urinary concentration. Patient 28.1 presented at the age of 1 month with recurrent vomiting and hypernatraemia. His brother 28.2 was electively re- viewed at 3 days of age due to the family history. Both received a clinical diagnosis of NDI based on the inappropriately low urine osmolality. Both showed a spontan- eous improvement in symptoms and urinary concentration over time. Uosm, urine osmolality; Posm, plasma osmolality. Overall our data are consistent with the notion that severe There were no episodes of hypernatraemic dehydration after intellectual impairment can be prevented with adequate diagnosis and start of treatment apparent from the biochemis- treatment. try results available at GOSH. Yet, since GOSH is a pure tertiary Yet, despite the overall favourable prognosis, patients clearly paediatric center without provision of primary or emergency have complications from the polyuria. Almost half of all pa- care, acute illnesses would have presented to the respective tients had radiological evidence of a flow uropathy. While this local hospital and thus would not be systematically captured or was only transient in some it was severe in others and associ- reflected in laboratory results obtained at GOSH. ated with loss of renal cortex in one (22) (Figure 2). Similarly, Of interest is the apparent change in response to medical nocturnal enuresis was a common problem and resolution was treatment. Thiazide and PSI have been shown to effectively re- much delayed at a median age of over 11 years. Typical advice duce urine output in NDI during the first few years of life and treatment given to patients with nocturnal enuresis, such [19, 20]. Indeed, one patient (2.1) developed asymptomatic hypo- as decreased fluid intake before bedtime or DDAVP tablets, obvi- natraemia (130 mmol/L) after commencement of indomethacin ously does not work in patients with NDI. and the drug was transiently withheld. Yet, in our experience, Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 8| S. Sharma et al. 4. Bichet DG, Bockenhauer D. Genetic forms of nephrogenic many patients stop medications during school age without noticing an appreciable difference in urine output. While diabetes insipidus (NDI): vasopressin receptor defect (X- Patient 2.2 developed severe hydronephrosis first noted linked) and aquaporin defect (autosomal recessive and dom- 4 months after stopping indomethacin, this did not improve inant). Best Pract Res Clin Endocrinol Metab 2016; 30: 263–276 after restarting the medication. Moreover, his last previous 5. Hoekstra JA, van Lieburg AF, Monnens LA et al. Cognitive ultrasound, which showed no dilatation, had been 5 years ear- and psychosocial functioning of patients with congenital nephrogenic diabetes insipidus. Am J Med Genet 1996; 61: lier and thus it is likely that the hydronephrosis had developed even before the medication was stopped and was related to vol- 81–88 untary urinary retention, reflected in his large bladder volume. 6. van Lieburg AF, Knoers NV, Monnens LA. Clinical presenta- Medications were typically discontinued during teenage years, tion and follow-up of 30 patients with congenital nephro- genic diabetes insipidus. J Am Soc Nephrol 1999; 10: 1958–1964 an age in which adherence to medications is a common prob- lem [21]. Indeed, one patient (2.3) openly admitted that he had 7. Schofer O, Beetz R, Kruse K et al. Nephrogenic diabetes insipidus stopped taking the medications and in others, either the patient and intracerebral calcification. Arch Dis Child 1990; 65: 885–887 or a parent had reported intermittent missed doses. Thus, 8. Gonzalez Celedon C, Bitsori M, Tullus K. Progression of chronic renal failure in children with dysplastic kidneys. whether the apparent lack of efficacy reflects a true change in the response to medications or mainly non-adherence cannot Pediatr Nephrol 2007; 22: 1014–1020 9. Bockenhauer D, Carpentier E, Rochdi D, et al. Vasopressin be discerned from our data. The initial management of Patient 15 with normal saline for type 2 receptor V88M mutation: molecular basis of partial his dehydration and subsequent severe hypernatraemia and and complete nephrogenic diabetes insipidus. Nephron encephalopathy illustrates the difficulties patients with this Physiol 2010; 114: p1–p10 10. Jaureguiberry G, Van’t Hoff W, Mushtaq I et al. A patient with rare disease encounter [12]. Most general physicians and even paediatricians will have never have encountered a patient with polyuria and hydronephrosis: question. Pediatr Nephrol 2011; NDI before and thus follow guidelines for patients in general. 26: 1977–1978, 1979–1980 Provision of a letter or leaflet that the patient or family can pre- 11. Bichet DG, El Tarazi A, Matar J et al. Aquaporin-2: new muta- tions responsible for autosomal-recessive nephrogenic dia- sent at an emergency visit, that details the diagnosis and ex- plains emergency management that is critical to prevent such betes insipidus—update and epidemiology. Clin Kidney J complications. 2012; 5: 195–202 In conclusion, we show a generally favourable long-term 12. Bockenhauer D, Bichet DG. Nephrogenic diabetes insipidus. outcome and an apparent loss of efficacy of medical treatment Curr Opin Pediatr 2017; 29: 199–205 during school age. 13. Bockenhauer D, van’t Hoff W, Dattani M et al. Secondary nephrogenic diabetes insipidus as a complication of in- herited renal diseases. Nephron Physiol 2010; 116: p23–p29 FUNDING 14. Hillman DA, Neyzi O, Porter P et al. Renal (vasopressin-resist- ant) diabetes insipidus; definition of the effects of a homeo- Support to DB and RK was provided by Kids Kidney Research, static limitation in capacity to conserve water on the Kidney Research UK, St Peter’s Trust for Kidney, Bladder and physical, intellectual and emotional development of a child. Prostate Research, The David and Elaine Potter Foundation Pediatrics 1958; 21: 430–435 and the European Union, FP7 (grant agreement 2012-305608 15. Forssman H. Is hereditary diabetes insipidus of nephrogenic “European Consortium for High-Throughput Research in type associated with mental deficiency? Acta Psychiatr Neurol Rare Kidney Diseases (EURenOmics”). WH, WvH, RK and DB Scand 1955; 30: 577–587 are supported by the Biomedical Research Centre at Great 16. de Wied D, Diamant M, Fodor M. Central nervous system ef- Ordmond Street Hospital/UCL Institute of Child Health. fects of the neurohypophyseal hormones and related pep- tides. Front Neuroendocrinol 1993; 14: 251–302 CONFLICT OF INTEREST STATEMENT 17. Beckwith BE, Petros TV, Couk DI et al. The effects of vaso- pressin on memory in healthy young adult volunteers. The authors declare that they have no conflict of interest and Theoretical and methodological issues. Ann N Y Acad Sci that this work has not been published previously in whole or 1990; 579: 215–226 part. 18. Schliebe N, Strotmann R, Busse K et al. V2 vasopressin recep- tor deficiency causes changes in expression and function of REFERENCES renal and hypothalamic components involved in electrolyte and water homeostasis. Am J Physiol Renal Physiol 2008; 295: 1. Bockenhauer D, Bichet DG. Pathophysiology, diagnosis and F1177–F1190 management of nephrogenic diabetes insipidus. Nat Rev 19. Monnens L, Jonkman A, Thomas C. Response to indometh- Nephrol 2015; 11: 576–588 acin and hydrochlorothiazide in nephrogenic diabetes insip- 2. Bockenhauer D, Bichet DG. Inherited secondary nephrogenic idus. Clin Sci (Lond) 1984; 66: 709–715 diabetes insipidus: concentrating on humans. Am J Physiol 20. Pattaragarn A, Alon US. Treatment of congenital nephro- Renal Physiol 2013; 304: F1037–F1042 genic diabetes insipidus by hydrochlorothiazide and 3. Bichet DG, Razi M, Lonergan M et al. Hemodynamic and co- cyclooxygenase-2 inhibitor. Pediatr Nephrol 2003; 18: 1073–1076 agulation responses to 1-desamino[8-D-arginine] vasopres- 21. Beier UH, Green C, Meyers KE. Caring for adolescent renal sin in patients with congenital nephrogenic diabetes patients. Kidney Int 2010; 77: 285–291 insipidus. N Engl J Med 1988; 318: 881–887 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press
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Clinical Kidney Journal, 2018, 1–8 doi: 10.1093/ckj/sfy027 Original Article OR I G I N AL A R T I C L E Long-term outcome in inherited nephrogenic diabetes insipidus 1,2 3 3,4 5,6 Sonia Sharma , Emma Ashton , Daniela Iancu , Marie-Francoise Arthus , 1 1 1,4 5,6 Wesley Hayes , William van’t Hoff , Robert Kleta , Daniel G. Bichet and 1,4 Detlef Bockenhauer Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, 2 3 London, UK, Max Super Speciality Hospital & PSRI Hospital, New Delhi, India, North East Thames Regional Genetics Service Laboratories, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK, 4 5 Centre for Nephrology, University College London, London, UK, Departments of Medicine, Pharmacology and Physiology, Universite ´ de Montre ´ al, Montre ´ al, Que ´ bec, Canada and Unite ´ de recherche clinique, Centre de recherche et Service de ne ´ phrologie, Ho ˆ pital du Sacre ´ -Coeur de Montre ´ al, Que ´ bec, Canada Correspondence and offprint requests to: Detlef Bockenhauer; E-mail: d.bockenhauer@ucl.ac.uk ABSTRACT Background. Inherited nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by impaired urinary concentrating ability. Little clinical data on long-term outcome exists. Method. This was a single-centre retrospective medical record review of patients with a diagnosis of NDI followed between 1985 and 2017. We collected available data on growth, weight, school performance, complications and comorbidities. Results. We identified 36 patients with available data and a clinical diagnosis of NDI, which was genetically confirmed in 33 of them. Patients presented at a median age of 0.6 years and median length of follow-up was 9.5 years. Chief symptoms at presentation were faltering growth, vomiting/feeding concerns, polyuria/polydipsia, febrile illness and hypernatraemic dehydration. Median weight standard deviation scores (SDS) improved from 2.1 at presentation to 0.2 at last follow-up. In contrast, height SDS remained essentially unchanged at 1.1 at presentation and 0.9 at last follow-up. Most patients were treated with prostaglandin synthesis inhibitors and thiazides, yet weaned off during school age without an obvious change in urine output. Median estimated glomerular filtration rate at last follow-up was 81 mL/min/1.73 m . Urological complications were noted in 15 patients, constipation in 11 and learning difficulties in 5. Median age at resolution of nocturnal enuresis was 11 years. Estimated median daily fluid intake at median age of 13 years was 3800 mL/m . Conclusion. The overall prognosis in inherited NDI is favourable with regular treatment. As expected, most complications were related to polyuria. There is an apparent loss of efficacy of medications during school age. Our data inform the prognosis and management of patients with NDI. Keywords: AVPR2, AQP2, congenital nephrogenic diabetes insipidus, hypernatraemia, polyuria Received: 4.12.2017. Editorial decision: 22.2.2018 V C 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 Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| S. Sharma et al. Molecular details INTRODUCTION Twenty-six patients had mutations in AVPR2 (all boys) and Inherited nephrogenic diabetes insipidus (NDI) is a rare disorder seven in AQP2 (four boys, three girls) (Table 1). All were in- characterized by an insensitivity of the kidneys to arginine- herited in a recessive fashion. Mutations and selected clinical vasopressin (AVP) and a consequent inability to concentrate the details for some patients have been reported previously [9–12]. urine [1]. There are primary and secondary forms of inherited NDI [2]. In primary inherited NDI, we distinguish between an X- linked form, due to mutations in the gene encoding the vaso- Presenting features pressin type 2 receptor, namely arginine vasopressin receptor-2 Congenital NDI was diagnosed during the first year of life in (AVPR2) and an autosomal form, due to mutations in the gene 23 (69%) patients. The median age of diagnosis was 0.6 years encoding the water channel aquaporin2 (AQP2). In addition to (range 0.01–9). A family history of NDI was noted in 11 patients. NDI, patients with the X-linked form also have an impaired hae- One patient (23.2) had a prenatal diagnosis. Chief complaints at modynamic and coagulation response to AVPR2 stimulation [3]. time of admission were faltering growth, vomiting, polyuria/ Both forms are typically inherited in a recessive fashion, polydipsia and febrile illness with hypernatraemic dehydration although rare dominant cases have been described [4]. (Figure 1). Four (12%) were investigated due to a positive family Approximately 90% of cases are due to mutations in AVPR2 and history. to date more than 250 mutations have been described. As with Ten patients were treated for a different diagnosis before the most rare diseases, little long-term clinical data exists to inform establishment of NDI, most commonly gastroesophageal reflux management and prognosis. Previous reports have highlighted disease (n¼ 5). A pyloric web was diagnosed in one case (26), the potential complications of flow uropathy, behavioural based on vomiting and hypernatraemia, and surgically cor- abnormalities, such as attention deficit disorders as well as se- rected. One patient (19) was given an initial diagnosis of central vere developmental delay, sometimes associated with intracra- DI at his local hospital based on a partial response to 1-desa- nial calcifications [5–7]. Some of these, such as the mino-8-D-arginine vasopressin (DDAVP) (maximal urine osmo- developmental delay and the intracranial calcification, are con- lality 602 mOsm/kg), but was subsequently found to have a sidered preventable by appropriate treatment. Here we review clinical diagnosis of partial NDI, confirmed by genetic testing. the clinical course of patients in the tubulopathy clinic at Great Interestingly, a repeat DDAVP test at the age of 10 years showed Ormond Street Hospital (GOSH) for Children NHS Foundation no response to DDAVP. Two premature neonates (18, 20) were Trust. diagnosed in the neonatal intensive care unit based on polyuria. One patient (21) presented with global developmental delay and hypernatraemic dehydration at the age of 0.6 years. Magnetic MATERIALS AND METHODS resonance imaging of the brain had been performed in five pa- We performed a retrospective review of the medical records of tients. One patient (15) showed signs suggestive of myelinolysis patients with a clinical diagnosis of primary congenital NDI after experiencing severe acute hypernatraemia in the context who were followed in the specialized clinic for tubular disorders of treatment with 0.9% saline [12]. at GOSH between 1985 and 2017. We ascertained available mo- Median SDS or score and range for height at presentation lecular, as well as clinical data, including symptoms and age was 1.06 (4.94 to 1.9) and for weight: 2.1 (8.25 to 2.6). at presentation and last follow-up, family history, medical Weight for length (for children <3 years), SDS was 1.98 (7.5 to treatments, growth indicators, complications, comorbidities 2.3). and biochemical parameters (plasma sodium, creatinine and osmolality, as well as urine osmolality) at the time of presenta- Feeding tion and at last follow-up. Patients without genetic confirm- ation of the diagnosis were excluded from the main analysis to Treatment included input from a renal dietician and an osmotic maintain a clearly defined cohort. Standard deviation scores load<15 mOsm/kg was targeted. Tube feeding was performed (SDS) for anthropometric measures were calculated using in 34% (n¼ 12) of which 24% (n¼ 8) were fed via gastrostomy. growth charts based on National Health and Nutrition The indication for tube feeding was persistent growth failure in Examination Survey (NHANES), center for disease control (CDC)/ all (weight<0.4th percentile for age and no evidence of catch-up National Center for Health Statistics. Estimated glomerular fil- growth). Initially, a nasogastric tube was placed and, if tube tration rate (eGFR) was calculated with the Schwartz formula feeding was deemed necessary for several months, a gastros- modified for GOSH, using a k-value of 33 [8]. Statistical calcula- tomy was considered. Tube feeding was discontinued at a me- tions were performed using Microsoft Excel 2011 and GraphPad dian age of 2 years (range 2–4) once growth failure had resolved Prism software. and oral intake was deemed adequate. Medications RESULTS For drug treatment, all patients bar one (25) received thiazides Patients at diagnosis and 28 (84%) received an additional prostaglandin We identified 41 patients with a clinical diagnosis of NDI. Five synthesis inhibitor (PSI), mostly indomethacin (n¼ 25), or, alter- patients were excluded, due to untraceable records. The re- natively, celecoxib (n¼ 2) or ibuprofen (n¼ 1). PSI was discontin- maining 36 patients all had genetic testing performed and the ued in 10 (indomethacin in 9, ibuprofen in 1) because of diagnosis was confirmed in 33, of which 29 were male. Median perceived lack of efficacy at median age 12 years (range 4–16). In follow-up was 9.5 years (range 0.8–16.8) and median age at last addition, it was changed to celecoxib in one patient (15, at age follow-up was 11.9 years (range 0.8–17). 3 years) due to a gastrointestinal bleed and stopped in another Details of selected genetic and clinical data are presented in one (7.1) due to concerns over renal function associated with an Table 1. obstructive uropathy (at age 12 years). Five patients (2.3, 6, 7.2, Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Clinical outcomes in inherited NDI | 3 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 1. Clinical and molecular details of the 33 patients with identified causative mutations Genetic details Clinical details At presentation At last follow-up Plasma eGFR Uosm after eGFR Age osmolality (mL/min/ DDAVP Weight Height Age Weight Height (mL/min/ Remarks (complications/ 2 2 Nucleotide Protein Sex (years) (mOsm/kg) 1.73 m ) (mOsm/kg) SDS SDS (years) SDS SDS 1.73 m ) Meds comorbidities) Patients with mutations in AVPR2 1 c.851G>A p.(Trp284*) M 0.25 304 43 65 2.62 1.25 11.9 0.02 1.68 90 Indomethacin, thiazide Feeding difficulty, esophagitis 2.1 c.999dup p.(Ser334Leufs*23) M 0.016 300 44 73 0.44 0.51 15.3 1.03 1.16 76 Indomethacin, thiazide Transient hydronephrosis, large bladder, PVR, constipation 2.2 c.999dup p.(Ser334Leufs*23) M 0.021 310 34 53 0.84 0.89 16.7 0.34 0.53 75 Indomethacin, thiazide Hydronephrosis, constipation 2.3 c.999dup p.(Ser334Leufs*23) M 0.08 310 45 50 0.73 1.06 17 0.08 1.13 77 Indomethacin, thiazide ADHD, impaired concentration, mild hydronephrosis 2.4 c.999dup p.(Ser334Leufs*23) M 0.16 307 38 89 0.87 0.54 17 0.01 0.86 65 Indomethacin, thiazide Mild hydronephrosis, migraine 3 c.871C>T p.(Glu291*) M 0.83 304 54 111 0.91 0.76 16.3 0.29 0.89 79 Indomethacin, thiazide 4 c.27_54del p.(Val10Cysfs*18) M 0.3 301 43 129 3.01 0.86 14.1 1.49 0.92 76 Indomethacin, thiazide Transient hydronephrosis, growth hormone deficiency, impaired concentration 5 c.299del p.(Lys100Argfs*16) M 0.58 325 44 40 2.61 2.02 11.8 0.74 0.7 72 Indomethacin, thiazide Constipation 6 c.332T>C p.(Leu211Pro) M 0.66 354 34 197 4.08 3.19 14.2 1.11 2.4 106 Indomethacin, thiazide Constipation 7.1 c.262G>A p.(Val88Met) M 2 294 83 570 2.8 2.87 1 0.51 0.37 81 Indomethacin, thiazide Hydronephrosis, large bladder, PVR, constipation 7.2 c.262G>A p.(Val88Met) M 0.04 292 26 63 1.88 1.59 10 0.27 0.01 92 Indomethacin, thiazide ADHD, impaired concentration/ school performance 8 c.316C>T p.(Arg106Cys) M 2.9 294 140 173 1.78 1.56 17 0.31 0.97 85 Indomethacin, thiazide 9 c.809_810del p.(Val270Glyfs*86) M 0.5 319 69 173 3.38 2.25 10 0.19 0.66 95 Indomethacin, thiazide Mild hydronephrosis, constipation 10.1 c.316C>T p.(Arg106Cys) M 7 298 63 50 0.9 0.45 15 0.37 0.27 70 Indomethacin, thiazide Hydronephrosis, large bladder, PVR, PUV with left VUR 10.2 c.316C>T p.(Arg106Cys) M 9 N/A 89 220 1.39 0.62 14 0.82 0.78 80 Indomethacin, thiazides Hydronephrosis, constipation 11.1 c. (-1069_1007) p.? M 0.15 320 54 114 0.96 1.17 9 1.57 0.38 66 Indomethacin, thiazide del ins168 11.2 c.(-1069_1007) p.? M 0.5 328 41 179 2.66 0.33 5 0.92 0.68 67 Indomethacin, amiloride, ADHD, impaired concentration del ins168 thiazide 12 c.del970 p.(Ile324Serfs*112) M 8 298 69 55 2.6 1.59 17 0.92 1.42 56 Thiazide Hydronephrosis, single kidney, large bladder þ PVR 13 c.491G>A p.(W146X) M 1.83 277 103 44 2.55 2.13 15 0.7 0.23 86 Indomethacin, thiazide Large bladder, PVR, ADHD, dys- lexia mild hydronephrosis (continued) 4| S. Sharma et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 1. (Continued) Genetic details Clinical details At presentation At last follow-up Plasma eGFR Uosm after eGFR Age osmolality (mL/min/ DDAVP Weight Height Age Weight Height (mL/min/ Remarks (complications/ 2 2 Nucleotide Protein Sex (years) (mOsm/kg) 1.73 m ) (mOsm/kg) SDS SDS (years) SDS SDS 1.73 m ) Meds comorbidities) 14 c.357G>C p.(Glu119His) M 0.16 359 45 50 2.25 14 0.98 1.54 91 Indomethacin, thiazides 15 c.599G>A p.(Trp200*) M 1.66 290 102 147 1.98 1.02 3 1.64 1.3 114 Indomethacin, thiazide, Transient neurological impair- amiloride ment associated with acute hypernatraemia 16 c.604C>T p.(Arg202Cys) M 0.58 287 111 76 2.83 0.33 2.2 1.65 3.5 90 Amiloride, thiazide 17 c.(?-1) _(*1_?) p.? M 0.03 337 49 185 0.34 0.89 0.83 1.06 0.76 89 Celecoxib, thiazide del 18 c.348C>G p.(Lys116Asn) M 0.91 298 73 95 4.47 4.02 3.6 1.89 4.15 81 Indomethacin, thiazide, IUGR, necrotizing enterocolitis amiloride 19 c.830T>C p.(Val277Ala) M 8 338 41 73 2.2 1.9 16 2.3 2.1 83 Indomethacin, thiazide 20 c.332T>C p.(Leu111Pro) M 0.01 293 95 65 2.42 1.06 6.1 1.43 0.34 66 Celecoxib, thiazide, Rhomboencephalo-synapsis amiloride Patients with mutations in AQP2 21 c.377C>T p.(Thr126Met) M 0.58 354 62 95 2.8 2.97 13 0.23 0.9 60 Indomethacin, thiazide Global developmental delay 22 c.253C>T p.(Arg85*) M 3.6 304 85 177 1.49 1.86 17 3.06 1.39 81 Ibuprofen, thiazide Left hydronephrosis with 10% divided function, large blad- der, PVR 23.1 c.337C>T p.(Arg113Cys) F 0.33 340 45 158 2.83 2.23 7.9 2.58 2.85 67 Indomethacin, thiazide Constipation 23.2 c.337C>T p.(Arg113Cys) F0 280 52 114 2.55 1.33 3 2.75 1.72 97 Indomethacin, thiazide Constipation 24 c.211G>A p.(Val71Met) F 0.25 350 69 158 2.1 0.59 16 1.54 1.67 72 Indomethacin, thiazide Hydronephrosis 25 c.299G>T/ p.(Gly100Val)/ M 6.5 284 50 86 4.65 2.02 10.5 1.51 3.02 84 Celecoxib c.763C>T p.(Gln255*) 26 c.211G>A p.(Val71Met) M 1.75 295 107 100 8.25 4.94 5 1.92 1.32 129 Indomethacin, thiazide Mild hydronephrosis, constipation Shown are pertinent molecular and clinical details. Mutations in AQP2 are all homozygous, except for Patient 25, who is compound heterozygous. ‘?’ is standard genetic annotation for Unknown. Uosm, urine osmolality; PUV, posterior urethral valves; VUR, vesico-ureteric reflux; IUGR, intra-uterine growth retardation. Clinical outcomes in inherited NDI | 5 Biochemistries at last follow-up showed persistent NDI with a median (range) urine osmolality of 84 (31–215) mOsm/kg, but now with normal plasma values: median osmolality 292 (281– 307) mOsm/kg and sodium 143 (133–149) mmol/L. Growth Median SDS or z-score for weight (range) improved from: 2.1 (8.3 to 2.6) at presentation to 0.2 (2.8 to 3) at last follow-up (Table 2). In contrast, height SDS (range) remained essentially unchanged: 1.06 (4.94 to 1.9) at presentation and 0.9 (4.2 to 1.3) at last follow-up. Urological problems Urological complications were noted in 46% (n¼ 15) of patients. Nocturnal enuresis and incomplete voiding were the most com- mon concerns. Large bladder capacity and incomplete bladder emptying was noted in eight patients. During follow-up of mild- to-moderate severity, unilateral or bilateral hydronephosis was noticed in 14 patients and 7 of these had persistence of hydro- nephrosis and a large bladder capacity, whereas in 7 the dilata- tion was only mild and transient (Figure 2). Resolution of nocturnal enuresis was seen in 19 patients at a median age of FIGURE 1: Symptoms at initial presentation. Shown is the frequency of the chief 11.3 (range 5–16) years. Interestingly, one child (7.1) with partial complaints at presentation. NDI had resolution of nocturnal enuresis with desmopressin 20 and 25) switched from indomethacin to ibuprofen due to dif- therapy [9]. One patient (10.1) with hydronephrosis and multiple ficulties with medication availability. One patient (25) de- urinary tract infection was found to have posterior urethral veloped nausea after commencement of celecoxib and it was valves, and had a left nephroureterectomy and Mitrofanoff for- changed to ibuprofen. One patient (2.2) developed severe hydro- mation [10]. His brother (10.2) shared the diagnosis of NDI but nephrosis and a distended bladder with a volume of 1500 mL had no evidence of an obstructive uropathy. and post-void residual (PVR), which was noted for a first few months after stopping indomethacin. The drug was restarted Estimated glomerular filtration rate but without apparent change in urine volume and the hydro- Median eGFR at last follow-up was 81 (range 56–129) mL/min/ nephrosis persisted. The median daily dose of indomethacin at 1.73 m and was comparable between patients with AVPR2 and the time of discontinuation due to perceived lack of efficacy AQP2 mutations (Table 2). was available in eight patients and was 1.1 mg/kg (range 0.4– Fluid intake at last follow-up, as estimated by patients and/ 1.7). Those patients continuing indomethacin (n¼ 7) were pre- or family was available in 28 patients. Estimated median daily scribed at last follow-up a median daily dose of 1.4 mg/kg. fluid intake at a median age of 13 years was 3800 mL/m (range Similarly, thiazides were discontinued in eight patients at a 1600–9200). median age of 14 years (range 5–17). At this age, all eight were receiving bendroflumethiazide with a median daily dose of 0.08 mg/kg (range 0.06–0.11). In those continuing bendroflu- Constipation methiazide (n¼ 15), the median prescribed daily dose was Constipation remained a concern in our cohort in 11 patients. It 0.1 mg/kg. Urine output was not formally measured before and was often noted during the initial years with mild-to-moderate after stopping medications, but patients reported no apparent severity. Regular intake of laxatives was prescribed in most of change. these patients. Amiloride was given in four patients (Table 1) to maintain normokalaemia. Apart from these drugs, potassium chloride Intelligence and school performance was prescribed in 19% of patients. Other prescribed medications mostly included laxatives, antacids and prokinetics. Five pa- One patient (21) had severe global developmental delay already tients were able to stop all medications at median age of noted at his presentation at 7 months of age with faltering 14 years (12.56 3.8). growth and hypernatraemic (170 mmol/L) dehydration. Data on learning or behaviour problems were available in 5 (17.8%) out of 28 school-age children, who had been diagnosed with atten- tion-deficit hyperactivity disorder (ADHD) and/or learning diffi- Biochemistries culties and/or impaired concentration (Table 1). Biochemistries at presentation were consistent with the clinical No complaints on school performance were noted in the re- diagnosis of NDI: median (range) for urine osmolality was 86 cords of the remaining patients. (46–177) mOsm/kg, for plasma osmolality 303 (277–359) mOsm/kg and for plasma sodium 148 (133–177) mmol/L. Median eGFR at Genotype–phenotype correlation presentation was 54 mL/min/1.73 m (range 26–140). Interestingly, urine osmolality in patient 7.1 increased after We compared clinical parameters of the 26 patients with AVPR2 DDAVP to 570 mOsm/kg, consistent with a diagnosis of partial mutations to the 7 with AQP2 mutation. No significant differ- NDI [9]. ence was seen (see Table 2). Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| S. Sharma et al. Patients without genetic confirmation In three patients, no mutation in AVPR2 or AQP2 could be identi- fied: two male siblings and one female child presented at a median age of 0.16 (range 0.01–0.16) years. Further genetic analysis showed that both brothers had inherited the same X-chromosome from their mother. The girl, born to consanguin- eous parents, was homozygous at the AQP2 locus. Thus, it is pos- sible that these three patients have non-coding mutations in these genes, which were not assessed by the testing procedure in the laboratory. All three were unresponsive to intravenous DDAVP at presentation with median maximum osmolality of 97 (range 91–114) mOsm/kg, consistent with NDI. There were no clinical features that would suggest a diagnosis of secondary NDI [2, 13]. Median plasma sodium at presentation was 154 (150–157) mmol/L and osmolality 309 (307–317) mOsm/kg. Of specific inter- est was a spontaneous improvement of urinary concentrating ability in the two brothers, with a DDAVP test at 11 and 15 years of age showing a maximum urine osmolality of 536 and 752 mOsm/kg, respectively (Table 3). DISCUSSION We here report long-term clinical data on a single-centre cohort of patients with congenital NDI. Overall, our data show a favourable outcome: growth is in the normal range for the vast majority of patients, although median height at follow-up was slightly below the average at 0.9 SDS. Kidney function, as as- sessed by eGFR at last follow-up, was within chronic kidney dis- ease (CKD) Stages 1 or 2 in all except for Patient 12, who was born with a single kidney. Previous reports have highlighted the complications of NDI with regards to intellectual function [6, 14, 15]. Unfortunately, data on school performance were not systematically captured in the medical records and thus may be underestimated in our study, but intellectual and/or behavioural problems were noted in five patients (see Table 1), mostly in the form of a diagnosis of ADHD and/or impaired concentration and learning difficulties. This is considerably less than in a previous report where patients were systematically assessed and almost half had a diagnosis of ADHD and 70% a low score on short-term memory [5]. It has been debated whether ADHD is an intrinsic aspect of the disorder, as there are data suggesting at least temporary expression of AVPR2 in the brain, as well as an effect of AVP on learning and memory [16, 17]. Moreover, AVPR2 knock-out mice show altered expres- sion of genes in the hypothalamus [18]. Alternatively, ADHD and problems with concentration or memory may be secondary to the constant craving for water and the frequent need to void. In this context, it is interesting that we saw this complication only in patients with AVPR2. Yet, this difference in the proportion of patients with noted learning or behavioural problems was not statistically significant between AVPR2 and AQP2 (P¼ 0.2). Early reports on patients with NDI suggested severe intellec- tual impairment as an almost invariant feature of the disease, but subsequent observations indicate that this complication can be prevented in most by adequate treatment [5, 6, 15]. The latter is consistent with our observations here, as we saw severe global developmental delay in only one patient (21). Interestingly, while presenting with hypernatraemic dehydra- tion, his features were not substantially different from other pa- tients in this cohort. It is thus unclear whether for some reason this patient is more susceptible to brain damage, or whether his developmental delay is unrelated to the NDI. Brain imaging to assess for intracerebral calcifications had not been performed. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 2. Comparison between patient with AVPR2 and AQP2 mutations At presentation At last follow-up Median eGFR Median eGFR No. with Age of resolution No. with reported Median height Median weight (mL/min/ Median height Median weight (mL/min/ urological of nocturnal school/behavioural 2 2 Gene SDS (range) SDS (range) 1.73 m ) (range) SDS (range) SDS (range) 1.73 m ) (range) complication (%) enuresis complications AVPR2 1.0 (4 to 1.9) 1.9 (4.5 to 2.6) 51 (26–140) 0.7 (4.2 to 1.3) 0.3 (1.9 to 1.6) 80.5 (56–114) 10 (38.5) 10 (4–15) 5 AQP2 2.0 (4.9 to  0.6) 2.8 (8.3 to 1.5) 61 (45–107) 1.7 (3to 0.9) 1.5 (2.8 to 3) 81 (59.6–129) 5 (71) 12.4 (9.4–14) 0 Combined 1.1 (4.9 to 1.9) 2.1 (8.3 to 2.6) 54 (26–140) 0.9 (4.2 to 1.3) 0.2 (2.8 to 3) 81 (56–129) 15 (46) 11.3 (4–15) 5 Shown are selected data for patients with X-linked versus autosomal NDI. No significant differences were seen. Clinical outcomes in inherited NDI | 7 FIGURE 2: Examples of flow uropathy. Shown are ultrasound images detailing flow uropathy. (A) Marked hydronephrosis of single right kidney with loss of renal cortex in Patient 22 (at age 17 years). (B) Hydronephrosis, (C) Dilated bladder and ureter, (D) PVR in Patient 2.1 (all images at age 15 years). Hydronephrosis in this patient de- veloped after the age of 8 years. Table 3. Spontaneous improvement in urinary concentration in the two brothers without identified mutation Presentation Last follow-up Patient Age (months) Posm (mOsm/kg) Max Uosm after DDAVP Age (years) Posm (mOsm/kg) Max Uosm after DDAVP 28.1 1.5 317 114 15.3 298 536 28.2 0.1 309 91 11.5 285 752 Shown are data on urinary concentration. Patient 28.1 presented at the age of 1 month with recurrent vomiting and hypernatraemia. His brother 28.2 was electively re- viewed at 3 days of age due to the family history. Both received a clinical diagnosis of NDI based on the inappropriately low urine osmolality. Both showed a spontan- eous improvement in symptoms and urinary concentration over time. Uosm, urine osmolality; Posm, plasma osmolality. Overall our data are consistent with the notion that severe There were no episodes of hypernatraemic dehydration after intellectual impairment can be prevented with adequate diagnosis and start of treatment apparent from the biochemis- treatment. try results available at GOSH. Yet, since GOSH is a pure tertiary Yet, despite the overall favourable prognosis, patients clearly paediatric center without provision of primary or emergency have complications from the polyuria. Almost half of all pa- care, acute illnesses would have presented to the respective tients had radiological evidence of a flow uropathy. While this local hospital and thus would not be systematically captured or was only transient in some it was severe in others and associ- reflected in laboratory results obtained at GOSH. ated with loss of renal cortex in one (22) (Figure 2). Similarly, Of interest is the apparent change in response to medical nocturnal enuresis was a common problem and resolution was treatment. Thiazide and PSI have been shown to effectively re- much delayed at a median age of over 11 years. Typical advice duce urine output in NDI during the first few years of life and treatment given to patients with nocturnal enuresis, such [19, 20]. Indeed, one patient (2.1) developed asymptomatic hypo- as decreased fluid intake before bedtime or DDAVP tablets, obvi- natraemia (130 mmol/L) after commencement of indomethacin ously does not work in patients with NDI. and the drug was transiently withheld. Yet, in our experience, Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018 8| S. Sharma et al. 4. Bichet DG, Bockenhauer D. Genetic forms of nephrogenic many patients stop medications during school age without noticing an appreciable difference in urine output. While diabetes insipidus (NDI): vasopressin receptor defect (X- Patient 2.2 developed severe hydronephrosis first noted linked) and aquaporin defect (autosomal recessive and dom- 4 months after stopping indomethacin, this did not improve inant). Best Pract Res Clin Endocrinol Metab 2016; 30: 263–276 after restarting the medication. Moreover, his last previous 5. Hoekstra JA, van Lieburg AF, Monnens LA et al. Cognitive ultrasound, which showed no dilatation, had been 5 years ear- and psychosocial functioning of patients with congenital nephrogenic diabetes insipidus. Am J Med Genet 1996; 61: lier and thus it is likely that the hydronephrosis had developed even before the medication was stopped and was related to vol- 81–88 untary urinary retention, reflected in his large bladder volume. 6. van Lieburg AF, Knoers NV, Monnens LA. Clinical presenta- Medications were typically discontinued during teenage years, tion and follow-up of 30 patients with congenital nephro- genic diabetes insipidus. J Am Soc Nephrol 1999; 10: 1958–1964 an age in which adherence to medications is a common prob- lem [21]. Indeed, one patient (2.3) openly admitted that he had 7. Schofer O, Beetz R, Kruse K et al. Nephrogenic diabetes insipidus stopped taking the medications and in others, either the patient and intracerebral calcification. Arch Dis Child 1990; 65: 885–887 or a parent had reported intermittent missed doses. Thus, 8. Gonzalez Celedon C, Bitsori M, Tullus K. Progression of chronic renal failure in children with dysplastic kidneys. whether the apparent lack of efficacy reflects a true change in the response to medications or mainly non-adherence cannot Pediatr Nephrol 2007; 22: 1014–1020 9. Bockenhauer D, Carpentier E, Rochdi D, et al. Vasopressin be discerned from our data. The initial management of Patient 15 with normal saline for type 2 receptor V88M mutation: molecular basis of partial his dehydration and subsequent severe hypernatraemia and and complete nephrogenic diabetes insipidus. Nephron encephalopathy illustrates the difficulties patients with this Physiol 2010; 114: p1–p10 10. Jaureguiberry G, Van’t Hoff W, Mushtaq I et al. A patient with rare disease encounter [12]. Most general physicians and even paediatricians will have never have encountered a patient with polyuria and hydronephrosis: question. Pediatr Nephrol 2011; NDI before and thus follow guidelines for patients in general. 26: 1977–1978, 1979–1980 Provision of a letter or leaflet that the patient or family can pre- 11. Bichet DG, El Tarazi A, Matar J et al. Aquaporin-2: new muta- tions responsible for autosomal-recessive nephrogenic dia- sent at an emergency visit, that details the diagnosis and ex- plains emergency management that is critical to prevent such betes insipidus—update and epidemiology. Clin Kidney J complications. 2012; 5: 195–202 In conclusion, we show a generally favourable long-term 12. Bockenhauer D, Bichet DG. Nephrogenic diabetes insipidus. outcome and an apparent loss of efficacy of medical treatment Curr Opin Pediatr 2017; 29: 199–205 during school age. 13. Bockenhauer D, van’t Hoff W, Dattani M et al. Secondary nephrogenic diabetes insipidus as a complication of in- herited renal diseases. Nephron Physiol 2010; 116: p23–p29 FUNDING 14. Hillman DA, Neyzi O, Porter P et al. Renal (vasopressin-resist- ant) diabetes insipidus; definition of the effects of a homeo- Support to DB and RK was provided by Kids Kidney Research, static limitation in capacity to conserve water on the Kidney Research UK, St Peter’s Trust for Kidney, Bladder and physical, intellectual and emotional development of a child. Prostate Research, The David and Elaine Potter Foundation Pediatrics 1958; 21: 430–435 and the European Union, FP7 (grant agreement 2012-305608 15. Forssman H. Is hereditary diabetes insipidus of nephrogenic “European Consortium for High-Throughput Research in type associated with mental deficiency? Acta Psychiatr Neurol Rare Kidney Diseases (EURenOmics”). WH, WvH, RK and DB Scand 1955; 30: 577–587 are supported by the Biomedical Research Centre at Great 16. de Wied D, Diamant M, Fodor M. Central nervous system ef- Ordmond Street Hospital/UCL Institute of Child Health. fects of the neurohypophyseal hormones and related pep- tides. Front Neuroendocrinol 1993; 14: 251–302 CONFLICT OF INTEREST STATEMENT 17. Beckwith BE, Petros TV, Couk DI et al. The effects of vaso- pressin on memory in healthy young adult volunteers. The authors declare that they have no conflict of interest and Theoretical and methodological issues. Ann N Y Acad Sci that this work has not been published previously in whole or 1990; 579: 215–226 part. 18. Schliebe N, Strotmann R, Busse K et al. V2 vasopressin recep- tor deficiency causes changes in expression and function of REFERENCES renal and hypothalamic components involved in electrolyte and water homeostasis. Am J Physiol Renal Physiol 2008; 295: 1. Bockenhauer D, Bichet DG. Pathophysiology, diagnosis and F1177–F1190 management of nephrogenic diabetes insipidus. Nat Rev 19. Monnens L, Jonkman A, Thomas C. Response to indometh- Nephrol 2015; 11: 576–588 acin and hydrochlorothiazide in nephrogenic diabetes insip- 2. Bockenhauer D, Bichet DG. Inherited secondary nephrogenic idus. Clin Sci (Lond) 1984; 66: 709–715 diabetes insipidus: concentrating on humans. Am J Physiol 20. Pattaragarn A, Alon US. Treatment of congenital nephro- Renal Physiol 2013; 304: F1037–F1042 genic diabetes insipidus by hydrochlorothiazide and 3. Bichet DG, Razi M, Lonergan M et al. Hemodynamic and co- cyclooxygenase-2 inhibitor. Pediatr Nephrol 2003; 18: 1073–1076 agulation responses to 1-desamino[8-D-arginine] vasopres- 21. Beier UH, Green C, Meyers KE. Caring for adolescent renal sin in patients with congenital nephrogenic diabetes patients. Kidney Int 2010; 77: 285–291 insipidus. N Engl J Med 1988; 318: 881–887 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy027/4969891 by Ed 'DeepDyve' Gillespie user on 12 July 2018

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Clinical Kidney JournalOxford University Press

Published: Apr 13, 2018

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