Is mild dehydration a risk for progression of childhood chronic kidney disease?

Children with chronic kidney disease (CKD) can have an inherent vulnerability to dehydration. Younger children are unable to freely access water, and CKD aetiology and stage can associate with reduced kidney concentrating capacity, which can also impact risk. This article aims to review the risk factors and consequences of mild dehydration and underhydration in CKD, with a particular focus on evidence for risk of CKD progression. We discuss that assessment of dehydration in the CKD population is more challenging than in the healthy population, thus complicating the definition of adequate hydration and clinical research in this field. We review pathophysiologic studies that suggest mild dehydration and underhydration may cause hyperfiltration injury and impact renal function, with arginine vasopressin as a key mediator. Randomised controlled trials in adults have not shown an impact of improved hydration in CKD outcomes, but more vulnerable populations with baseline low fluid intake or poor kidney concentrating capacity need to be studied. There is little published data on the frequency of dehydration, and risk of complications, acute or chronic, in children with CKD. Despite conflicting evidence and the need for more research, we propose that paediatric CKD management should routinely include an assessment of individual dehydration risk along with a treatment plan, and we provide a framework that could be used in outpatient settings.

Hospital admissions associated with dehydration in childhood kidney transplantation.

BACKGROUND: Paediatric kidney transplant recipients may be at a particular risk of dehydration due to poor kidney concentrating capacity and illness associated with poor fluid intake or losses. In this population, creatinine rise may be more likely with relatively mild dehydration, which may trigger hospital admission. This study describes hospital admissions in the first 12 months after transplantation with diagnosis of graft dysfunction associated with dehydration due to illness or poor fluid intake. We assess risk factors for these admissions. METHODS: Data was extracted from medical records of patients transplanted in two tertiary children hospitals. Following descriptive analysis, multiple failure regression analyses were used to identify factors associated with admission for acute kidney allograft dysfunction associated with dehydration. RESULTS: Of 92 children, 42% had at least 1 dehydration admission in the 12 months following transplantation. Almost half of the dehydration admissions were due to poor fluid intake, which accounted for 1/5 of all unplanned hospital admissions. Target fluid intake at first discharge of > 100 ml/kg/day was associated with dehydration admissions of all types (hazard ratio (HR) 2.04 (95% CI 1.13-3.68)). Teen age was associated with poor fluid intake dehydration admissions (HR 4.87 (95% CI 1.19-19.86)), which were more frequent in mid-summer. Use of enteric feeding tube, which correlated with age under 4, associated with contributing illness dehydration admissions (HR 2.18 (95% CI 1.08-4.41)). CONCLUSIONS: Dehydration admissions in the 12 months following childhood kidney transplantation are common. Highlighted admission risk factors should prompt further study into optimal fluid intake prescription and hydration advice given to children, teenagers, and their carers following kidney transplantation. Use of an enteric feeding tube may not protect patients from admission with dehydration associated with contributing illness. A highger resolution version of the Graphical abstract is available as Supplementary information.

Echocardiogram screening in pediatric dialysis and transplantation.

Transthoracic echocardiography is commonly used to identify structural and functional cardiac abnormalities that can be prevalent in childhood chronic kidney failure (KF). Left ventricular mass (LVM) increase is most frequently reported and may persist post-kidney transplant especially with hypertension and obesity. While systolic dysfunction is infrequently seen in childhood chronic KF, systolic strain identified by speckle tracking echocardiography has been frequently identified in dialysis and it can also persist post-transplant. Echocardiogram association with long-term outcomes has not been studied in childhood KF but there are many adult studies demonstrating associations between increased LVM, systolic dysfunction, strain, diastolic dysfunction, and cardiovascular events and mortality. There has been limited study of interventions to improve echocardiogram status. In childhood, improved blood pressure has been associated with better LVM, and conversion from hemodialysis to hemodiafiltration has been associated with better diastolic and systolic function. Whether long-term cardiac outcomes are also improved with these interventions is unclear. Echocardiography is a well-established technique, and regular use in childhood chronic KF seems justified. A case can be made to extend screening to include speckle tracking echocardiography and intradialytic studies in high-risk populations. Further longitudinal studies including these newer echocardiogram modalities, interventions, and long-term outcomes would help clarify recommendations for optimal use as a screening tool.

Impact of initial steroid response on transplant outcomes in children with steroid-resistant nephrotic syndrome.

BACKGROUND: Limited data suggest children with secondary steroid-resistant nephrotic syndrome (secondary SRNS) have increased risk of recurrence post transplantation. There are no data on the association between secondary steroid resistance and risk of transplant loss. METHODS: Children who received kidney transplantation between 2000 and 2019 for either primary or secondary SRNS in Australia and New Zealand were included. Children presenting with nephrotic syndrome before 12 months were excluded. Data were gathered from chart reviews and ANZDATA. Transplant survival was estimated using the Kaplan-Meier estimator with Cox modelling used to explore predictors of survival. RESULTS: There were seventy children, 38 (55%) male, median age at presentation 4 years (IQR 2-7) and 46 (66%) Caucasian. Median age at transplant was 11 years (IQR 7-15) and 39 (55%) received living donor transplant. Secondary SRNS occurred in 20/70 (29%). For those with secondary SRNS, 18/20 (90%) had recurrence post-transplant, compared to 18/50 (36%) with primary SRNS (p = 0.001). Every child with history of atopy (n = 11) or with hypoalbuminaemia at time of transplant (n = 13) experienced immediate recurrence. For children with secondary SRNS, 8/18 (44%) with post-transplant recurrence had no response to therapy. For children with primary SRNS, 4/18 (22%) with recurrence had no response to therapy (p = 0.3). Overall, 10-year transplant survival was 47% (95%CI 29-77%) for those with secondary SRNS, compared to 71 (95%CI 57-88%) for those with primary SRNS (p = 0.05). CONCLUSIONS: Secondary steroid resistance is strongly associated with SRNS recurrence. Atopy and hypoalbuminaemia at transplant may be novel risk factors for recurrence. Further research is needed to assess if secondary steroid resistance is associated with poorer transplant outcomes. "A higher resolution version of the Graphical abstract is available as Supplementary information".

Transition from a renal paediatric clinic to an adult clinic: Perspectives of adolescents and young adults, parents and health professionals.

The management of chronic kidney disease is complex. With disease management being the responsibility of parents in the paediatric renal clinic, the responsibility is gradually shifted to adolescents and young adults during the transition to adult care. This multi-perspective qualitative study aimed to explore the experiences of adolescents and young adults, their parents and health professionals to gain an insight into transitional care. Focussing on the transition process and transfer to adult care, 18 adolescents and young adults and eight mothers participated in individual semi-structured interviews. Additionally, three focus groups were conducted with 20 multidisciplinary health professionals. Data were transcribed verbatim and analysed thematically. Similar responses from adolescents and young adults and mothers included the reluctance to leave the paediatric health service. Mothers found the transition to adult care more challenging than the adolescents and young adults. While health professionals acknowledged that engaging adolescents and young adults in their own care was challenging, they believed parents had an important role in facilitating their child's independence. This study highlights that health professionals in both paediatric and adult health services need to work collaboratively. However, importantly, health professionals need to be mindful that parents require an equal amount of engagement as adolescents and young adults, if not more, to mitigate parental barriers in achieving a successful transfer.

Incidence and predictors of vascular events following end-stage kidney disease in childhood.

AIM: Cardiovascular death is a leading cause of mortality in paediatric end-stage kidney disease (ESKD). There is however little known about the clinically relevant vascular disease in this population. We aimed to describe the incidence of new onset vascular disease and vascular death in Australian children receiving renal replacement therapy (RRT). We also aimed to identify demographic or childhood risk factors for these endpoints, and whether vascular disease predicts mortality. METHODS: Data on Australian patients who commenced RRT at <18 years of age from 1991 to 2017 were extracted from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA). Multivariable competing risks regression was used to identify factors associated with vascular events. RESULTS: A cohort of 1268 patients were followed up for a median of 10.31 years. Vascular disease was reported in 5.4%, and vascular death in 4.1%. The cumulative incidence of any vascular event, that is, disease or death, at 10 and 20 years was 5.5% and 12.8%, respectively. Childhood vascular events were associated with non-Caucasian, non-Indigenous ethnicity, and for the 804 patients followed up after 18 years of age, vascular events were associated with lack of childhood transplantation, longer childhood dialysis duration and Indigenous ethnicity. Vascular disease was only reported for 25.49% of patients who had a vascular death, and although a significant risk factor for mortality, it had limited ability to predict mortality. CONCLUSION: Cumulative incidence of vascular events is significant after commencing RRT during childhood and is associated with ethnicity, longer childhood dialysis duration and lack of childhood transplantation.

Paediatric deceased donor kidney transplant in Australia: A 30-year review-What have paediatric bonuses achieved and where to from here?

BACKGROUND: In this 30-year national review, we describe trends in DD transplantation for paediatric recipients, assess the impact of paediatric allocation bonuses and identify outstanding areas of need for this population. METHODS: A retrospective review of all DD kidney only transplants to paediatric recipients (<18 years old) in Australia between 1989 and 2018 was conducted using deidentified extracts from the ANZDATA. RESULTS: Of the 1011 kidney only transplants performed in paediatric recipients during the study period, 426 (42%) were from deceased donors. Paediatric candidates on the DD waiting list had consistently higher rates of transplantation and shorter time from dialysis initiation to transplantation compared with adult candidates (median 372 vs 832 days in 2018, for example). Donor characteristics remained more favourable for paediatric recipients, despite a decline in the overall quality of the donor pool. The mean number of HLA antigen mismatches for paediatric recipients of DD transplants increased each decade (2.86 [1989-1998], 3.85 [1999-2008], 4.01 [2009-2018]). Both patient and graft survival have improved for paediatric DD transplant recipients in the most recent era (5-year graft and patient survival 85% vs 65% and 99% vs 94%, respectively, for 2009-2018 vs 1999-2008). CONCLUSIONS: The current DD kidney allocation system in Australia provides rapid access to high-quality organs for paediatric recipients, and early graft loss has decreased significantly in recent years; however, additional targeted interventions to address HLA matching may improve long-term outcomes in this population.

Survival and transplant outcomes among young children requiring kidney replacement therapy.

BACKGROUND: Young children starting kidney replacement therapy (KRT) suffer high disease burden with unique impacts on growth and development, timing of transplantation and long-term survival. Contemporary long-term outcome data and how these relate to patient characteristics are necessary for shared decision-making with families, to identify modifiable risk factors and inform future research. METHODS: We examined outcomes of all children ≤ 5 years enrolled in the Australia and New Zealand Dialysis and Transplant Registry, commencing KRT 1980-2017. Primary outcomes were patient and graft survival. Final height attained was also examined. We used generalized additive modelling to investigate the relationship between age and graft loss over time post-transplant. RESULTS: In total, 388 children were included, of whom 322 (83%) received a kidney transplant. Cumulative 1-, 5- and 10-year patient survival probabilities were 93%, 86% and 83%, respectively. Death censored graft survival at 1, 5 and 10 years was 93%, 87% and 77%, respectively. Most children were at least 10 kg at transplantation (n = 302; 96%). A non-linear relationship between age at transplantation and graft loss was observed, dependent on time post-transplant, with increased risk of graft loss among youngest recipients both initially following transplantation and subsequently during adolescence. Graft and patient survival have improved in recent era. CONCLUSIONS: Young children commencing KRT have good long-term survival and graft outcomes. Early graft loss is no reason to postpone transplantation beyond 10 kg, and among even the youngest recipients, late graft loss risk in adolescence remains one of the greatest barriers to improving long-term outcomes.

Human leukocyte antigen eplet mismatches and long-term clinical outcomes in pediatric renal transplantation: A pragmatic, registry-based study.

BACKGROUND: HLA epitope-based matching offers the potential to improve immunological risk prediction and management in children receiving renal allografts; however, studies demonstrating the association between systems for defining epitope mismatches and clinical end-points are lacking in this population. METHODS: We conducted a pragmatic, retrospective, registry-based study of pediatric recipients of primary renal allografts in Victoria, Australia between 1990 and 2014 to determine the association between HLA EpMM and clinical outcomes including graft failure, re-transplantation and dnDSA formation. RESULTS: A total of 196 patients were included in the analysis with a median age of 11 years. Median follow-up period was 15 years during which time 108 (55%) primary grafts failed and 72 patients were re-transplanted. HLA class I but not class II EpMM was a significant predictor of graft failure on univariate analysis but not in adjusted models. EpMM was associated with reduced likelihood of re-transplantation in univariate but not adjusted analysis. Within the limitations of the study, class-specific EpMM was a strong predictor of dnDSA formation. Associations were stronger when considering only the subset of antibody-verified EpMM. CONCLUSION: Associations between HLA EpMM and clinical outcomes in pediatric renal allograft recipients seen on univariate analysis were attenuated following adjustment for confounders. These findings are inconclusive but suggest that HLA EpMM may provide one tool for assessing long-term risk in this population while highlighting the need for further clinical studies.

Allograft outcome following repeat transplantation of patients with non-adherence-related first kidney allograft failure: a population cohort study.

Nonadherence is an important risk factor for premature allograft failure after kidney transplantation, but outcomes after re-transplantation remain uncertain. Using data from the Australian and New Zealand Dialysis and Transplant registry, the associations between causes of first allograft failure and acute rejection-related and non-adherence-related allograft failure following re-transplantation were examined using competing risk analyses, treating the respective alternative causes of allograft failure and death with functioning graft as competing events. Fifty-nine of 2450 patients (2%) lost their first allografts from nonadherence. Patients who lost their first kidney allograft from nonadherence were younger at the time of first kidney allograft failure but waited longer for a second allograft (>5 years: 54% vs. 20%, P < 0.001) compared with other causes. Compared with patients who lost their first allograft from causes other than nonadherence, the adjusted subdistribution hazard ratio (HR and 95% CI) for acute rejection-related second allograft failure was 0.58 (0.08, 4.07; P = 0.582) for patients with allograft failure attributed to nonadherence and was 6.30 (1.34, 29.67; P = 0.020) for non-adherence-related second allograft failure. In this cohort of transplant recipients who have received second allografts, first allograft failure secondary to nonadherence was associated with a marginally greater risk of allograft failure attributed to nonadherence in subsequent transplantation.

The Use of Peritoneal Dialysis in Phenobarbitone Toxicity in a Critically Unwell Neonate.

BACKGROUND: Phenobarbitone (PB) is the first-line anti-convulsant for neonatal seizures. The use of peritoneal dialysis (PD) to enhance drug elimination in cases of neonatal PB overdose has not been reported. OBJECTIVE: To report a case of neonatal severe PB toxicity and review the elimination of PB by PD. METHODS: Assessment of PD drug clearance. RESULTS: A neonate with prolonged seizures was administered PB. Encephalopathy and myocardial failure developed, which were initially suspected to be secondary to hypoxia. At 42 h of age, the serum PB concentration was in the toxic range at 131 mg/L. Despite supportive care, the infant's condition deteriorated with escalating inotropes and the need for CPR. Enhanced PB elimination via multiple-dose activated charcoal and exchange transfusion were considered too risky. Hourly PD cycles via Tenckhoff catheter were commenced, based on reports suggesting that PD enhances PB clearance. The clinical state of the infant then improved. PD administration was continued for 60 h, recovering 20% of the estimated total PB body load. The infant survived and there were no PD complications. CONCLUSIONS: PD increased PB clearance in this neonate, correlating with clinical recovery. Where other techniques are not possible, PD may have a role to play in enhancing PB elimination.

Australian deceased donor kidney allocation protocols: Transplant waiting and graft quality for children and adolescents.

DD kidney allocation protocols may influence timing of transplantation and graft quality for pediatric recipients. This study aimed to evaluate the effects of these protocols, including pediatric priority, on waiting time on dialysis, transplant type, donor age, and HLA matching according to state of transplant in Australia. De-identified information on patients <15 yr of age who commenced RRT in NSW, Qld, and Victoria from 2002 to 2011 was retrieved from the ANZDATA. Transplant type, donor age, and HLA mismatching were compared between states, with competing risk regression used to examine the time to transplant. There were significant differences in waiting time to DD transplantation between the three states. Children in NSW and Qld waited a median of 14 and 11 months vs. 21 months in Victoria. The ratio of LD to DD transplants was lower in NSW and Qld. Differences correlated with DD pediatric priority in NSW and Qld. DDs in NSW were older than in the other states. HLA matching did not differ. DD kidney allocation protocols with pediatric priority in Australian states were associated with shorter waiting times and increased DD proportion.

Cytomegalovirus & Epstein Barr Virus serostatus as a predictor of the long-term outcome of kidney transplantation.

AIM: Cytomegalovirus (CMV) and Epstein Barr Virus (EBV) disease and asymptomatic infection have been associated with poor outcomes in kidney transplantation. Recipients who acquire primary infection through transplantation from a seropositive donor may be at particular risk of complications. The primary aim of this study was to evaluate the relationship between donor/recipient (D/R) CMV and EBV serostatus pretransplant and allograft and patient survival in a large cohort of kidney transplant recipients. METHODS: Data were obtained from the Australian and New Zealand Dialysis and Transplant Registry and the Australian and New Zealand Organ Donation Registry on 4516 first deceased donor kidney transplants performed between 1998 and 2010. Graft and patient survival were analysed using the Kaplan-Meier method. RESULTS: Pretransplant CMV D/R serostatus was available for the whole cohort, with EBV D/R serostatus available for 2566 transplants (56.8%). Serostatus for both viruses was significantly associated with donor and recipient age and recipient smoking status. For both viruses the majority of transplants were in a D+/R+ serostatus setting: 45.3% for CMV and 77.9% for EBV. D/R serostatus for either virus did not have a significant effect on graft or patient survival. CONCLUSION: We conclude that in the current era of viral prophylaxis and surveillance, long-term outcome for the kidney transplant population is unaffected by D/R CMV and EBV serostatus.

International survey of cytomegalovirus management in solid organ transplantation after the publication of consensus guidelines.

BACKGROUND: The Transplantation Society published guidelines on cytomegalovirus (CMV) management after solid organ transplantation in 2010, which provide recommendations on prevention, treatment, diagnostics, and resistance. We aimed to survey international clinicians on their posttransplantation CMV management practices with reference to these guidelines to see if they altered the management of clinicians caring for transplant patients. METHODS: The members of The Transplantation Society were emailed an electronic survey 12 months after the guideline publication. RESULTS: A total of 155 clinicians responded, representing 126 centers in 41 countries. Overall, there was a high uptake of usage of the guidelines. High rates of initial CMV prevention were used (93%), with 46% using only universal prophylaxis, 21% only preemptive therapy, and 33% a hybrid combination dependent on recipient risk for CMV. Socioeconomic and geographic influence was evident, with 26% of respondents from developing countries using no CMV prevention, and more preemptive therapy used in Asia. Valganciclovir was the most common antiviral used, with dosing often below recommendations (33% in infection). Molecular monitoring was used by 84% of clinicians. Management of antiviral-associated neutropenia commonly included antiviral dose reduction or withdrawal (51%). CONCLUSIONS: We conclude that there is significant geographic variation in CMV management after solid organ transplantation. Although the majority of clinicians adhere to consensus guidelines, opportunity exists to encourage better guideline uptake.