Diagnosis and management of primary hyperoxalurias: best practices.

The primary hyperoxalurias (PH 1, 2, and 3) are rare autosomal recessive disorders of glyoxylate metabolism resulting in hepatic overproduction of oxalate. Clinical presentations that should prompt consideration of PH include kidney stones, nephrocalcinosis, and kidney failure of unknown etiology, especially with echogenic kidneys on ultrasound. PH1 is the most common and severe of the primary hyperoxalurias with a high incidence of kidney failure as early as infancy. Until the recent availability of a novel RNA interference (RNAi) agent, PH care was largely supportive of eventual need for kidney/liver transplantation in PH1 and PH2. Together with the Oxalosis and Hyperoxaluria Foundation, the authors developed a diagnostic algorithm for PH1 and in this report outline best clinical practices related to its early diagnosis, supportive treatment, and long-term management, including the use of the novel RNAi. PH1-focused approaches to dialysis and kidney/liver transplantation for PH patients with progression to chronic kidney disease/kidney failure and systemic oxalosis are suggested. Therapeutic advances for this devastating disease heighten the importance of early diagnosis and informed treatment.

PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2.

Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90-180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs -1664 [1190], respectively; difference, 5172; 95% CI 2929-7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH.

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis.

PURPOSE: Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC. METHODS: Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized. RESULTS: Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ2 = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca2+ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca2+ uptake, demonstrating loss of function. CONCLUSION: Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.

Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria.

Primary hyperoxaluria (PH) is a family of ultra-rare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by oxalate overproduction. Nedosiran is an RNA interference agent that inhibits hepatic lactate dehydrogenase, the enzyme responsible for the common, final step of oxalate production in all three genetic subtypes of PH. Here, we assessed in a two-part, randomized, single-ascending-dose, phase 1 study (PHYOX1) the safety, pharmacokinetics, pharmacodynamics, and exposure-response of subcutaneous nedosiran in 25 healthy participants (Group A) and 18 patients with PH1 or PH2 (Group B). Group A received nedosiran (0.3, 1.5, 3.0, 6.0, then 12.0 mg/kg) or placebo, and Group B received open-label nedosiran (1.5, 3.0, or 6.0 mg/kg). No significant safety concerns were identified. Injection site reactions (four or more hours post dose) occurred in 13.3% of participants in Group A and 27.8% of participants in Group B. Mean maximum reduction in 24-hour urinary oxalate excretion from baseline to day 57 (end of study) across Group B dose cohorts was 55% (range: 22%-100%) after single-dose nedosiran, with 33% participants reaching normal 24-hour urinary oxalate excretion. Based on the available modeling and simulation data, a fixed monthly dose of nedosiran 160 mg (free acid; equivalent to 170 mg sodium salt) in adults was associated with the highest proportion of simulated individuals achieving normal or near-normal 24-hour urinary oxalate excretion and fewest fluctuations in urinary oxalate response. Thus, single-dose nedosiran demonstrated acceptable safety and evidence of a pharmacodynamic effect in both PH1 and PH2 subpopulations consistent with its mechanism of action.

Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT.

PURPOSE: Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES. METHODS: We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping. RESULTS: In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype-phenotype correlation. CONCLUSION: We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.

Whole exome sequencing identifies potential candidate genes for spina bifida derived from mouse models.

Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by (i) generating a list of 136 candidate genes for SB, and (ii) by unbiased exome-wide analysis. We generated a list of 136 potential candidate genes from three categories and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate genes exome-wide. We identified 6 likely deleterious variants in 6 of the 136 potential SB candidate genes in 6 of the 50 SB cases, whereof 4 genes were derived from mouse models, 1 gene was derived from human nonsyndromic SB, and 1 gene was derived from candidate genes known to cause human syndromic SB. In addition, by unbiased exome-wide analysis, we identified 12 genes as potential candidates for SB. Identification of these 18 potential candidate genes in larger SB cohorts will help decide which ones can be considered as novel monogenic causes of human SB.

Incidence of Urinary Tract Infections in Newborns with Spina Bifida-Is Antibiotic Prophylaxis Necessary?

PURPOSE: Urinary tract infections commonly occur in patients with spina bifida and pose a risk of renal scarring. Routine antibiotic prophylaxis has been utilized in newborns with spina bifida to prevent urinary tract infections. We hypothesized that prophylaxis can safely be withheld in newborns with spina bifida until clinical assessment allows for risk stratification. MATERIALS AND METHODS: Newborns with myelomeningocele at 9 institutions were prospectively enrolled in the UMPIRE study and managed by a standardized protocol with a strict definition of urinary tract infection. Patient data were collected regarding details of reported urinary tract infection, baseline renal ultrasound findings, vesicoureteral reflux, use of clean intermittent catheterization and circumcision status in boys. Risk ratios and corresponding 95% confidence intervals were calculated using log-binomial models. RESULTS: From February 2015 through August 2019 data were available on 299 newborns (50.5% male). During the first 4 months of life, 48 newborns (16.1%) were treated for urinary tract infection with 23 (7.7%) having positive cultures; however, only 12 (4.0%) met the strict definition of urinary tract infection. Infants with grade 3-4 hydronephrosis had an increased risk of urinary tract infection compared to infants with no hydronephrosis (RR=10.1; 95% CI=2.8, 36.3). Infants on clean intermittent catheterization also had an increased risk of urinary tract infection (RR=3.3; 95% CI=1.0, 10.5). CONCLUSIONS: The incidence of a culture positive, symptomatic urinary tract infection among newborns with spina bifida in the first 4 months of life was low. Patients with high grades of hydronephrosis or those on clean intermittent catheterization had a significantly greater incidence of urinary tract infection. Our findings suggest that routine antibiotic prophylaxis may not be necessary for most newborns with spina bifida.

Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis.

Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.

Kidney Function Surveillance in the National Spina Bifida Patient Registry: A Retrospective Cohort Study.

PURPOSE: Chronic kidney disease affects 25% to 50% of patients with spina bifida. Guidelines recommend kidney function surveillance in these patients but practice patterns are unknown. Variations in kidney function surveillance were assessed in patients with spina bifida based on the hypothesis that the treating clinic and spina bifida type would be associated with kidney function surveillance. MATERIALS AND METHODS: A retrospective cohort study was conducted of U.S. patients in the National Spina Bifida Patient Registry from 2013 to 2018. Followup was anchored at the 2013 visit. Participants with either an outcome event within 2 years of followup or more than 2 years of followup without an outcome event were included. Primary outcome was kidney function surveillance, defined as at least 1 renal ultrasound and serum creatinine within 2 years of followup. Primary exposures were clinic and spina bifida type, which were analyzed with covariates including sociodemographic and clinical characteristics in logistic regression models for their association with the outcome. Sensitivity analyses were performed using different kidney function surveillance definitions. RESULTS: Of 8,351 patients 5,445 were included with a median followup of 3.0 years. Across 23 treating clinics kidney function surveillance rates averaged 62% (range 6% to 100%). In multivariable models kidney function surveillance was associated with treating clinic, younger patient age, functional lesion level, nonambulatory status and prior bladder augmentation. Treating clinic remained a significant predictor of kidney function surveillance in all sensitivity analyses. CONCLUSIONS: Within the National Spina Bifida Patient Registry wide variation exists in practice of kidney function surveillance across treating clinics despite adjustment for key patient characteristics.

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients.

BACKGROUND: Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. METHODS: To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children's Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. RESULTS: By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients. CONCLUSIONS: Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

Baseline Urinary Tract Imaging in Infants Enrolled in the UMPIRE Protocol for Children with Spina Bifida.

PURPOSE: The lifetime risk of renal damage in children with spina bifida is high but only limited baseline imaging data are available for this population. We evaluated a large prospective cohort of infants with spina bifida to define their baseline imaging characteristics. MATERIALS AND METHODS: The UMPIRE Protocol for Young Children with Spina Bifida is an iterative quality improvement protocol that follows a cohort of newborns at 9 United States centers. Using descriptive statistics, we report the initial baseline imaging characteristics, specifically regarding renal bladder ultrasound, cystogram and dimercaptosuccinic acid nuclear medicine scan. RESULTS: Data on 193 infants from 2015 to 2018 were analyzed. Renal-bladder ultrasound was normal in 55.9% of infants, while 40.4% had Society for Fetal Urology grade 1 to 2 hydronephrosis in at least 1 kidney, 3.7% had grade 3 to 4 hydronephrosis in either kidney and 21.8% had grade 1 or higher bilateral hydronephrosis. There was no vesicoureteral reflux in 84.6% of infants. A third of enrolled infants underwent dimercaptosuccinic acid nuclear medicine renal scan, of whom 92.4% had no renal defects and 93.9% had a difference in differential function of less than 15%. CONCLUSIONS: The majority of infants born with spina bifida have normal baseline imaging characteristics and normal urinary tract anatomy at birth. This proactive protocol offers careful scheduled surveillance of the urinary tract with the goal of lifelong maintenance of normal renal function and healthy genitourinary development.

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. RESULTS: In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis.

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

Imaging in the diagnosis of pediatric urolithiasis.

Pediatric urolithiasis is an important and increasingly prevalent cause of pediatric morbidity and hospital admission. Ultrasound (US) is the recommended primary imaging modality for suspected urolithiasis in children. There is, however, widespread use of CT as a first-line study for abdominal pain in many institutions involved in pediatric care. The objective of this review is to outline state-of-the-art imaging modalities and methods for diagnosing urolithiasis in children. The pediatric radiologist plays a key role in ensuring that the appropriate imaging modality is performed in the setting of suspected pediatric urolithiasis. Our proposed imaging algorithm starts with US, and describes the optimal technique and indications for the use of CT. We emphasize the importance of improved communication with a greater collaborative approach between pediatric and general radiology departments so children undergo the appropriate imaging evaluation.

Design and Methodological Considerations of the Centers for Disease Control and Prevention Urologic and Renal Protocol for the Newborn and Young Child with Spina Bifida.

PURPOSE: Care of children with spina bifida has significantly advanced in the last half century, resulting in gains in longevity and quality of life for affected children and caregivers. Bladder dysfunction is the norm in patients with spina bifida and may result in infection, renal scarring and chronic kidney disease. However, the optimal urological management for spina bifida related bladder dysfunction is unknown. MATERIALS AND METHODS: In 2012 the Centers for Disease Control and Prevention convened a working group composed of pediatric urologists, nephrologists, epidemiologists, methodologists, community advocates and Centers for Disease Control and Prevention personnel to develop a protocol to optimize urological care of children with spina bifida from the newborn period through age 5 years. RESULTS: An iterative quality improvement protocol was selected. In this model participating institutions agree to prospectively treat all newborns with spina bifida using a single consensus based protocol. During the 5-year study period outcomes will be routinely assessed and the protocol adjusted as needed to optimize patient and process outcomes. Primary study outcomes include urinary tract infections, renal scarring, renal function and bladder characteristics. The protocol specifies the timing and use of testing (eg ultrasonography, urodynamics) and interventions (eg intermittent catheterization, prophylactic antibiotics, antimuscarinic medications). Starting in 2014 the Centers for Disease Control and Prevention began funding 9 study sites to implement and evaluate the protocol. CONCLUSIONS: The Centers for Disease Control and Prevention Urologic and Renal Protocol for the Newborn and Young Child with Spina Bifida began accruing patients in 2015. Assessment in the first 5 years will focus on urinary tract infections, renal function, renal scarring and clinical process improvements.

Characteristics and survival of patients with end stage renal disease and spina bifida in the United States renal data system.

PURPOSE: We describe the characteristics, treatments and survival of patients with spina bifida in whom end stage renal disease developed from 2004 through 2008 in the United States Renal Data System. MATERIALS AND METHODS: We used ICD-9-CM code 741.* to identify individuals with spina bifida using hospital inpatient data from 1977 to 2010, and physician and facility claims from 2004 to 2008. We constructed a 5:1 comparison group of patients with end stage renal disease without spina bifida matched by age at first end stage renal disease service, gender and race/ethnicity. We assessed the risk of mortality and of renal transplantation while on dialysis using multivariate cause specific proportional hazards survival analysis. We also compared survival after the first renal transplant from the first end stage renal disease service to August 2011. RESULTS: We identified 439 patients with end stage renal disease and spina bifida in whom end stage renal disease developed at an average younger age than in patients without spina bifida (41 vs 62 years, p <0.001) and in whom urological issues were the most common primary cause of end stage renal disease. Compared to patients with end stage renal disease without spina bifida those who had spina bifida showed a similar mortality hazard on dialysis and after transplantation. However, patients with end stage renal disease without spina bifida were more likely to undergo renal transplantation than patients with spina bifida (HR 1.51, 95% CI 1.13-2.03). Hospitalizations related to urinary tract infections were positively associated with the risk of death on dialysis in patients with end stage renal disease and spina bifida (HR 1.42, 95% CI 1.33-1.53). CONCLUSIONS: Spina bifida was not associated with increased mortality in patients with end stage renal disease on dialysis or after renal transplantation. Proper urological and bladder management is imperative in patients with spina bifida, particularly in adults.

Nonrenal indications for continuous renal replacement therapy: A report from the Prospective Pediatric Continuous Renal Replacement Therapy Registry Group.

OBJECTIVE: Continuous renal replacement therapy is the most often implemented dialysis modality in the pediatric intensive care unit setting for patients with acute kidney injury. However, it also has a role in the management of patients with nonrenal indications such as clearance of drugs and intermediates of disordered cellular metabolism. MEASUREMENTS AND METHODS: Using data from the multicenter Prospective Pediatric Continuous Renal Replacement Therapy Registry, we report a cohort of pediatric patients receiving continuous renal replacement therapy for nonrenal indications. Nonrenal indications were obtained from the combination of "other" category for continuous renal replacement therapy initiation and patient diagnosis (both primary and secondary). This cohort was further divided into three subgroups: inborn errors of metabolism, drug toxicity, and tumor lysis syndrome. RESULTS: From 2000 to 2005, a total of 50 continuous renal replacement therapy events with nonrenal indications for therapy were included in the Prospective Pediatric Continuous Renal Replacement Therapy Registry. Indication-specific survival of the subgroups was 62% (inborn errors of metabolism), 82% (tumor lysis syndrome), and 95% (drug toxicity). The median small solute dose delivered among the subgroups ranged from 2125 to 8213 mL/1.73 m/hr, with 54%-59% receiving solely diffusion-based clearance as continuous venovenous hemodialysis. No association was established between survival and dose delivered, modality of continuous renal replacement therapy, or use of intermittent hemodialysis prior to continuous renal replacement therapy. CONCLUSIONS: Pediatric patients requiring continuous renal replacement therapy for nonrenal indications are a distinct cohort within the population receiving renal replacement therapy with little published experience of outcomes for this group. Survival within this cohort varies by indication for continuous renal replacement therapy and is not associated with continuous renal replacement therapy modality. Additionally, survival is not associated with small solute doses delivered within a cohort receiving >2000 mL/1.73 m/hr. Our data suggest metabolic control is established rapidly in pediatric patients and that acute detoxification may be provided with continuous renal replacement therapy for both the initial and maintenance phases of treatment using either convection or diffusion at appropriate doses.

Treatment of primary hyperoxaluria type 1.

Supportive treatment for primary hyperoxaluria type 1 (PH1) focuses on high fluid intake and crystallization inhibitors. A subset of patients with specific PH1 genotypes (c.508G>A and c.454T>A) will respond to pyridoxine, defined as a >30% reduction in urinary oxalate excretion. Response to pyridoxine is variable and in some patients, urinary oxalate may normalize. The first focused treatment for PH1 using an RNA interference agent to reduce urinary oxalate was approved in 2020, and such therapies may significantly alter treatment approaches and long-term outcomes in PH1. Currently PH1 often presents with kidney function impairment and frequently results in end-stage kidney disease (ESKD). With kidney dysfunction, urinary oxalate clearance decreases and multisystem deposition of oxalate (oxalosis) occurs, commonly in bones, eyes, heart and skin. Once plasma oxalate levels exceed 30 µmol/L, aggressive haemodialysis is indicated to prevent oxalosis, even if the glomerular filtration rate (GFR) remains better than for typical dialysis initiation. Peritoneal dialysis alone does not achieve the needed oxalate clearance. Dialysis is a bridge to future transplantation. Liver transplantation restores hepatic alanine-glyoxylate transaminase enzyme activity, allowing glyoxylate detoxification and preventing further oxalosis. The native liver must be removed as part of this process to avoid ongoing pathologic oxalate production. The timing and type of liver transplantation are dependent on pyridoxine sensitivity, age, weight, residual GFR and evidence of systemic oxalate deposition in extrarenal organs. Liver transplant can be isolated or combined with kidney transplantation in a sequential or simultaneous fashion. Isolated kidney transplantation is generally reserved for pyridoxine-sensitive patients only. Although liver transplantation is curative for PH1 and kidney transplantation treats ESKD, ensuing necessary immunosuppression and potential allograft dysfunction impart significant long-term risks.

Pathophysiology and Treatment of Enteric Hyperoxaluria.

Enteric hyperoxaluria is a distinct entity that can occur as a result of a diverse set of gastrointestinal disorders that promote fat malabsorption. This, in turn, leads to excess absorption of dietary oxalate and increased urinary oxalate excretion. Hyperoxaluria increases the risk of kidney stones and, in more severe cases, CKD and even kidney failure. The prevalence of enteric hyperoxaluria has increased over recent decades, largely because of the increased use of malabsorptive bariatric surgical procedures for medically complicated obesity. This systematic review of enteric hyperoxaluria was completed as part of a Kidney Health Initiative-sponsored project to describe enteric hyperoxaluria pathophysiology, causes, outcomes, and therapies. Current therapeutic options are limited to correcting the underlying gastrointestinal disorder, intensive dietary modifications, and use of calcium salts to bind oxalate in the gut. Evidence for the effect of these treatments on clinically significant outcomes, including kidney stone events or CKD, is currently lacking. Thus, further research is needed to better define the precise factors that influence risk of adverse outcomes, the long-term efficacy of available treatment strategies, and to develop new therapeutic approaches.