Chronic kidney disease following twin-to-twin transfusion syndrome-long-term outcomes.

BACKGROUND: Amongst other sequelae, acute kidney injury (AKI) is a well-recognised post-natal complication of twin-to-twin transfusion syndrome (TTTS). Despite this, there has been a lack of data reporting long-term renal outcomes. Our aim was to report the long-term renal outcomes of infants born with TTTS. METHODS: We performed a retrospective case note review of all infants referred to our centre between 1998 and 2018 with a primary diagnosis of TTTS. Subjects with confirmed TTTS were divided into a chronic kidney disease (CKD) group and a non-CKD group for comparison. RESULTS: Twenty-six infants with TTTS were included for analysis. Eight (31%) subjects developed CKD. Within the CKD group, 50% went on to require long-term renal replacement therapy (RRT) of whom all underwent renal transplantation. For subjects who had neonatal AKI, cumulative survival rate before RRT at 5 and 10 years was 79% and 70%, respectively. Subjects with CKD had a significantly higher incidence of AKI in the neonatal period and were more likely to be the donor twin. Gestational age at birth, gender, antenatal interventions and comorbidities did not affect long-term renal outcome between the two groups. CONCLUSION: This is the first long-term follow-up study demonstrating that CKD progressing to the need for RRT can develop after TTTS. Donor-twin status and neonatal AKI associated with adverse long-term outcomes warranting long-term surveillance in this group.

Hypervitaminosis A is prevalent in children with CKD and contributes to hypercalcemia.

BACKGROUND: Vitamin A accumulates in renal failure, but the prevalence of hypervitaminosis A in children with predialysis chronic kidney disease (CKD) is not known. Hypervitaminosis A has been associated with hypercalcemia. In this study we compared dietary vitamin A intake with serum retinoid levels and their associations with hypercalcemia. METHODS: We studied the relationship between vitamin A intake, serum retinoid levels, and serum calcium in 105 children with CKD stages 2-5 on dialysis and posttransplant. Serum retinoid measures included retinol (ROH), its active retinoic acid (RA) metabolites [all-trans RA (at-RA) and 13-cis RA] and carrier proteins [retinol-binding protein-4 (RBP4) and transthyretin (TTR)]. Dietary vitamin A intake was assessed using a food diary. RESULTS: Twenty-five children were in CKD 2-3, 35 in CKD 4-5, 23 on dialysis and 22 posttransplant; 53 % had vitamin A intake above the Reference Nutrient Intake (RNI) value. Children receiving supplemental feeds compared with diet alone had higher vitamin A intake (p = 0.02) and higher serum ROH (p < 0.001). Notably, increased ROH was seen as early as CKD stage 2. For every 10 ml/min/1.73 m(2) fall in estimated glomerular filtration rate (eGFR), there was a 13 % increase in ROH. RBP4 levels were increased in CKD 3-5 and dialysis patients. The lowest ratios of ROH:RBP4 were seen in dialysis compared with CKD 2-3 (p = 0.03), suggesting a relative increase in circulating RBP4. Serum ROH, RBP4 and at-RA were associated with serum calcium. On multivariable analysis RBP4 levels and alfacalcidol dose were significant predictors of serum calcium (model R (2) 32 %) in dialysis patients. CONCLUSIONS: Hypervitaminosis A is seen in early CKD, with highest levels in children on supplemental feeds compared with diet alone. Serum retinoid levels significantly predict hypercalcemia.

Evaluation of quality of life by young adult survivors of severe chronic kidney disease in infancy.

BACKGROUND: The health related quality of life (HRQoL) of young adults treated for chronic kidney disease (CKD) stage 4/5 from infancy is unknown. METHODS: A HRQoL questionnaire was sent to all 41 patients aged >16 years from a previously characterised cohort of infants with CKD stage 4/5 born between 1986 and 1997. Patient scores were compared with a previously reported cohort of patients who needed renal replacement therapy (RRT) in mid childhood and in the normal population. RESULTS: All patients (11 women) completed the questionnaire at a median (range) age of 19.2 (16.3-23.4) years. At the time of the survey, 5 (12.5 %) were on dialysis, 35 (85.5 %) had a functioning kidney transplant, one (2 %) was still conservatively treated and 22 (54 %) had comorbidities; 68 % were either studying or in paid employment, with 17 % actively seeking employment. Although patients described a lower HRQoL than a healthy, age-matched UK group, in some aspects, scores were comparable with patients needing RRT in later childhood. Lower scores were associated with comorbidities, dialysis at last follow-up, more than one treatment modality change and short stature. CONCLUSIONS: Our survey demonstrates very encouraging results for long-term HRQoL of infants with severe CKD and highlights the negative impact of comorbidities. These data will help clinicians to counsel and inform families.

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.

Urinary and dialysate losses of vitamin D-binding protein in children on chronic peritoneal dialysis.

BACKGROUND: Vitamin D deficiency is widely prevalent in chronic kidney disease [CKD] patients. The aim of our study was to determine whether losses of vitamin D binding protein [VDBP] in urine and dialysate contribute to circulating 25-hydroxyvitamin D [25OHD] levels in chronic peritoneal dialysis [PD] patients. METHODS: Dialysate, serum, and urine VDBP levels were measured in 16 children on PD and compared with serum and urine VDBP in ten CKD4-5 patients. Serum VDBP levels were correlated with total circulating 25OHD and peritoneal VDBP losses. RESULTS: The mean age of the study population was 9.4 ± 3.8 years and the median time on dialysis 7.5 (1-18) months. In CKD4-5 patients, urinary VDBP losses were >300-fold higher than seen in age-matched healthy children and correlated with urinary albumin loss (p = 0.0008). There was a significant correlation between serum VDBP and total dialysate and urine losses of VDBP (p = 0.03, r = -0.53). Dialysate VDBP losses correlate with dialysate albumin loss (p = 0.01). VDBP losses in the long daytime dwell were higher than in the overnight drain (p = 0.04). Serum VDBP levels were lower in children with a longer dialysis vintage (p = 0.0004, r = -0.77). In PD patients, the mean total loss of VDBP in dialysate and urine was 1.91 ± 1.6 µmol/day, equivalent to ~7% of the total circulating level of VDBP in healthy controls. There was no correlation between 25(OH)D and VDBP. CONCLUSIONS: Peritoneal VDBP losses mirror both dialysate and urinary albumin losses, and are associated with a longer dialysis vintage but do not contribute to vitamin D deficiency in children on PD.

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.

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.

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 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.

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

OBJECTIVE: To identify whether the order of performing transplant and bladder reconstruction operations in children who need both operations affects outcome of either operation. PATIENTS AND METHODS: A retrospective case note review was performed of children identified from our database, who had undergone both renal transplantation and bladder augmentation between 1990 and 2005. RESULTS: In all, 18 renal transplants (eight live-related) were performed in 16 children with 10 transplants done after bladder augmentation and eight transplants done before augmentation. The median age at transplantation was 7.5 years and at augmentation was 7.0 years. The median interval between the operations was 33.5 months and the median follow-up was 58.4 months after transplantation. Outcomes were compared between the two groups of patients: those who received their transplantation before bladder augmentation, and those who were transplanted after bladder augmentation. There was no difference between these groups in: the pre- transplant estimated glomerular filtration rate, inpatient stay after transplantation or after augmentation, and incidence of urinary tract infection in the 3 months after renal transplantation or after bladder augmentation. There was no statistical difference in renal allograft loss with one graft failure in the group who were augmented first, and four graft failures in the group who were transplanted first. However, it is of note that the single graft failure in the patient augmented first was due to renal artery thrombosis on the first day related to a double arterial anastomosis, whilst in the other group, three of the graft failures were in transplants that had initially been drained by ureterostomy. Three patients in the group transplanted first developed significant ureteric pathology, of which one developed graft failure. CONCLUSION: Bladder reconstruction can be performed safely before transplantation; it does not increase complications and might better protect the renal graft and specifically the transplant ureter.

CT findings in gastrocolic fistula following percutaneous endoscopic gastrostomy.

We describe the CT findings in an initially asymptomatic boy aged 2 years 9 months with a gastrocolic fistula following percutaneous endoscopic gastrostomy (PEG) placement. The findings consisted of an unusual configuration of the gastrostomy tubing on an abdominal radiograph and upper gastrointestinal study indicating the possibility of transcolic PEG placement, which was confirmed with limited section CT. This well-known and major complication following a common procedure may be recognized on plain abdominal radiography, but it has not to our knowledge been documented previously on CT in a child.

Long-term outcome of chronic dialysis in children.

We describe the outcome since 1984 of all children receiving chronic dialysis in our centre for >3 months with a minimum follow-up of 5 (median 7.2) years. There were 98 children (61 boys), with a median age at the start of dialysis of 4.2 (range: birth to 16.2) years. Twenty-one children started dialysis at <1 year of age and 54 under <5 years. Thirty children had significant comorbidity. The median time on dialysis was 1.4 (0.3 to 14.4) years, giving a total dialysis experience of 296 patient-years. Fifty-three children received a renal transplant as their first change of treatment modality, but 31 switched between PD and HD, with a total of 54 changes of dialysis modality pre-transplantation. Twenty-one of the transplanted patients (39%) returned to dialysis. There were a total of 115 transplants in 88 patients. There was a positive increase for both the weight and height SDS for all the age groups while on dialysis, but this did not reach statistical significance. There were 17 deaths over the 20-year study period; of these, 10 died on dialysis. The overall patient survival was 83%. The mortality rate was 2.7 times greater in children who required renal replacement therapy under the age of 5 years. Of the deaths, 76% were in association with comorbid conditions. In conclusion, both a younger age at the start of renal replacement therapy and comorbidity are significant risk factors for death. The number of returnees to dialysis highlights the importance of conserving dialysis access.

Catch-up growth with normal parathyroid hormone levels in chronic renal failure.

The optimum range for parathyroid hormone (PTH) levels in children with chronic renal failure (CRF) remains undefined. We aimed to determine growth velocity in children with CRF managed with normal PTH levels. We performed a retrospective case note review of 99 children (77 boys), with a glomerular filtration rate (GFR) <41 ml/min per 1.73 m(2), who had at least 2 years of 3-monthly follow-up. The age range at entry was 0.5-6.0 years; data collection was continued until 10 years of age or the commencement of growth hormone or renal replacement therapy. The median GFR was 22 ml/min per 1.73 m(2); over the study period mean serum calcium and phosphate levels were approximately equal to the mid-point of the respective normal ranges. Median PTH levels were equal to the upper limit of the normal range. Height standard deviation score (Ht SDS) at entry was -1.73. During the study period the overall mean change in Ht SDS was +0.3, significantly greater than the no change expected of a normal population ( P=0.004). The median dose of calcium carbonate was 150 mg/kg per day and 1-alpha calcidol 0.015 microg/kg per day. The growth rate was independent of all parameters, including age, PTH levels, the use of enteral feeds, and 1-alpha calcidol prescription. Our results indicate that catch-up growth can occur in infants and children with CRF when medical therapy is aimed at normalizing PTH levels.

Chronic hemodialysis in infants and children under 2 years of age.

Over the past 16 years, 18 children under 2 years of age received chronic hemodialysis (HD) at our center. Five children were anuric at the start of HD and 6 had significant co-morbidity. The most common underlying diagnosis was posterior urethral valves. The median age at the start of HD was 12.2 months. A total of 39 episodes (defined as a discrete time period during which HD was the principle form of renal replacement therapy) of HD were performed, with a median duration of 7 months and 91.3 dialysis sessions per episode. Problems with vascular access were very common, with a revision ratio of 40%. Twenty-two line revisions were required for 36 episodes of line infection, with a median rate of line infection of 2.7 infections/patient years. The most commonly encountered organism was coagulase-negative Staphylococcus (69%). Twenty-three lines needed revision due to poor line function, despite the routine use of heparin. The effectiveness of HD was assessed in 11 patients who received HD for a continuous period of 3 or more months. The median urea reduction rate was 72%, while the parathyroid hormone levels improved to within twice the upper limit of the reference range in 69%. While there was no significant change in the median weight and height standard deviation score (SDS), the median SDS for head circumference showed significant improvement ( P=0.04). Both growth and developmental outcomes were strongly influenced by existing co-morbidity. Sixteen (89%) children were transplanted. Four (22%) children died, 3 after successful transplants. None of the deaths occurred on HD or resulted from its complications. In conclusion, HD in infants and small children is an effective and safe form of renal replacement therapy, but problems with vascular access limit its long-term use.

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.