ePHex: a phase 3, double-blind, placebo-controlled, randomized study to evaluate long-term efficacy and safety of Oxalobacter formigenes in patients with primary hyperoxaluria.

BACKGROUND: Primary hyperoxalurias (PHs) are rare genetic diseases that increase the endogenous level of oxalate, a waste metabolite excreted predominantly by the kidneys and also the gut. Treatments aim to improve oxalate excretion, or reduce oxalate generation, to prevent kidney function deterioration. Oxalobacter formigenes is an oxalate metabolizing bacterium. This Phase III, double-blind, placebo-controlled randomized trial investigated the effectiveness of orally administered Oxabact™, a lyophilized O. formigenes formulation, at reducing plasma oxalate levels in patients suffering from PH. METHODS: Subjects (≥ 2 years of age) with a diagnosis of PH and maintained but suboptimal kidney function (mean estimated glomerular filtration rate at baseline < 90 mL/min/1.73 m2) were eligible to participate. Subjects were randomized to receive Oxabact or placebo twice daily for 52 weeks. Change from baseline in plasma oxalate concentration at Week 52 was the primary study endpoint. RESULTS: Forty-three subjects were screened, 25 were recruited and one was discontinued. At Week 52, O. formigenes was established in the gut of subjects receiving Oxabact. Despite decreasing plasma oxalate level in subjects treated with Oxabact, and stable/increased levels with placebo, there was no significant difference between groups in the primary outcome (Least Squares mean estimate of treatment difference was - 3.80 µmol/L; 95% CI: - 7.83, 0.23; p-value = 0.064). Kidney function remained stable in both treatments. CONCLUSIONS: Oxabact treatment may have stabilized/reduced plasma oxalate versus a rise with placebo, but the difference over 12 months was not statistically significant (p = 0.06). A subtle effect observed with Oxabact suggests that O. formigenes may aid in preventing kidney stones. A higher resolution version of the Graphical abstract is available as Supplementary information.

Illness-related parental stress and quality of life in children with kidney diseases.

BACKGROUND: This cross-sectional study investigated quality of life (QoL) and illness-related parental stress in children with kidney diseases by (1) comparing mean levels of these two variables between several kidney disease categories; (2) exploring correlations between QoL and parental stress; and (3) describing which disease category reports lowest QoL and highest parental stress. METHODS: We included 295 patients with a kidney disease (0-18 years) and their parents, followed at 6 reference centers for pediatric nephrology. Children's QoL was assessed by the PedsQL™ 4.0 Generic Core Scales, and illness-related stress by the Pediatric Inventory for Parents. All patients were divided into 5 kidney disease categories according to the multidisciplinary care program criteria prescribed by the Belgian authorities: (1) structural kidney diseases, (2) tubulopathies and metabolic diseases, (3) nephrotic syndrome, (4) acquired diseases with proteinuria and hypertension, and (5) kidney transplantation. RESULTS: Child self-reports showed no differences in QoL between kidney disease categories, in contrast to parent proxy reports. Parents of transplant patients reported lower QoL in their child and more parental stress compared with the 4 non-transplant categories. QoL and parental stress were negatively correlated. Lowest QoL and highest parental stress scores were mainly found in transplant patients. CONCLUSIONS: This study showed lower QoL and higher parental stress in pediatric transplant patients compared with non-transplants, based on parent reports. Higher parental stress is associated with worse QoL in the child. These results highlight the importance of multidisciplinary care for children with kidney diseases, with special attention to transplant patients and their parents. A higher resolution version of the Graphical abstract is available as Supplementary information.

Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.

Children on dialysis as well as renal transplanted children report severely impaired health-related quality of life.

OBJECTIVES: To assess health-related quality of life (HRQoL) across three renal replacement therapy modalities (preemptive transplant, non-preemptive transplant, and dialysis) in comparison with the healthy norm and other chronic health conditions, and to explore related patient factors. STUDY DESIGN: All prevalent end-stage renal disease (ESRD) patients aged 8-18 years who spent at least 6 months on their current treatment modality in the Netherlands, Belgium, and part of Germany were approached to complete the Pediatric Quality of Life Inventory 4.0 (PedsQL™) questionnaire. We determined the differences between groups on PedsQL™ mean scores, the proportion of children with an impaired HRQoL (≥ 1 SD lower than the healthy norm), the proportion of problems on individual items of the PedsQL™, and the effect of time on current treatment. Linear regression models were used to explore determinants of HRQoL. RESULTS: 192 out of 278 patients (20% preemptive transplant, 58% non-preemptive transplant, 22% dialysis) filled in the PedsQL™ (response rate 69%). Independent of treatment modality, patients had significantly lower mean scores and consequently higher proportions of impaired HRQoL on almost all domains compared to the healthy norm and other chronic health conditions. Patients with a preemptive transplant only reported higher scores on physical health compared to the other treatment modalities. Having comorbidities was the most important determinant associated with lower HRQoL scores. CONCLUSION: Dialysis and renal transplantation both have a severe impact on the HRQoL of children with ESRD. Physicians should be aware of this continuous burden. Furthermore, to develop tailored interventions for children with ESRD, qualitative studies are needed to gain more insight in the determinants of HRQoL in the different treatment modalities.

In-depth phenotyping of a Donnai-Barrow patient helps clarify proximal tubule dysfunction.

BACKGROUND: The megalin/cubilin/amnionless complex is essential for albumin and low molecular weight (LMW) protein reabsorption by renal proximal tubules (PT). Mutations of the LRP2 gene encoding megalin cause autosomal recessive Donnai-Barrow/facio-oculo-acoustico-renal syndrome (DB/FOAR), which is characterized by LMW proteinuria. The pathophysiology of DB/FOAR-associated PT dysfunction remains unclear. CLINICAL CASE: A 3-year-old girl presented with growth retardation and proteinuria. Clinical examination was unremarkable, except for a still-opened anterior fontanel and myopia. Psychomotor development was delayed. At 6, she developed sensorineural hearing loss. Hypertelorism was noted when she turned 12. Blood analyses, including renal function parameters, were normal. Urine sediment was bland. Proteinuria was significant and included albumin and LMW proteins. Immunoblotting analyses detected cubilin and type 3 carbonic anhydrase (CA3) in the urine. Renal ultrasound was unremarkable. Optical examination of a renal biopsy did not disclose any tubular or glomerular abnormality. Electron microscopy revealed that PT apical endocytic apparatus was significantly less developed. Immunostaining for megalin showed a faint signal in PT cytosol contrasting with the distribution of cubilin at the apical membrane. The diagnostic procedure led to identifying two mutations of the LRP2 gene. CONCLUSIONS: The functional loss of megalin in DB/FOAR causes PT dysfunction characterized by increased urinary shedding of CA3 and cubilin.

Children of non-Western origin with end-stage renal disease in the Netherlands, Belgium and a part of Germany have impaired health-related quality of life compared with Western children.

BACKGROUND: Many children with end-stage renal disease (ESRD) living in Western Europe are of non-Western European origin. They have unfavourable somatic outcomes compared with ESRD children of Western origin. In this study, we compared the Health-related Quality of Life (HRQoL) of both groups. METHODS: All children (5-18 years) with ESRD included in the RICH-Q project (Renal Insufficiency therapy in Children-Quality assessment and improvement) or their parents were asked to complete the generic version of the Paediatric Quality-of-Life Inventory 4.0 (PedsQL). RICH-Q comprises the Netherlands, Belgium and a part of Germany. Children were considered to be of non-Western origin if they or at least one parent was born outside Western-European countries. Impaired HRQoL for children with ESRD of Western or non-Western origin was defined as a PedsQL score less than fifth percentile for healthy Dutch children of Western or non-Western origin, respectively. RESULTS: Of the 259 eligible children, 230 agreed to participate. One hundred and seventy-four children responded (response rate 67%) and 55 (32%) were of non-Western origin. Overall, 31 (56%) of the ESRD children of non-Western origin, and 58 (49%) of Western origin had an impaired total HRQoL score. Total HRQoL scores of children with ESRD of Western origin and non-Western origin were comparable, but scores on emotional functioning and school functioning were lower in non-Western origin (P=0.004 and 0.01, respectively). The adjusted odds ratios (95% confidence interval) for ESRD children of non-Western origin to have impaired emotional functioning and school functioning, compared with Western origin, were 3.3(1.5-7.1) and 2.2(1.1-4.2), respectively. CONCLUSION: Children with ESRD of non-Western origin in three Western countries were found to be at risk for impaired HRQoL on emotional and school functioning. These children warrant special attention.

Indoxyl Sulfate Contributes to Impaired Height Velocity in (Pre)School Children.

Introduction: Growth failure is considered the most important clinical outcome parameter in childhood chronic kidney disease (CKD). Central to the pathophysiology of growth failure is the presence of a chronic proinflammatory state, presumed to be partly driven by the accumulation of uremic toxins. In this study, we assessed the association between uremic toxin concentrations and height velocity in a longitudinal multicentric prospective pediatric CKD cohort of (pre)school-aged children and children during pubertal stages. Methods: In a prospective, multicentric observational study, a selection of uremic toxin levels of children (aged 0-18 years) with CKD stage 1 to 5D was assessed every 3 months (maximum 2 years) along with clinical growth parameters. Linear mixed models with a random slope for age and a random intercept for child were fitted for height (in cm and SD scores [SDS]). A piecewise linear association between age and height was assumed. Results: Data analysis included data from 560 visits of 81 children (median age 9.4 years; 2/3 male). In (pre)school aged children (aged 2-12 years), a 10% increase in concurrent indoxyl sulfate (IxS, total) concentration resulted in an estimated mean height velocity decrease of 0.002 SDS/yr (P < 0.05), given that CKD stage, growth hormone (GH), bicarbonate concentration, and dietary protein intake were held constant. No significant association with height velocity was found in children during pubertal stages (aged >12 years). Conclusion: The present study demonstrated that, especially IxS contributes to a lower height velocity in (pre)school children, whereas we could not find a role for uremic toxins with height velocity during pubertal stages.

Assessment of Within- and Inter-Patient Variability of Uremic Toxin Concentrations in Children with CKD.

To promote improved trial design in upcoming randomized clinical trials in childhood chronic kidney disease (CKD), insight in the within- and inter-patient variability of uremic toxins with its nutritional, treatment- and patient-related confounding factors is of utmost importance. In this study, the within- and inter-patient variability of a selection of uremic toxins in a longitudinal cohort of children diagnosed with CKD was assessed, using the intraclass correlation coefficient (ICC) and the within-patient coefficient of variation (CV). Subsequently, the contribution of anthropometry, estimated glomerular filtration rate (eGFR), dietary fiber and protein, and use of (prophylactic) antibiotics to uremic toxin variability was evaluated. Based on 403 observations from 62 children (median seven visits per patient; 9.4 ± 5.3 years; 68% males; eGFR 38.5 [23.1; 64.0] mL/min/1.73 m2) collected over a maximum of 2 years, we found that the within-patient variability is high for especially protein-bound uremic toxins (PBUTs) (ICC < 0.7; within-patient CV 37-67%). Moreover, eGFR was identified as a predominant contributor to the within- and inter-patient variability for the majority of solutes, while the impact of the child's anthropometry, fiber and protein intake, and antibiotics on the variability of uremic toxin concentrations was limited. Based on these findings, we would recommend future intervention studies that attempt to decrease uremic toxin levels to select a (non-dialysis) CKD study population with a narrow eGFR range. As the expected effect of the selected intervention should exceed the inter-patient variability of the selected uremic toxins, a narrow eGFR range might aid in improving the trial design.

Intrafamilial Disease Heterogeneity in Primary Hyperoxaluria Type 1.

Introduction: Primary hyperoxaluria type 1 (PH1) is known for its variable clinical course, even within families. However, the extent of this heterogeneity has not been well-studied. We aimed to analyze intrafamilial clinical heterogeneity and disease course among siblings in a large cohort of familial PH1 cases. Methods: A retrospective registry study was performed using data from OxalEurope. All PH1 families with 2 or more affected siblings were included. A 6-point PH1 clinical outcome scoring system was developed to grade heterogeneity within a family. Intrafamilial clinical heterogeneity was defined as a score ≥2. Kaplan-Meier analyses were used to analyze differences in kidney survival between index cases and siblings. Results: We included 88 families, encompassing 193 patients with PH1. The median interquartile range (IQR) follow-up time was 7.8 (1.9-17) years. Intrafamilial clinical heterogeneity, as defined by our score, was found in 38 (43%) PH1 families. In 54% of the families, affected siblings had a better outcome than the index case. Clinically asymptomatic siblings at the time of their diagnosis had a significantly more favorable clinical outcome based on the authors' scoring system than siblings with clinical signs and index cases (P < 0.001). Kaplan-Meier analyses revealed that index cases reached kidney failure at an earlier age and earlier in follow-up compared to siblings (P < 0.001). Conclusions: Intrafamilial clinical heterogeneity was found in a substantial number of familial PH1 cases. Compared to index cases, siblings had significantly better clinical outcomes and kidney survival; thereby supporting the policy of family screening to diagnose affected siblings early to improve their prognosis.

Policy variation in donor and recipient status in 11 pediatric renal transplantation centers.

BACKGROUND: Evidence-based guidelines for pediatric renal transplantation (Tx) are lacking. This may lead to unwanted treatment variations. We aimed to quantify the variation in treatment policies and its consequences in daily practice in 11 centers that provide renal Tx for children in three European countries. METHODS: We surveyed Tx policies in all ten centers in the Netherlands and Belgium and one center in Germany. We compared Tx policies with the therapies actually provided and with recommendations from available published guidelines and existing literature. Information on treatment policies was obtained by a questionnaire; information on care actually provided was registered prospectively from 2007 to 2011. The clinical guidelines were identified by searches of MEDLINE and websites of pediatric nephrology organizations. RESULTS: Between centers, we found discrepancies in policies on: the minimum accepted recipient weight (8-12 kg), the maximum living and deceased donor age (50-75 and 45-60 years, respectively). HLA-match policies varied between acceptation of all mismatches to at least 1A1B1DR match donor transplantations amounting to 49 % in the Netherlands versus 26 % in Belgium (p = 0.006). CONCLUSIONS: Management policies for renal Tx in children vary considerably between centers and nations. This has a direct impact on the delivered care, and by extrapolation, on health outcome.

Determinants of Kidney Failure in Primary Hyperoxaluria Type 1: Findings of the European Hyperoxaluria Consortium.

Introduction: Primary hyperoxaluria type 1 (PH1) has a highly heterogeneous disease course. Apart from the c.508G>A (p.Gly170Arg) AGXT variant, which imparts a relatively favorable outcome, little is known about determinants of kidney failure. Identifying these is crucial for disease management, especially in this era of new therapies. Methods: In this retrospective study of 932 patients with PH1 included in the OxalEurope registry, we analyzed genotype-phenotype correlations as well as the impact of nephrocalcinosis, urolithiasis, and urinary oxalate and glycolate excretion on the development of kidney failure, using survival and mixed model analyses. Results: The risk of developing kidney failure was the highest for 175 vitamin-B6 unresponsive ("null") homozygotes and lowest for 155 patients with c.508G>A and c.454T>A (p.Phe152Ile) variants, with a median age of onset of kidney failure of 7.8 and 31.8 years, respectively. Fifty patients with c.731T>C (p.Ile244Thr) homozygote variants had better kidney survival than null homozygotes (P = 0.003). Poor outcomes were found in patients with other potentially vitamin B6-responsive variants. Nephrocalcinosis increased the risk of kidney failure significantly (hazard ratio [HR] 3.17 [2.03-4.94], P < 0.001). Urinary oxalate and glycolate measurements were available in 620 and 579 twenty-four-hour urine collections from 117 and 87 patients, respectively. Urinary oxalate excretion, unlike glycolate, was higher in patients who subsequently developed kidney failure (P = 0.034). However, the 41% intraindividual variation of urinary oxalate resulted in wide confidence intervals. Conclusion: In conclusion, homozygosity for AGXT null variants and nephrocalcinosis were the strongest determinants for kidney failure in PH1.

Fewer pre-emptive renal transplantations and more rejections in immigrant children compared to native Dutch and Belgian children.

BACKGROUND: In the Netherlands and Belgium, an increasing number of children who have end-stage renal disease (ESRD) are of non-Western origin. We analysed renal transplantation practices and outcome for immigrant ESRD children as compared to native children in both countries. METHODS: All Dutch and Belgian children aged <19 years who received their first renal transplantation between 1 September 2007 and 1 January 2011 were included. Therapy characteristics and outcomes were registered prospectively on a 3-monthly basis. Immigrants were defined as children of whom one or both parents had been born outside Western European countries. Multivariable Cox regression analysis was used to quantify the hazard ratio for acute rejection. RESULTS: One hundred and nineteen first renal transplant recipients were included, of which 41 (34%) were immigrants. Median [range] follow-up time of transplantation was 18 [2-28] months. Compared to native children, immigrants had pre-emptive transplantations (15 versus 32%, P = 0.040) and transplantations with a kidney from a living donor less often (24 versus 59%, P < 0.001). Survival analysis in 96 children with at least 3 months of follow-up showed an increased risk for acute rejection in immigrants adjusted for donor source, duration of dialysis and number of HLA mismatches on the DR locus [hazard ratio (95% confidence interval) 2.5 (1.1-5.9)]. CONCLUSIONS: Immigrant children receive fewer pre-emptive and living donor transplantations compared to native children. After transplantation, immigrant children are at higher risk for acute rejection irrespective of the mode of transplantation.

Important differences in management policies for children with end-stage renal disease in the Netherlands and Belgium--report from the RICH-Q study.

BACKGROUND: The low prevalence of childhood end-stage renal disease and the small centre sizes have been a barrier for clinical studies and the development of evidence-based guidelines for chronic renal replacement therapy (cRRT) in children. Few data exist on the quality of care for these patients and the applicability of existing guidelines. The aim of this study is to quantify variation in treatment policies and actually delivered care in nine centres that deliver cRRT for children. METHODS: We surveyed treatment policies in all nine centres in the Netherlands and Belgium and compared them with the actually provided therapies and with recommendations from available guidelines. Data on treatment policies were gathered by questionnaires; actually provided care and outcomes were registered prospectively from 2007 to 2010. RESULTS: Data on policies and actual patient care were obtained from all nine centres. We found relevant differences between centres in treatment policies on various topics, e.g. estimated glomerular filtration rate threshold as an indication for initiation of cRRT, preferred initial mode of cRRT, peritoneal dialysis catheter care, haemodialysis frequency and vascular access. Discrepancies were seen between stated treatment policies and actual performed therapies. For the majority of policies, no evidence-based guidelines are available. CONCLUSIONS: Health care disparities exist due to large and unwanted variation in treatment policies between hospitals providing cRRT for children. Delivered care does not live up to stated policies, for which clear and internationally accepted guidelines are lacking.

Disparities in dialysis treatment and outcomes for Dutch and Belgian children with immigrant parents.

BACKGROUND: In Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-Western European origin (non-Western). Concerns exist regarding whether these non-Western patients receive the same quality of care as children with parents of Western European origin (Western). We compared initial dialysis, post-initial treatment, and outcomes between non-Western and Western patients on dialysis. METHODS: All children <19 years old on chronic dialysis in the Netherlands and Belgium between September 2007 and May 2011 were included in the study. Non-Western patients were defined as children of whom one or both parents were born in non-Western countries. RESULTS: Seventy-nine of the 179 included patients (44%) were non-Western children. Compared to Western patients, non-Western patients more often were treated with hemodialysis (HD) instead of peritoneal dialysis (PD) as first dialysis mode (52 vs. 37%, p = 0.046). Before renal transplantation, non-Western patients were on dialysis for a median (range) of 30 (5-99) months, vs. 15 (0-66) months in Western patients (p = 0.007). Renal osteodystrophy was diagnosed in 34% of non-Western vs. 18% of Western patients (p = 0.028). The incidence rate ratio [95% confidence interval] for acute peritonitis was 2.44 [1.43-4.17] (p = 0.032) for non-Western compared to Western patients. CONCLUSIONS: There are important disparities between children on chronic dialysis with parents from Western European origin and those from non-Western European origin in the choice of modality, duration, and outcomes of dialysis therapy.

Improved Outcome of Infantile Oxalosis Over Time in Europe: Data From the OxalEurope Registry.

Introduction: Infantile oxalosis is the most severe form of primary hyperoxaluria type 1 (PH1), with onset of end-stage kidney disease (ESKD) during infancy. We aimed to analyze the outcome of these patients as our current understanding is limited owing to a paucity of reports. Methods: A retrospective registry study was conducted using data from the OxalEurope registry. All PH1 patients with ESKD onset at age <1 year were analyzed. Results: We identified 95 patients born between 1980 and 2018 with infantile oxalosis. Median (interquartile range [IQR]) age at ESKD was 0.4 (0.3-0.5) year. There were 4 patients diagnosed by family screening who developed ESKD despite early diagnosis. There were 11 patients who had biallelic missense mutations associated with vitamin B6 responsiveness. Of 89 patients, 27 (30%) died at a median age of 1.4 (0.6-2.0) years (5-year patient survival of 69%). Systemic oxalosis was described in 54 of 56 screened patients (96%). First transplantation was performed at a median age of 1.7 (1.3-2.9) years. In 42 cases, this procedure was a combined liver-kidney transplantation (LKTx), and in 23 cases, liver transplantations (LTx) was part of a sequential procedure. Survival rates of both strategies were similar. Patient survival was significantly higher in patients born after 2000. Intrafamilial phenotypic variability was present in 14 families of patients with infantile oxalosis. Conclusion: Nearly all screened patients with infantile oxalosis developed systemic disease. Mortality is still high but has significantly improved over time and might further improve under new therapies. The intrafamilial phenotypic variability warrants further investigation.

Long-Term Transplantation Outcomes in Patients With Primary Hyperoxaluria Type 1 Included in the European Hyperoxaluria Consortium (OxalEurope) Registry.

INTRODUCTION: In primary hyperoxaluria type 1 (PH1), oxalate overproduction frequently causes kidney stones, nephrocalcinosis, and kidney failure. As PH1 is caused by a congenital liver enzyme defect, combined liver-kidney transplantation (CLKT) has been recommended in patients with kidney failure. Nevertheless, systematic analyses on long-term transplantation outcomes are scarce. The merits of a sequential over combined procedure regarding kidney graft survival remain unclear as is the place of isolated kidney transplantation (KT) for patients with vitamin B6-responsive genotypes. METHODS: We used the OxalEurope registry for retrospective analyses of patients with PH1 who underwent transplantation. Analyses of crude Kaplan-Meier survival curves and adjusted relative hazards from the Cox proportional hazards model were performed. RESULTS: A total of 267 patients with PH1 underwent transplantation between 1978 and 2019. Data of 244 patients (159 CLKTs, 48 isolated KTs, 37 sequential liver-KTs [SLKTs]) were eligible for comparative analyses. Comparing CLKTs with isolated KTs, adjusted mortality was similar in patients with B6-unresponsive genotypes but lower after isolated KT in patients with B6-responsive genotypes (adjusted hazard ratio 0.07, 95% CI: 0.01-0.75, P = 0.028). CLKT yielded higher adjusted event-free survival and death-censored kidney graft survival in patients with B6-unresponsive genotypes (P = 0.025, P < 0.001) but not in patients with B6-responsive genotypes (P = 0.145, P = 0.421). Outcomes for 159 combined procedures versus 37 sequential procedures were comparable. There were 12 patients who underwent pre-emptive liver transplantation (PLT) with poor outcomes. CONCLUSION: The CLKT or SLKT remains the preferred transplantation modality in patients with PH1 with B6-unresponsive genotypes, but isolated KT could be an alternative approach in patients with B6-responsive genotypes.

A promising pediatric peritoneal dialysis experience in a resource-limited setting with the support of saving young lives program.

In the Democratic Republic of Congo (DRC), acute kidney injury (AKI) contributes to the high rate of child mortality owing to the conjunction of poverty, deficiency of qualified health-care providers in pediatric nephrology, and the lack of pediatric dialysis programs. We aimed to describe the recent experience of the first pediatric acute peritoneal dialysis (PD) program in DRC. This is a retrospective cohort study on epidemiology, clinical features and outcomes of children admitted from January 2018 to January 2019 at the University Hospital of Kinshasa for AKI and treated with PD. This pediatric PD program started by a team of one physician and one nurse who were trained in the local production of PD fluids and bedside catheter insertion technique in Benin Republic. The training was jointly supported by the Flemish Inter-University Council (VLIR) TEAM project and Saving Young Lives (SYL) program of ISN, ISPD, EuroPD, and IPNA. From January 2018 to January 2019, 49 children (aged 4 months-15 years) were admitted for AKI mainly due to severe malaria and sepsis. Dialysis was indicated in 35 of 49 (71.4%), 32 of 35 (91.4%) were treated with PD, two with hemodialysis (HD) in adult ward and one died at admission. Data of the two patients transferred for HD were not available for follow-up. The main indications were uremia and prolonged anuria. Of 32 dialyzed patients, 24 (75%) recovered normal renal function 3 months after discharge. Peritonitis was observed in 2 of 32 (6.2%) patients and the mortality was 18.7%. This promising experience proves that with simple means including use of locally produced dialysis fluids and low peritonitis rates, we can effectively save lives of children suffering from AKI.

Uremic Toxin Concentrations are Related to Residual Kidney Function in the Pediatric Hemodialysis Population.

Protein-bound uremic toxins (PBUTs) play a role in the multisystem disease that children on hemodialysis (HD) are facing, but little is known about their levels and protein binding (%PB). In this study, we evaluated the levels and %PB of six PBUTs cross-sectionally in a large pediatric HD cohort (n = 170) by comparing these with healthy and non-dialysis chronic kidney disease (CKD) stage 4-5 (n = 24) children. In parallel ß2-microglobulin (ß2M) and uric acid (UA) were evaluated. We then explored the impact of age and residual kidney function on uremic toxin levels and %PB using analysis of covariance and Spearman correlation coefficients (rs). We found higher levels of ß2M, p-cresyl glucuronide (pCG), hippuric acid (HA), indole acetic acid (IAA), and indoxyl sulfate (IxS) in the HD compared to the CKD4-5 group. In the HD group, a positive correlation between age and pCG, HA, IxS, and pCS levels was shown. Residual urine volume was negatively correlated with levels of ß2M, pCG, HA, IAA, IxS, and CMPF (rs -0.2 to -0.5). In addition, we found overall lower %PB of PBUTs in HD versus the CKD4-5 group, and showed an age-dependent increase in %PB of IAA, IxS, and pCS. Furhtermore, residual kidney function was overall positively correlated with %PB of PBUTs. In conclusion, residual kidney function and age contribute to PBUT levels and %PB in the pediatric HD population.

[Type 1 primary hyperoxaluria: From childhood to adult, how to manage adequately medical therapy compliance?] / Hyperoxalurie primaire de type 1 : de l'enfance à l'âge adulte, comment gérer adéquatement l'adhésion au traitement médical ?

We report the cases of three young patients suffering from type 1 primary hyperoxaluria, a metabolic genetic disorder characterized by intracellular accumulation of oxalate and which may result in end-stage renal disease with systemic impairment. A number of effective conservative therapeutic means are available for early management of affected children particularly when he is growing older. Despite the demonstrated efficacy of conservative therapy, compliance represents a major and daily challenge. Monitoring therapeutic compliance is thus an important task for physicians in charge of this disease. A better understanding of non-compliance causes is required to improve the follow-up of patients for whom treatment education must be a priority.

Schimke immunoosseous dysplasia: suggestions of genetic diversity.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.