Angélique Dachy

Justine Bacchetta

Anne-Laure Sellier-Leclerc

Aurélia Bertholet- Thomas

Delphine Demède

Pierre Cochat

François Nobili

Bruno Ranchin
email: bruno.ranchin@chu-lyon.fr

Long term outcomes of peritoneal dialysis started in infants below 6 months of age: An experience from two tertiary centers

Keywords:

Background: Little data are available for infants who started renal replacement therapy before 6 months of age. Because of extra-renal comorbidities and uncertain outcomes, whether renal replacement therapy in neonates is justified remains debatable. Methods: We performed a retrospective analysis of all patients who began chronic peritoneal dialysis below 6 months between 2007 and 2017 in two tertiary centers. Results are presented as median (min;max). Results: 17 patients (10 boys) were included (8 prenatal diagnoses, 6 premies), with the following diagnoses: congenital anomalies of kidney and urinary tract (n=9), oxalosis (n=5), congenital nephrotic syndrome (n=2) and renal vein thrombosis (n=1). Five patients had associated co-morbidities. At peritoneal dialysis initiation, age was 2.6 (0.1;5.9) months, height-standard deviation score (SDS) -1.3 (-5.7;1.6) and weight-SDS -1.4 (-3.6;0.6). Peritoneal dialysis duration was 12 (2;32) months, and at peritoneal dialysis discontinuation height-SDS was -1.0 (-4.3;0.7) weight-SDS -0.7 (-3.2;0.2), parathyroid hormone 123 (44;1540) ng/L, and hemoglobin 110 (73;174) g/L. During the first 6 months of peritoneal dialysis, the median time of hospitalization stay was 69 (15;182) days. Ten patients presented a total of 27 peritonitis episodes. Reasons for peritoneal dialysis discontinuation were switch to hemodialysis (n=6), transplantation (n=6), recovery of renal function (n=2) and death (n=1). After a follow-up of 4.3 (1.7;10.3) years, 12 patients were transplanted, 2 patients were still on peritoneal dialysis, 2 patients were dialysis free with severe chronic kidney disease and 1 patient had died. Seven patients displayed neurodevelopmental delay, of whom five needed special schooling.

Conclusion:

We confirm that most infants starting peritoneal dialysis before 6 months of age will be successfully transplanted and will have a favorable growth outcome. Their quality of life will be impacted by recurrent hospitalizations and neurodevelopmental delay is frequent.

Introduction

Little information is available for infants who started chronic PD before 6 months of age. Children who start RRT within the first months of life have more clinical complications, an increased risk of peritonitis and more technical failure of dialysis compared to children who start RRT later [START_REF] Vidal | Peritoneal dialysis in infants: The experience of the Italian Registry of Paediatric Chronic Dialysis[END_REF][START_REF] Carey | Outcome of patients initiating chronic peritoneal dialysis during the first year of life[END_REF][START_REF]USRDS annual data report: Epidemiology of kidney disease in the United States[END_REF][START_REF] Van Stralen | Survival and clinical outcomes of children starting renal replacement therapy in the neonatal period[END_REF][START_REF] Sanderson | End-stage kidney disease in infancy: an educational review[END_REF]. Besides, comorbidities are more prevalent in this population with coexisting extrarenal involvement due to primary disease, making prenatal counselling more complicated [START_REF] Vidal | Peritoneal dialysis in infants: The experience of the Italian Registry of Paediatric Chronic Dialysis[END_REF][START_REF] Carey | Outcome of patients initiating chronic peritoneal dialysis during the first year of life[END_REF][START_REF]USRDS annual data report: Epidemiology of kidney disease in the United States[END_REF][START_REF] Van Stralen | Survival and clinical outcomes of children starting renal replacement therapy in the neonatal period[END_REF][START_REF] Sanderson | End-stage kidney disease in infancy: an educational review[END_REF][START_REF] Weaver | Clinical outcomes and survival in pediatric patients initiating chronic dialysis: a report of the NAPRTCS registry[END_REF][START_REF] Wedekin | Renal replacement therapy in infants with chronic renal failure in the first year of life[END_REF][START_REF] Ledermann | Long-term outcome of peritoneal dialysis in infants[END_REF][START_REF] Zurowska | Clinical practice recommendations for the care of infants with stage 5 chronic kidney disease (CKD5)[END_REF][START_REF] Chan | Chronic peritoneal dialysis in Chinese infants and children younger than two years[END_REF][START_REF] Mekahli | Evaluation of quality of life by young adult survivors of severe chronic kidney disease in infancy[END_REF]. As summarized in Table 1, long-term data outcomes are scarce, raising the ethical issues whether PD in neonates is justified and leading to different managements between centers [START_REF] Rees | Renal replacement therapies in neonates: issues and ethics[END_REF]. The objective of this retrospective study was to report the experience of two French tertiary pediatric nephrology centers on 17 infants who began chronic PD before 6 months of age, on a 10-year period, to provide additional evidence for the discussion.

Patients and methods

We performed a retrospective analysis of all patients followed in two tertiary centers (Lyon and Besançon) who began chronic PD below 6 months of age between January 2007 and January 2017. The following clinical data were recorded: term of the pregnancy, biometric data (height, body weight, head circumference) at birth, PD initiation, 15 days after PD initiation, every 3 months during the first year of PD, and every 6 months until 3 years or until the last follow-up on PD. Biometrical parameters were normalized as SDS according to chronological age and gender according to French growth reference charts [START_REF] Sempé | Auxologie méthode et séquences[END_REF]. The surgical procedure for PD catheter insertion was described: catheter placement, associated omentectomy. The primary diagnosis and the presence of a prenatal diagnosis were also recorded. Dialysis was initiated on manual mode (initial volume of 10 mL/kg), with progressive increase until 80 to 100 mL. This volume enabled the use of an automated cycler (Sleep Safe cycler, Fresenius Medical Care AG & Co., Bad Homburg vor der Höhe, Germany). Cycle volume was gradually increased to 800 mL/m 2 before 2 years of age and 1400 mL/m 2 after 2 years of age, with 5 to 15 cycles per night and daytime dwell if needed. PD fluid used for nightime cycles was biocompatible with a neutral pH, bicarbonate buffer, and low levels of glucose degradation products (Bicavera or Balance, Fresenius Medical Care AG & Co., Bad Homburg vor der Höhe, Germany); for daytime cycles icodextrine (Extraneal, Baxter Healthcare LTD, Norfolk, England) was used. Hemoglobin and PTH status before PD start, 3 months after the beginning of PD, after one year and at last PD follow-up were registered. In the absence of other formula in this age group, the 2009 Schwartz formula was used to evaluate the eGFR at the beginning of PD [START_REF] Schwartz | New equations to estimate GFR in children with CKD[END_REF]. Treatment in terms of active vitamin D doses (µg/kg/d), phosphate binders use and type, EPO week dose (IU/kg/week) and GH treatment if present (mg/kg/week) were recorded before the beginning of PD, at 3 and 6 months after the PD start, at the end of PD and at the end of the follow-up. Complications assessment includes incidence and characteristics of peritonitis, catheter complications (exit site infection ESI, obstruction, leaks and cuff extrusion). Consequences were reflected by the hospitalization rate (the number of hospitalization and cumulative duration at 6 months and 12 months after PD initiation). Peritonitis was defined according to ISPD recommendations [START_REF] Warady | Consensus guidelines for the prevention and treatment of catheter-related infections and peritonitis in pediatric patients receiving peritoneal dialysis: 2012 update[END_REF]: signs and symptoms of peritoneal irritation, peritoneal cellularity in cloudy effluent >100 cells/mm 3 or a positive culture. Catheter ESI was defined as the presence of purulent discharge from the catheter or marked peri-catheter swelling, redness, tenderness with or without pathogenic germs cultured. If available, data on cardiological ultra-sounds were recorded. LVH was defined as a left ventricular mass index >38 g/m 2,7 according to the definition of the International Pediatric Peritoneal Dialysis Network [START_REF] Borzych | Defining left ventricular hypertrophy in children on peritoneal dialysis[END_REF]. We used the International Pediatric Peritoneal Dialysis Network calculator to define the left ventricular mass index according to height, left ventricular end-diastolic diameter, posterior wall thickness and intraventricular septal diastolic thickness (www.pedpd.org). HTN was define as blood pressure ≥95 th percentile for age and height according to the TASK Force on Blood Pressure Control in Children [START_REF] Horan | Report of the second task force on blood pressure control in children -1987 -Task Force on Blood Pressure Control in Children[END_REF]. Final outcomes were defined as transplantation, hemodialysis switch, PD arrest and/or death. Time before transplantation, height and weight at the time of transplantation and type of donor were reported. Graft survival and causes of graft loss were also collected. Neurodevelopmental outcomes were determined by the clinical status of patients at the end of the follow-up (whether he was presenting developmental delay or not) and the type of schooling (normal schooling or special education). Statistical analyses were mainly descriptive, and results are presented as median (range). Paired tests were used to compare the evolution of the different parameters at the different time points. Spearman bivariate analyses were performed. A P-value below 0.05 was considered statistically significant. This retrospective study was approved by the local IRB (Comité d'éthique des hospices civils de Lyon, session June 7 th 2018). By French law, retrospective studies do not require a written consent from the patients/parents but an oral information.

Results

Clinical characteristics

A total of 17 patients (10 boys) begun chronic PD before 6 months of age. Their characteristics are reported in Table 2. Median age at PD start was 2.6 (0.1;5.9) months with 11 infants starting dialysis between 0-3 months. Median PD duration was 12 (2;32) months and follow-up was 4.3 (0.7;10.3) years. Residual diuresis was observed during PD in 11 patients, whilst 4 patients were completely anuric at PD start, and data were missing for 2 patients. The eGFR at PD start was 5 (2;17) mL/min per 1.73 m 2 . Five out of the 17 patients were moderate to late preterm and one was very preterm (30 weeks of gestation). Eight out of 12 children had a prenatal diagnosis; medical abortion was refused by parents in 2 cases, and antenatal data were missing for the last 5 cases. The primary diagnosis was: CAKUT (n=9), oxalosis (n=5), congenital nephrotic syndrome (n=2) and renal vein thrombosis (n=1). Five patients presented at least one associated co-morbidity: lungs hypoplasia in two babies, neurological comorbidities resulting from perinatal asphyxia in two and Prune-Belly like syndrome in one.

Growth

Median birth weight and height were 3071 (1570;3870) grams and 48.5 (41.5;51.5) cm, respectively. The median body weight at PD start was of 4.6 (1.5;5.8) kg and -1.4 (-3.6;0.6) SDS. The median SDS for weight at PD discontinuation was -0.7 (-3.2;0.2) (P=NS from PD initiation), with a median delta SDS for weight between the beginning of PD and the end of PD of -0.6 (-2.4;1.7). Median height SDS was -1.3 (-5.7;1.6) at the start of PD and -1.0 (-4.3;0.7) at the end of PD treatment (P=NS). Median delta SDS for height between the beginning of PD and the end of PD was 0.2 (-3.9;4.8). Median SDS BMI was at the beginning of PD -3.3 (-4.3;-1.0) and -1.7 (-3.3;1.0) at the end of PD (P=0.005).

Sixteen patients required enteral feeding, 11 by gastrostomy and 5 by nasogastric tube. Gastrostomy were surgically placed at 3.3 (1.4;12.1) months of age, 14 (10;22) days before PD start for 9 patients; it is noteworthy that two patients had a gastrostomy placed after the beginning of PD (respectively 296 and 465 days after). One patient had no enteral feeding at all but also demonstrated catch-up growth. Three infants received rhGH because of severe growth retardation.

Peritoneal access and PD complications

Twenty-nine PD catheters were surgically placed in 17 patients, with associated omentectomy in 10 infants. Data about omentectomy were missing for 7 patients. The time between catheter placement and the beginning of PD was 4 (0;22) days. Six patients required 11 catheter replacements because of catheter obstruction (n=3), dysfunction (n=4), infections (n=2) and leakage (n=2). Of those, one patient needed replacement of the peritoneal access twice, two patients needed three different replacements and three patients needed only one catheter replacement. Nine catheter obstructions occurred in four patients, resolving after urokinase treatment in eight cases, and surgical procedure in one case. Four catheter leakages occur in three infants. Cuff extrusion occurred only once in one patient. Twenty-seven episodes of peritonitis occurred in 10 infants. Eight infants were affected by ≥ two episodes, two patients underwent a single peritonitis episode and seven patients did not present any peritonitis. One peritonitis episode occurred every 7.6 months-patient. Most frequent organisms were Gram-positive cocci (n=13, Staphylococcus aureus n=7, coagulase-negative Staphylococcus n=5, Streptococcus n=1), followed by Gram-negative bacillus (n=9, Escherichia Coli n=4, Pseudomonas n=2, Klebsiella n=3). One patient had a peritonitis episode with multiple bacteria. Three patients had clinical signs and symptoms of peritonitis with a cloudy effluent and increased effluent cellularity but a negative culture. In one patient, no data were found on the involved organism. ESI were found in two patients, who presented associated peritonitis. During the first six months of PD, the median number of hospitalizations was 3 (1;10). Six patients were hospitalized only once during this time and all the others underwent two to ten hospitalizations. The total duration of hospitalization stays was 69 (15;182) days. Most of the reason for hospital stays were dialysis initiation with education of parents (n=7) and infections (n=10). Between the 6 th and 12 th month on PD, the number of hospitalizations was 3 (1;11) with a total duration of hospitalization stays of 25 (1;186) days. The most common cause of hospitalization during this period were infections (n=12) and clinical complications (dehydration, vomiting, n=4).

Anemia and CKD-MBD

The biochemical evolution of patients is summarized in Table 3. Before PD, median PTH levels were 212 (6;799) ng/L, decreasing to 130 (23;732) ng/L 3 months after the beginning of PD, and reaching 123 (44;1540) ng/L at the end of PD (P=NS between PD initiation and the end of PD). Phosphate binders were prescribed in five patients before the start of PD, data for 3 patients were missing. Only three patients still received phosphate binders at the end of PD, three data were missing. The most frequent type of phosphate binders remained calcium carbonate. One patient with severe hyperparathyroidism required calcium carbonate and sevelamer. Seven patients received active vitamin D analogs at the start of PD with a median daily dose of alfacalcidol of 0.06 (0.02;0.30) µg/kg. Six patients were still treated at the end of the PD with a median daily dose of 0.07 (0.02;0.20) µg/kg. Median hemoglobin levels at PD start were 94 (60;191) g/L, and 110 (73;174) g/L at the end of PD (P=NS). Before PD, 12 patients were receiving EPO, with a median of 369 (179;1235) UI/kg per week. One patient was not receiving EPO and data were not available for 4 patients. At the end of PD, EPO median dose was 333 (163;1250) UI/kg per week (12 treated patients, 2 non-treated patients and 3 missing data).

Cardiovascular impact

At the beginning of PD, 6 patients had an echocardiography. Of those, five patients demonstrated LVH with a median left ventricular mass index of 55 (34;63) g/m 2.7 . 3/5 patients with LVH received anti-hypertensive therapies (one missing data) and one patient displayed HTN. After 3 months on PD, 8/11 patients assessed for cardiovascular function displayed LVH with a median left ventricular mass index of 66 (34;108) g/m 2.7 . 4/8 patient had anti-hypertensive therapy and one patient had HTN. After one year on PD, 10/13 patients who had cardiovascular evaluation displayed LVH and a median left ventricular mass index of 59 (37;94) g/m 2.7 with associated HTN for 7/10 patients and antihypertensive treatment in 5/10 patients (one missing data). At the end of PD, among the 11 patients who underwent an echocardiography, ten still had LVH with a median left ventricular mass index of 72 (35;170) g/m 2.7 , 5/10 having HTN and 2/10 receiving antihypertensive therapies (one missing data).

Neurodevelopmental outcomes

Data concerning the head circumference SDS at PD start were collected in 11 patients with a head circumference SDS of -1.0 (-4.9;1.3), decreasing at -1.1 (-5.0;0.4) after 6 months of PD to -1.2 (-3.6;0.7) one year after PD start (P=NS) between PD initiation and one year after PD initiation. Data were insufficient to assess the cranial perimeter at the end of PD and beyond this date. Neurological status of the 16 surviving patients was reviewed. After a follow-up of 4.3 (1.7;10.3) years, seven patients displayed neurodevelopmental delay with five patients needing special schooling. Among those seven patients, four presented with severe extrarenal co-morbidities, and notably two had perinatal asphyxia with hypoxia. One perinatal asphyxia occurred in a context of congenital nephrotic syndrome with neonatal vascular stroke resulting in right hemiplegia. One patient presented pulmonary hypoplasia and one patient presented a Prune-Belly like syndrome. The last three patients with neurodevelopmental delay had no associated extra-renal co-morbidities.

Long-term outcomes

The causes of PD discontinuation were the following: • switch to hemodialysis (n=6); • transplantation (n=6); • recovery of renal function (n=2); • death (n=1). Reason for hemodialysis shift were oxalosis (n=4), catheter dysfunction (n=1) and recurrent peritonitis and pleural effusion (n=1). Oxalosis patients (n=5) underwent simultaneous hemodialysis and PD during 8.2 (4.4;11.9) months after 7.6 (4.4;10.7) months on PD. Two patients with primary hyperoxaluria were transplanted while they were still on simultaneous hemodialysis and PD, as previously reported [START_REF] Duclaux-Loras | Pediatric combined liver-kidney transplantation: a single-center experience of 18 cases[END_REF]. After a follow-up of 4.3 (1.7;10.3) years, 12 patients had received a kidney transplant, 2 patients were still on PD, 2 patients had spontaneous recovery of renal function (after 2.2 and 7.6 months of PD with respectively eGFR 45 mL/min per 1.73 m 2 one month postdiscontinuation and 23 mL/min per 1.73 m 2 four months after discontinuation). One patient died after 12 months on PD and 2.1 years of follow-up, shortly after central venous catheter positioning because of Staphylococcus sepsis. Median time between PD start and transplantation was 22 (8;32) months and median age at first transplantation was 25 (12;42) months with a median body weight of 11.3 (8.6;13.3) kg and a median height of 83 (72.5;87) cm. All kidney transplants were coming from deceased donors. Two patients lost their graft because of venous graft thrombosis, as previously reported [START_REF] Loiseau | Renal transplantation in children under 3 years of age: Experience from a single-center study[END_REF]. Long-term outcomes are summarized in Table 4.

Discussion

Even if the incidence of ESRD in children less than 4 years is low (5.2 per million agerelated inhabitants in France) [START_REF] Hogan | Patient and transplant outcome in infants starting renal replacement therapy before 2 years of age[END_REF], the initiation of chronic PD in infants below 6 months represents a challenge and dialysis in neonates is still debated [START_REF] Ranchin | Review: neonatal dialysis is technically feasible but ethical and global issues need to be addressed[END_REF]. In a recent study, which focused on maintenance dialysis that was started before one year of age, a younger age at RRT start was found to be a significant risk factor for death. This risk fell by 5% for each month that the infants aged [START_REF] Vidal | Infants requiring maintenance dialysis: Outcomes of hemodialysis and peritoneal dialysis[END_REF]. Ethical issues related to the high morbidity rate, the increased risk of peritonitis and the overall fragility of infants starting RRT at a young age need to be weighed against the important progress made in this field over the past years, allowing better chances of survival. In our center, the decision process from whether or not to start dialysis is mainly based on family information and multi-professional team ethical discussions about the main factors affecting the expected quality of life such as extra-renal comorbidities and /or anuria [START_REF] Zurowska | Clinical practice recommendations for the care of infants with stage 5 chronic kidney disease (CKD5)[END_REF][START_REF] Rees | Renal replacement therapies in neonates: issues and ethics[END_REF][START_REF] Ranchin | Review: neonatal dialysis is technically feasible but ethical and global issues need to be addressed[END_REF]. The majority of patients in our study were successfully transplanted, with favorable growth. This is consistent with the results found by others, which confirmed the good outcomes of children starting RRT before 2 years of age [START_REF] Vidal | Peritoneal dialysis in infants: The experience of the Italian Registry of Paediatric Chronic Dialysis[END_REF][START_REF] Ledermann | Long-term outcome of peritoneal dialysis in infants[END_REF][START_REF] Hogan | Patient and transplant outcome in infants starting renal replacement therapy before 2 years of age[END_REF]. In terms of growth, our report shows a slight increase of median height SDS during PD. This is consistent with the data published by others [START_REF] Vidal | Peritoneal dialysis in infants: The experience of the Italian Registry of Paediatric Chronic Dialysis[END_REF][START_REF] Van Stralen | Survival and clinical outcomes of children starting renal replacement therapy in the neonatal period[END_REF][START_REF] Weaver | Clinical outcomes and survival in pediatric patients initiating chronic dialysis: a report of the NAPRTCS registry[END_REF][START_REF] Ledermann | Long-term outcome of peritoneal dialysis in infants[END_REF][START_REF] Chan | Chronic peritoneal dialysis in Chinese infants and children younger than two years[END_REF]. In contrast, a Chinese cohort of nine children starting RRT below 2 years of age showed a satisfactory weight gain but a decline in height SDS from -0.7 SDS at PD initiation to -1.4 SDS at the end of follow-up [START_REF] Chan | Chronic peritoneal dialysis in Chinese infants and children younger than two years[END_REF]. Only three patients were treated by rGH at the end of PD in our cohort; we believe that optimization of nutritional status is most of the time sufficient to ensure growth catch-up in this age group [START_REF] Ledermann | Long-term outcome of peritoneal dialysis in infants[END_REF]. However, some children will have to be treated with rGH if the nutritional management is insufficient, as recently reviewed in the European guidelines on the use of rhGH in pediatric CKD [START_REF] Drube | Clinical practice recommendations for growth hormone treatment in children with chronic kidney disease[END_REF]. In a randomized study collecting 16 patients less than 24 months of age with severe CKD stage 3-4, seven patients were enterally fed and 80% of them had recommended daily calories, GH treated patients showed significantly higher length gains (14.5 versus 9.5 cm/year with mean height SDS +1.43 versus -0.11) [START_REF] Santos | Improvement in growth after 1 year of growth hormone therapy in well-nourished infants with growth retardation secondary to chronic renal failure: Results of a multicenter, controlled, randomized, open clinical trial[END_REF]. Concerning weight gain, we found a steadily increase in weight parameters during the time on PD. In our cohort, 11/17 patients were fed enterally by gastrostomy, which appeared to be the best way of enteral feeding in young children on chronic PD [START_REF] Rees | Growth in very young children undergoing chronic peritoneal dialysis[END_REF]. Only one patient had no enteral feeding at all (refused by parents), despite severe initial intra-uterine growth retardation, but growth was relatively correct provided a very intensive nutritional care (mean height SDS -5.7 at the start of PD to -1.8 after 23 months on PD; mean weight SDS -3.4 at the start of PD to -1.7 at the end of the 23 months on PD). However, this child displayed uncontrolled severe secondary hyperparathyroidism and severe orality troubles. A significant increase in BMI was found in our study from -3.3 SDS at PD beginning to -1.7 SDS at the end of PD. None of the patients had a BMI >2 SDS. In Brady's study evaluating carotid intima-media thickness of 101 children aged 2-18 years with mild to moderate CKD during 12 months of follow-up, dyslipidemia was an important cardiovascular risk factor significantly associated with increased intima-media thickness, although no direct correlation was found between BMI and increased carotid intima-media thickness [START_REF] Brady | Carotid intimamedia thickness in children with CKD: results from the CKiD study[END_REF]. According to the study of Bonthuis and al., who evaluated the prevalence of obesity and underweight among 4474 patients less than 16 years on RRT in 25 European countries, the prevalence of underweight was 3.5%, whereas 12.5% were obese [START_REF] Bonthuis | Underweight, overweight and obesity in paediatric dialysis and renal transplant patients[END_REF]. As obesity seems more prevalent than underweight in European children on RRT, it seems necessary to avoid a too important catch-up weight gain in these youngest children, so as to avoid to worsen the cardiovascular risk on the long term [START_REF] Bonthuis | Underweight, overweight and obesity in paediatric dialysis and renal transplant patients[END_REF]. Indeed, a significant proportion of our patients on PD already displayed LVH, and previous works have shown that the control of arterial hypertension in children on PD is far from optimal [START_REF] Van Stralen | Survival and clinical outcomes of children starting renal replacement therapy in the neonatal period[END_REF][START_REF] Weaver | Clinical outcomes and survival in pediatric patients initiating chronic dialysis: a report of the NAPRTCS registry[END_REF]. As it was previously reported, we found an increased risk of peritonitis and PD catheter complication in infants [START_REF] Vidal | Peritoneal dialysis in infants: The experience of the Italian Registry of Paediatric Chronic Dialysis[END_REF][START_REF] Weaver | Clinical outcomes and survival in pediatric patients initiating chronic dialysis: a report of the NAPRTCS registry[END_REF][START_REF] Ledermann | Long-term outcome of peritoneal dialysis in infants[END_REF][START_REF] Zaritsky | Epidemiology of peritonitis following maintenance peritoneal dialysis catheter placement during infancy: a report of the SCOPE collaborative[END_REF]. Compared to previous reports on the subject, our series has an important proportion of patients with hyperoxaluria (our unit is a reference center for this disease), these patients are known to display severe growth retardation, malnutrition and systemic disease [START_REF] Cochat | Primary hyperoxaluria[END_REF]. Oxalosis (n=4) was the major cause of PD discontinuation, followed by catheter dysfunction (n=1) and recurrent peritonitis (n=1). As described in the two large studies evaluating survival among infants less than 1 year of age who initiated chronic PD [START_REF] Weaver | Clinical outcomes and survival in pediatric patients initiating chronic dialysis: a report of the NAPRTCS registry[END_REF][START_REF] Sanderson | Outcomes of infants receiving chronic peritoneal dialysis: an analysis of the USRDS registry[END_REF], most of the infants terminated dialysis for transplantation. This is consistent with the results of the Italian, the French and the GOSH series [START_REF] Vidal | Peritoneal dialysis in infants: The experience of the Italian Registry of Paediatric Chronic Dialysis[END_REF][START_REF] Ledermann | Long-term outcome of peritoneal dialysis in infants[END_REF][START_REF] Hogan | Patient and transplant outcome in infants starting renal replacement therapy before 2 years of age[END_REF]. However, they reported a 4-fold greater mortality than in older children and mortality rates were 2-fold higher in infants who had at least one medical comorbidity such as prematurity, hypoxic-ischemic encephalopathy, Wilm's Tumor, pulmonary hypoplasia [START_REF] Vidal | Peritoneal dialysis in infants: The experience of the Italian Registry of Paediatric Chronic Dialysis[END_REF]. Interestingly, Sanderson found no significant difference in the risk of mortality based on age of dialysis initiation in the USA [START_REF] Sanderson | Outcomes of infants receiving chronic peritoneal dialysis: an analysis of the USRDS registry[END_REF], as opposed to Vidal who found a 5% lower risk of death per month of later initiation [START_REF] Vidal | Peritoneal dialysis in infants: The experience of the Italian Registry of Paediatric Chronic Dialysis[END_REF]. Nevertheless, in both studies, infectious complications remain the main cause of death in younger children on PD [START_REF] Vidal | Peritoneal dialysis in infants: The experience of the Italian Registry of Paediatric Chronic Dialysis[END_REF][START_REF] Borzych-Duzalka | Peritoneal dialysis access revision in children: Causes, interventions, and outcomes[END_REF][START_REF] Vidal | Peritoneal dialysis and infants: further insights into a complicated relationship[END_REF]. In our cohort, one patient with hyperoxaluria died from an infectious complication. Concerning neurodevelopmental outcomes, a Chinese cohort of nine children starting RRT below 2 years of age showed a developmental delay in 44% of children [START_REF] Chan | Chronic peritoneal dialysis in Chinese infants and children younger than two years[END_REF]. In our study, 7/16 patients displayed neurodevelopmental delay with five patients needing special schooling. Of those, four patients had associated-comorbidities, which are known to be strongly associated with poor neurodevelopmental outcomes [START_REF] Warady | Consensus guidelines for the prevention and treatment of catheter-related infections and peritonitis in pediatric patients receiving peritoneal dialysis: 2012 update[END_REF]. A positive neurodevelopmental outcome after prolonged period on PD is however frequently observed as reported by Lederman [START_REF] Ledermann | Long-term outcome of peritoneal dialysis in infants[END_REF], who showed normal developmental scores 1 and 4 years after PD start in 34 infants who started PD before 3 months of age: in this series, 79% of the school-aged children attended normal school. Obviously, a longer follow-up and an evaluation in early adulthood would be crucial, but data are missing, and in the course of CKD in infancy, many events may occur between the first year of age and late teenage, all being able to further compromise developmental outcomes. We found no significant differences in outcomes for growth, neurological development, infections, catheter-related complications, extra-renal comorbidities and kidney transplant between anuric infants (n=4) compared to those with residual diuresis. We have to acknowledge some limitations to this study, mainly inherent to the retrospective design in a small population concerning extra-rare conditions. However, the design allowed us to have detailed data on these 17 patients, which represent one of the largest series ever published on the topic (excepting registry data that usually include high numbers of patients with a relative scarcity of data).

Conclusion

We focused our study on the outcomes of infants starting PD before 6 months of age and aimed to provide new data in this specific population. Our study suggests that with an intensive management, and close nutritional support, PD in infants can provide a favorable outcome concerning growth, development and transplantation [START_REF] Ledermann | Long-term outcome of peritoneal dialysis in infants[END_REF]. However, those youngest infants are at increased risk of PD catheter complication and peritonitis with prolonged hospitalizations, having a direct impact on their quality of life. Extra-renal comorbidities remain predictive factor of poor prognosis and need to be considered when counselling parents.

Normal

Table 2 Clinical characteristics of the 17 patients enrolled in the study

 2 Tx R: renal transplantation; Recovery: renal recovery PD: peritoneal dialysis; CNS: congenital nephrotic syndrome; CAKUT: congenital abnormalities of kidney and urinary tract

							14/16 (87%)		NS			4/8 (50%)		NS			NS			NS
			neurodevelopment
			NS: non-specified
	In fa nt	S e x	Ant ena tal dia gn osi s	B ir th ( w k)	Prim ary renal disea se	Com orbid ities	Enter al feedi ng	Res idu al Diur esis	Age at PD initi atio n (mo nth s)	Wei ght (g) at PD initi atio n	Dur atio n of PD (m ont hs)	Outc ome s	Fo llo w-up (ye ar s)	Tim e bef ore Tx (mo nth s)	Ag e at Tx (m on th s)	W eig ht at Tx (k g)	Gr aft los se	Peri toni tis epis ode s	Cath eter relat ed com plicat ions	De vel op -me nt al del ay	Age (end of follo w-up) non-trans plant ed	Wei ght (en d of foll ow-up) (SD S)	Heig ht (end of follo w-up) (SD S)
	1 F NO	3 4. 2	CNS	NO	Gastr osto my	YES 5.9	580 0	21. 8	Tx R 2.9 21.7	27. 7	11		3	NO	YE S		-0.6 0.1
	2 F NO	3 6	CNS	Neur ologic al	NG	NO	5.4	565 6	10. 0	Tx R 8.4 11	15 9.2		0	Obstr uctio n	YE S		0	-0.4
	3 M	YE S	4 0	CAK UT	NO	NG YES 0.9	260 0	22. 8	Tx R 3.2 22	23	11. 2		1	NO	N O		-0.6	0
	4 M NO	3 9	Oxalo sis	NO	NG	NO	3.0	460 0	4.4	HD -> Tx R	10. 5	27	21	11. 8		0	Leak age	YE S		-0.9 -2.3
	5 F NO	3 5	Oxalo sis	NO	Gastr osto my		2.2	425 0	11. 9	HD -> Tx R	4.5 18	42 13		3	NO	N O		-0.8 -2.5
	6 M NO		Oxalo sis	NO	Gastr osto my	NO	2.7	445 0	8.2	HD -> Tx R	5.4 26	30	11. 5		0	Obstr uctio n	N O		-1.1 -1.2
	7 M	YE S	3 8. 6	CAK UT	NO	NG YES 2.2	490 0	32. 0	Tx R	10. 1	32	34 13		3	NO	N O		-1.1 -2.7

Table 3 Biochemical evolution of patients during PD treatment

 3

	PD initation	M3	M12	PD withdrawal End of follow-up

Table 4 Flow Chart: long-term outcomes

 4

	Outcome Number of patients	Ongoing PD n=2	Switch to HD n=6	Transplantation n=6	Renal function recovery n=2	Death n=1
	Median follow-up (years) Height SDS	2.0 (1.7;2.3) -1.5 (-2.8;-0.3)	6.8 (4.3;10.3) -2.0 (-2.5;-0,0)	3.0 (2.8;10.1) -1.1 (-2.7;0.1)	4.4 (2.2;6.7) -0.9 (-1.6;-0.2)	2.2 -3.9
	Neurodevelopmental outcome	1 developmental delay 2 normal schooling (one child with	3 developmental delay 3 normal schooling 3 special schooling	2 developmental delay 5 normal schooling 1 special schooling	1 developmental delay 1 normal schooling 1 special schooling
	Evolution	developmental delay	6 transplanted With 1 graft loss	1 graft loss	2 CKD cases
			(early thrombosis)

Vidal and al. 1 Chan and al. 10 Van Stralen and al. 4 Hogan and al.