Sarah E. Ledermann

HNF1B Mutations Associate with Hypomagnesemia and Renal Magnesium Wasting

Mutations in hepatocyte nuclear factor 1B (HNF1B), which is a transcription factor expressed in tissues including renal epithelia, associate with abnormal renal development. While studying renal phenotypes of children with HNF1B mutations, we identified a teenager who presented with tetany and hypomagnesemia. We retrospectively reviewed radiographic and laboratory data for all patients from a single center who had been screened for an HNF1B mutation. We found heterozygous mutations in 21 (23%) of 91 cases of renal malformation. All mutation carriers had abnormal fetal renal ultrasonography. Plasma magnesium levels were available for 66 patients with chronic kidney disease (stages 1 to 3). Striking, 44% (eight of 18) of mutation carriers had hypomagnesemia (<1.58 mg/dl) compared with 2% (one of 48) of those without mutations (P < 0.0001). The median plasma magnesium was significantly lower among mutation carriers than those without mutations (1.68 versus 2.02 mg/dl; P < 0.0001). Because hypermagnesuria and hypocalciuria accompanied the hypomagnesemia, we analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. These results extend the phenotype of HNF1B mutations to include hypomagnesemia. HNF1B regulates transcription of FXYD2, which participates in the tubular handling of Mg(2+), thus describing a role for HNF1B not only in nephrogenesis but also in the maintenance of tubular function.

Long-term outcome of peritoneal dialysis in infants

Debate continues concerning the treatment of infants with end-stage renal disease. We evaluated progress and outcome of 20 infants with a mean age of 0.34 year (range, 0.02-1 year) in a long-term peritoneal dialysis program at a single center. Mean weight at the start of dialysis was 4.8 kg (range, 1.7-11.4 kg), and the duration of dialysis was 17.3 months (range, 1-59 months). Eleven infants received renal transplants, 4 were switched to hemodialysis and then received transplants, 4 died, and 1 continues to receive peritoneal dialysis. There was significant co-morbidity in 6 infants who died or required hemodialysis. Catheter interventions were frequent, with 12 infants requiring at least one replacement. There were 1.1 episodes of peritonitis per patient-year; 70% of infants had 0 to 1 episode. Mean weight standard deviation score (SDS) was -1.6 at the start, -0.3 at 1 year (P =.0008), and 0.3 at 2 years (P =.0008). Height SDSs were -1.8 at the start, -1.1 at 1 year (P =.046), and -0. 8 at 2 years (P =.06). Head circumference SDSs were -1.9 at the start, -1.3 at 6 months (P =.003), and -0.9 at 1 year (P =.015). Fourteen of 16 survivors are achieving normal developmental milestones or attend mainstream school. Peritoneal dialysis in infancy is a demanding treatment, but outcome for growth, development, and transplantation justifies this intensive approach. When parents are counseled, the importance of non-renal co-morbidity must be emphasized.

Long-term outcome of chronic dialysis in children.

As the prevalence of children on renal replacement therapy (RRT) increases world wide and such therapy comprises at least 2% of any national dialysis or transplant programme, it is essential that paediatric nephrologists are able to advise families on the possible outcome for their child on dialysis. Most children start dialysis with the expectation that successful renal transplantation is an achievable goal and will provide the best survival and quality of life. However, some will require long-term dialysis or may return intermittently to dialysis during the course of their chronic kidney disease (CKD). This article reviews the available outcome data for children on chronic dialysis as well as extrapolating data from the larger adult dialysis experience to inform our paediatric practice. The multiple factors that may influence outcome, and, particularly, those that can potentially be modified, are discussed.

Long-term enteral nutrition in infants and young children with chronic renal failure

Abstract An inadequate nutritional intake is common in infants and young children with chronic and end-stage renal failure (CRF/ESRF), causing poor weight gain and growth retardation. In a programme of enteral feeding (EF), growth, nutritional intake and outcome for oral feeding were evaluated in 35 children with CRF/ESRF, mean (range) age 1.6 (0–4.9) years at start of EF for 30 (12–60) months. Twenty-nine had a glomerular filtration rate of 12.1 (6–26) ml/min per 1.73 m2 and 6 were on peritoneal dialysis. Mean (SD) weight standard deviation scores (SDSs) in the 0 to 2-year age group (n=26) were –3.3 (1.0) 6 months before EF, –3.1 (1.3) at the start, –1.7 (1.4) at 1 year, (P=0.0003) and –1.4 (1.8) at 2 years, (P=0.0008). Height SDSs were –2.9 (0.7), –2.9 (1.2), –2.2 (1.2) (P=0.008) and –2.1 (1.3) (P=0.004). Weight SDSs in the 2 to 5-year age group (n=9) were –2.3 (1.2), –2.0 (1.1), –1.1 (1.3) (P=0.002) and –0.9 (1.0) (P=0.04). Height SDSs were –2.8 (0.6), –2.3 (0.7), –2.0 (0.7) and –2.0 (0.8). There was no change in energy intake as a percentage of the estimated average requirement, nor was this exceeded. Percentage energy from the EF in the 0 to 2 year age group remained unchanged despite an absolute increase in energy intake with age. Twenty-one have had renal transplants, of whom 86% eat and drink normally. Long-term EF prevents or reverses weight loss and growth retardation in children with CRF/ESRF, with the achievement of significant catch-up growth if started before age 2 years.

Gastrostomy feeding in infants and children on peritoneal dialysis

The majority of infants and young children on peritoneal dialysis (PD) require enteral feeding to achieve their growth potential. We report our experience of gastrostomy feeding in 29 children on PD over 11 years. Fifteen children, median age 3.9 (0.5–13.3) years had a percutaneous gastrostomy (PEG) or Nissen fundoplication and gastrostomy (N and G) or open gastrostomy (OG) before starting PD (group1). Nine children, age 0.7 (0.5–12.4) years, had a N and G or OG (group 2) and 5, age 5.1 (1–15.1) years, a PEG (group 3) after PD catheter insertion/start of PD. In group 1 (257 months gastrostomy feeding with PD), there were 0.6 episodes of peritonitis/patient year. Nine PEGs were replaced electively after 27 (19–50) months, with bleeding from an embedded flange the only complication. One PEG replaced by a button ruptured the track, causing Candida peritonitis. In group 2 (130 months G and PD), there were 1.4 episodes of peritonitis/patient year. Two children developed paraoesophageal hernias, which were successfully repaired. Four children in group 3 developed peritonitis soon after PEG placement. Two transferred to haemodialysis, 1 remained on PD after treatment of Candida peritonitis and 1 subsequently died. Only 2 of the 17 children who have had renal transplants still need gastrostomy feeds. We recommend placement of a PEG or OG if an anti-reflux procedure is necessary prior to starting PD. Placement of a PEG while on PD is contraindicated, but an OG is a safe alternative procedure.

Ergocalciferol Supplementation in Children with CKD Delays the Onset of Secondary Hyperparathyroidism: A Randomized Trial

BACKGROUND AND OBJECTIVES Vitamin D deficiency is an important contributor to the development of hyperparathyroidism and is independently associated with cardiovascular and bone disease. The hypothesis was that nutritional vitamin D (ergocalciferol) supplementation in children with CKD stages 2-4 delays the onset of secondary hyperparathyroidism. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A randomized, double-blinded, placebo-controlled study in children with CKD2-4 who had 25-hydroxyvitamin D [25(OH)D] deficiency was conducted. Ergocalciferol (or a matched placebo) was given daily as per Kidney Disease Outcomes Quality Initiative guidelines. The primary endpoint was the time to development of hyperparathyroidism. RESULTS Seventy-two children were screened. Forty-seven children were 25(OH)D-deficient and randomly assigned to receive ergocalciferol or placebo. Twenty children in each arm completed the study; median follow-up was 12 months. Groups were well matched for age, race, estimated GFR, and season when recruited. Nine of 20 children on placebo and 3 of 20 children on ergocalciferol developed hyperparathyroidism (odds ratio, 4.64; 95% confidence interval, 1.02-21.00). The time to development of hyperparathyroidism was significantly longer with ergocalciferol treatment compared with placebo (hazard ratio, 0.30; 95% confidence interval, 0.09-0.93, P=0.05). With ergocalciferol treatment, normal 25(OH)D levels were achieved in all 8 children with CKD2, 8 of 11 children with CKD3, but not in the single patient with CKD4. There were no ergocalciferol-related adverse events. 25(OH)D levels >100 nmol/L were required to achieve normal levels of 1,25-dihydroxyvitamin D. CONCLUSIONS Ergocalciferol is an effective treatment that delays the development of secondary hyperparathyroidism in children with CKD2-3.

Long-Term Outcome of Infants with Severe Chronic Kidney Disease

BACKGROUND AND OBJECTIVES In 2000, we reported the outcome of 101 children with a GFR <20 ml/min per 1.73 m2 at 0.3 yr of age (range 0.0 to 1.5 yr). Long-term data on such young children are scarce. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Mortality, treatment modalities, and growth were reanalyzed 9.9 yr later. RESULTS Of the 101 patients, 28 died and three were lost to follow-up during 13.90 yr (range 0.03 to 22.90 yr). One-, 2-, 5-, 10-, 15-, 20-, and 22-yr survivals were 87, 81, 77, 75, 73, 72, and 64%, respectively. Fifty-one children had comorbidities. Sixty-six percent were tube fed for 1.7 yr (range 0.1 to 6.9 yr), 37% had a gastrostomy, and 13% had a Nissen fundoplication. Mean height SD score (SD) was -0.42 (2.33) at birth (n = 40), -2.07 (1.34) at 0.5 (n = 62), -1.93 (1.38) at 1 (n = 72), -1.14 (1.14) at 5 (n = 67), -1.04 (1.15) at 10 (n = 62), -1.84 (1.32) at 15 (n = 40), and -1.68 (1.52) at age > or =18 yr (n = 32). Comorbidities adversely influenced growth (P < 0.01) and final height (P = 0.02): Mean height SD score (SD) was -1.16 (1.38) in otherwise normal adults. CONCLUSIONS Growth and final height in infants with severe chronic kidney disease are influenced by comorbidity. Intensive feeding and early transplantation resulted in a mean adult height within the normal range in patients without comorbidities. Overall mortality is comparable to that of older children.

Renal transplantation or bladder augmentation first? A comparison of complications and outcomes in children

Paediatric urology can uncover the most complicated cases that require careful attention to management details. Authors from the UK present a retrospective review of their experience of children who had undergone both renal transplantation and bladder augmentation. They recommend that the bladder be reconstructed before renal transplantation, as it might protect the transplanted kidney, and specifically the transplanted ureter.

Renal malformations associated with mutations of developmental genes: messages from the clinic

Renal tract malformations (RTMs) account for about 40% of children with end-stage renal failure. RTMs can be caused by mutations of genes normally active in the developing kidney and lower renal tract. Moreover, some RTMs occur in the context of multi-organ malformation syndromes. For these reasons, and because genetic testing is becoming more widely available, pediatric nephrologists should work closely with clinical geneticists to make genetic diagnoses in children with RTMs, followed by appropriate family counseling. Here we highlight families with renal cysts and diabetes, renal coloboma and Fraser syndromes, and a child with microdeletion of chromosome 19q who had a rare combination of malformations. Such diagnoses provide families with often long-sought answers to the question “why was our child born with kidney disease”. Precise genetic diagnoses will also help to define cohorts of children with RTMs for long-term clinical outcome studies.

When should gastrostomy tubes be removed following successful renal transplantation

Enteral feeding using gastrostomies has been a quiet revolution in the management of infants and children with chronic and end stage renal failure over the last 15 yr with improvement in quality of life, nutrition, growth, cognitive development and metabolic control (1, 2, 3). Ensuring consistent delivery of fluids, medications and nutritional requirements may also delay progression to end stage renal failure and improve longterm survival (4). Many paediatric nephrologists recall the frustration and impotence shared with parents trying to feed children with little or no spontaneous appetite who would then reward their efforts by vomiting and could only observe anxiously as they failed to thrive. Most would agree that early instigation of gastrostomy feeding, which may be combined with an anti-reflux procedure if indicated has improved outcome especially for younger children. Parents who initially may be reluctant to have a gastrostomy placed often express their relief after the procedure as the burden of responsibility for feeding their child is deflected to a pump. Children can often feed normally during the day with the feed delivered overnight to meet nutritional requirements. Potentially damaging effects on the parent-child relationship may be averted with improvement in the outcome for transition to oral feeding post-transplantation. Gastrostomies are placed by an open procedure (gastrostomy tube initially which can then be replaced by a button when the track is formed) or endoscopically (percutaneous gastrostomy/PEG) (5). Minor complications are well documented for both approaches particularly exit site infections. However gastrocolic fistulae and migration of the retention disc can present as significant late complications of PEG placement and gastrocutaneous fistulae may need surgical closure following gastrostomy button removal (6, 7). There were initial concerns of an increased risk of fungal peritonitis in children on peritoneal dialysis with gastrostomies but this has not been identified as a risk factor in more recent registry data (8). However complications should be minimized by surgical expertise and careful surveillance with adherence to management guidelines including antibiotic cover for PEG placements and planned endoscopic PEG changes every 18–24 months. Children already established on peritoneal dialysis must have an open surgical gastrostomy placement as PEG placement is associated with an unacceptably high risk of peritonitis (5). Wong and colleagues paper is a timely reminder that children continue to need their gastrostomies after renal transplantation (9). It is certainly unrealistic to suddenly expect adherence to the demands of a markedly increased fluid intake and taking critically important medications. As they emphasize this is particularly so in the younger children who may have been enterally fed since birth and have limited experience of normal feeding as well as those with significant co-morbidity. It is very important to recognize the special needs of this latter group, which can comprise up to 35–40% of an end stage renal failure programme. Psychological disturbance may adversely affect transition to oral feeding and should be considered a significant comorbid factor. Poor graft function may also delay gastrostomy removal. Wong’s findings have confirmed that there is no definitive time for gastrostomies to be removed post-transplant and we would support this approach. In our practice at the end of 2004, 135 children were being followed up in the posttransplant clinic. Sixty-nine of these children had gastrostomies of which 54 (79%) have been removed. Three children use their gastrostomies for medications and fluids only i.e. 82% of the children previously needing gastrostomy feeds eat normally post-transplant. This is similar to the figure of 86% reported in our previous Pediatr Transplantation 2005: 9: 553–554 Copyright 2005 Blackwell Munksgaard