Determinants of hyperparathyroidism in children after kidney transplantation.

INTRODUCTION: Hyperparathyroidism (HPT) can contribute to metabolic bone disease following kidney transplantation. We evaluated post-transplant trends in intact parathyroid hormone (iPTH) and determined predictors of HPT in pediatric kidney transplant (KTx) recipients. METHODS: In this single-center study, retrospective data were collected on 88 children from 2013 to 2019. Data collected included dialysis vintage, biochemical parameters, post-transplant trends in iPTH, 25(OH)Vitamin D levels and estimated glomerular filtration rate (eGFR ml/min/1.73 m2 ). Pre-transplant treatment for HPT was quantified with a Treatment Burden score (TB, score range: 0-100). After log-transforming skewed variables (iPTH and eGFR), multivariable linear regression was performed to determine predictors of log {iPTH} at 6 and 36 months (mo) post-transplant. RESULTS: Median age was 12.8 (range: 1.9-20.5) years, and dialysis vintage was 11.2 (range: 0.0-112.9) months. The majority were of Hispanic and African Ancestry (77.3%). Median post-transplant iPTH was 69.5 (range: 1.8-306.8) pg/ml at 6 mo with a gradual downward trend to 59.0 (range: 28.0-445.0) pg/ml at 36 mo. Significant multivariable predictors of higher log {iPTH} post-transplant included longer dialysis vintage, higher TB, and lower log{eGFR} at 6 mo, and higher TB, lower log{eGFR}, and deceased donor transplant at 36 mo. CONCLUSIONS: Recognition of risk factors for HPT and monitoring iPTH post-transplant may facilitate timely interventions to mitigate cardiovascular and bone disease in pediatric KTx recipients. KEY MESSAGE: Describe serial trends in intact PTH after kidney transplantation. Pre- and post-transplant factors that contribute to persistence or re-occurrence of hyperparathyroidism after kidney transplantation in children include longer dialysis vintage, high pre-transplant treatment burden and decreased post-transplant GFR. Recognition of these factors, and monitoring intact PTH after kidney transplantation, could facilitate timely interventions to mitigate cardiovascular and bone disease in children.

Prevalence of mycophenolate mofetil discontinuation and subsequent outcomes in pediatric kidney transplant recipients: A PNRC study.

BACKGROUND: Mycophenolate Mofetil (MMF) is an effective immunosuppressant used in kidney transplant recipients to prevent acute rejection. Complications such as diarrhea, leukopenia, and infections may necessitate the reduction or discontinuation of MMF. The objective of the study was to investigate the prevalence, timing, and reasons for MMF discontinuation and its association with outcomes in pediatric kidney transplant recipients. METHODS: Seven Pediatric Nephrology Research Consortium (PNRC) centers participated in a retrospective analysis of kidney transplant recipients <21 years of age. Characteristics and outcomes of patients in whom MMF was discontinued were compared to those who continued taking MMF throughout the first 2 years post-transplant. RESULTS: The study population included 288 participants (mean age 11.2 years) from 7 North American transplant centers. MMF was discontinued in 93/288 (32%) of participants. Common reasons for discontinuation included infections (35%), diarrhea (32%), leukopenia (15%), and others (18%). Increased cumulative alloimmunity (55% vs. 42%, p = .02), increased number of hospitalizations (82% vs. 67%, p = .01), and viral replications (79% vs. 47%, p < .0001) were observed in the MMF discontinuation group compared to the continuation group. Greater eGFR decline also occurred in the MMF discontinuation group over 2 years of follow-up (-7 vs. -1 mL/min/1.73 m2 , p = .05). CONCLUSIONS: Almost a third of pediatric kidney transplant recipients who begin MMF for maintenance immunosuppression have it discontinued within the first 2 years post-transplant, and this subset of patients is more likely to experience adverse outcomes. New strategies are needed to manage MMF therapy and improve post-transplant outcomes.

The Preserving Kidney Function in Children With CKD (PRESERVE) Study: Rationale, Design, and Methods.

Rationale & Objective: PRESERVE seeks to provide new knowledge to inform shared decision-making regarding blood pressure (BP) management for pediatric chronic kidney disease (CKD). PRESERVE will compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; expand the National Patient-Centered Clinical Research Network (PCORnet) common data model by adding pediatric- and kidney-specific variables and linking electronic health record data to other kidney disease databases; and assess the lived experiences of patients related to BP management. Study Design: Multicenter retrospective cohort study (clinical outcomes) and cross-sectional study (patient-reported outcomes [PROs]). Setting & Participants: PRESERVE will include approximately 20,000 children between January 2009-December 2022 with mild-moderate CKD from 15 health care institutions that participate in 6 PCORnet Clinical Research Networks (PEDSnet, STAR, GPC, PaTH, CAPRiCORN, and OneFlorida+). The inclusion criteria were ≥1 nephrologist visit and ≥2 estimated glomerular filtration rate (eGFR) values in the range of 30 to <90 mL/min/1.73 m2 separated by ≥90 days without an intervening value ≥90 mL/min/1.73 m2 and no prior dialysis or kidney transplant. Exposures: BP measurements (clinic-based and 24-hour ambulatory BP); urine protein; and antihypertensive treatment by therapeutic class. Outcomes: The primary outcome is a composite event of a 50% reduction in eGFR, eGFR of <15 mL/min/1.73 m2, long-term dialysis or kidney transplant. Secondary outcomes include change in eGFR, adverse events, and PROs. Analytical Approach: Longitudinal models for dichotomous (proportional hazards or accelerated failure time) and continuous (generalized linear mixed models) clinical outcomes; multivariable linear regression for PROs. We will evaluate heterogeneity of treatment effect by CKD etiology and degree of proteinuria and will examine variation in hypertension management and outcomes based on socio-demographics. Limitations: Causal inference limited by observational analyses. Conclusions: PRESERVE will leverage the PCORnet infrastructure to conduct large-scale observational studies that address BP management knowledge gaps for pediatric CKD, focusing on outcomes that are meaningful to patients. Plain-Language Summary: Hypertension is a major modifiable contributor to loss of kidney function in chronic kidney disease (CKD). The purpose of PRESERVE is to provide evidence to inform shared decision-making regarding blood pressure management for children with CKD. PRESERVE is a consortium of 16 health care institutions in PCORnet, the National Patient-Centered Clinical Research Network, and includes electronic health record data for >19,000 children with CKD. PRESERVE will (1) expand the PCORnet infrastructure for research in pediatric CKD by adding kidney-specific variables and linking electronic health record data to other kidney disease databases; (2) compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; and (3) assess the lived experiences of patients and caregivers related to blood pressure management.

Benefit of B7-1 staining and abatacept for treatment-resistant post-transplant focal segmental glomerulosclerosis in a predominantly pediatric cohort: time for a reappraisal.

BACKGROUND: Primary FSGS manifests with nephrotic syndrome and may recur following KT. Failure to respond to conventional therapy after recurrence results in poor outcomes. Evaluation of podocyte B7-1 expression and treatment with abatacept (a B7-1 antagonist) has shown promise but remains controversial. METHODS: From 2012 to 2020, twelve patients developed post-KT FSGS with nephrotic range proteinuria, failed conventional therapy, and were treated with abatacept. Nine/twelve (< 21 years old) experienced recurrent FSGS; three adults developed de novo FSGS, occurring from immediately, up to 8 years after KT. KT biopsies were stained for B7-1. RESULTS: Nine KTRs (75%) responded to abatacept. Seven of nine KTRs were B7-1 positive and responded with improvement/resolution of proteinuria. Two patients with rFSGS without biopsies resolved proteinuria after abatacept. Pre-treatment UPCR was 27.0 ± 20.4 (median 13, range 8-56); follow-up UPCR was 0.8 ± 1.3 (median 0.2, range 0.07-3.9, p < 0.004). Two patients who were B7-1 negative on multiple KT biopsies did not respond to abatacept and lost graft function. One patient developed proteinuria while receiving belatacept, stained B7-1 positive, but did not respond to abatacept. CONCLUSIONS: Podocyte B7-1 staining in biopsies of KTRs with post-transplant FSGS identifies a subset of patients who may benefit from abatacept. A higher resolution version of the Graphical abstract is available as Supplementary information.

Predictors of advanced chronic kidney disease in infancy after definitive vesicoamniotic shunting for congenital lower urinary tract obstruction.

Background: Severe congenital lower urinary tract obstruction (cLUTO) is associated with poor postnatal outcomes, including chronic and end stage kidney disease, and high mortality. Studies of the impact of fetal intervention through vesicoamniotic shunting are marred by a device malfunction rate of up to 60%. In this study, we delineate the postnatal course and infant kidney function following definitive urinary diversion in utero. Materials and Methods: This is a retrospective, single-center cohort study of 16 male infants who survived the fetal intervention to birth, from 2010 to 2014 at a single center. All had patent shunts in place at birth. Perinatal and biochemical characteristics were collected with patients followed for one year, or until demise, with serial measures of serum creatinine (SCr) and serum cystatin C (CysC). Results: Of the 16 males, 81% were non-white (38% black, 43% Hispanic). Shunts were placed at a median of 20 weeks (IQR 19,23) gestation, with median fetal bladder volume of 39 cm3 (IQR 9.9,65). All neonates were born preterm [median 34 weeks (IQR 31,35)] and the majority with low birth weight [median 2340 grams (1,895, 2,600)]. 63% required positive pressure ventilation. Advanced chronic kidney disease stage 4-5 at 1 year of age was predicted by neonatal characteristics: peak SCr ≥2 mg/dl, time to peak SCr > 6 days, discharge SCr ≥1.0 mg/dl, CysC ≥2.5 mg/l, urine protein:creatinine ≥4.8 mg/mg, urine microalbumin:creatinine ≥2.2 mg/mg. In infancy, a nadir SCr ≥0.5 mg/dl occurring before 160 days (5.3 months) of age was also predictive of advanced chronic kidney disease stage 4-5 at 1 year. Three patients died in the neonatal period, with 1 receiving kidney replacement therapy (KRT). Three additional patients required KRT before 12 months of age. Conclusions: Even with definitive vesicoamniotic shunting for cLUTO, postnatal morbidity and mortality remain high, emphasizing the role of renal dysplasia, in spite of urinary diversion, in postnatal kidney dysfunction. Neonatal and infant biochemical parameters exhibit distinct trends that offer families and physicians a better understanding of the prognosis of childhood kidney function.

Educational Review: The Impact of Perinatal Oxidative Stress on the Developing Kidney.

Oxidative stress occurs when there is an imbalance between reactive oxygen species/reactive nitrogen species and antioxidant systems. The interplay between these complex processes is crucial for normal pregnancy and fetal development; however, when oxidative stress predominates, pregnancy related complications and adverse fetal programming such as preterm birth ensues. Understanding how oxidative stress negatively impacts outcomes for the maternal-fetal dyad has allowed for the exploration of antioxidant therapies to prevent and/or mitigate disease progression. In the developing kidney, the negative impact of oxidative stress has also been noted as it relates to the development of hypertension and kidney injury mostly in animal models. Clinical research addressing the implications of oxidative stress in the developing kidney is less developed than that of the neurodevelopmental and respiratory conditions of preterm infants and other vulnerable neonatal groups. Efforts to study the oxidative stress pathway along the continuum of the perinatal period using a team science approach can help to understand the multi-organ dysfunction that the maternal-fetal dyad sustains and guide the investigation of antioxidant therapies to ameliorate the global toxicity. This educational review will provide a comprehensive and multidisciplinary perspective on the impact of oxidative stress during the perinatal period in the development of maternal and fetal/neonatal complications, and implications on developmental programming of accelerated aging and cardiovascular and renal disease for a lifetime.

Spectrum of Clinical Manifestations in Children With WT1 Mutation: Case Series and Literature Review.

Background: Mutations of the Wilms tumor suppressor-1 gene (WT1) are associated with life-threatening glomerulopathy, disorders of sexual development, Wilm's tumor, and gonadal malignancies. Our objectives were to describe the clinical presentations, age of progression, and onset of complications of WT1 mutation through a case series and literature review. Methods: A retrospective study included all patients followed at the University of Miami/Holtz Children's Hospital from January 2000 to December 2020 with a diagnosis of WT1 mutation. A literature review of WT1 mutation cases was analyzed for clinical manifestations, karyotype, and long-term outcomes. Results: The WT1 mutation was identified in 9 children, median age at presentation of 0.9 years (range 1 week to 7 years). A total of four had female phenotypes, and 5 had abnormalities of male external genitalia, while all had XY karyotypes. All progressed to end-stage kidney disease (ESKD) and received a kidney transplant at a median age of 5 years (1.5-15 years). During a median time of follow-up of 9 years (range 2-28 years), there were 2 allograft losses after 7 and 10 years and no evidence of post-transplant malignancy. From 333 cases identified from the literature review, the majority had female phenotype 66% (219/333), but the predominant karyotype was XY (55%, 183/333). Of the female phenotypes, 32% (69/219) had XY sex reversal. Wilm's tumor occurred in 24%, predominantly in males with gonadal anomalies. Conclusions: Early recognition of WT1 mutation is essential for comprehensive surveillance of potential malignancy, avoidance of immunosuppressants for glomerulopathy, and establishing long-term multidisciplinary management.

Case report: Bordetella holmesii: A rare pathogen causing infective endocarditis associated glomerulonephritis.

Infective endocarditis (IE) can cause multiorgan dysfunction and chronic kidney disease, in addition to cardiac sequelae. The presentation may be vague and can manifest as acute glomerulonephritis. While the most common pathogens of infective endocarditis are Staphylococcus and Streptococcus species, we report a rare pathogen Bordetella holmesii causing infective endocarditis associated glomerulonephritis. A 20-year-old male patient with tetralogy of Fallot with pulmonary atresia and aortopulmonary collaterals underwent several cardiac surgeries including prosthetic pulmonary valve replacement in the past. He was admitted for 3 days at an outside hospital for fever, cough, and hemoptysis, and diagnosed with streptococcal pharyngitis, for which he received antibiotics. Five weeks later, he presented to our institution with lower extremity edema and gross hematuria. On examination, he was afebrile, normotensive, had a 7-kg weight gain with anasarca, and a systolic murmur, without rash. Investigations revealed elevated serum creatinine, nephrotic range proteinuria, hematuria, and hypocomplementemia, consistent with acute glomerulonephritis. Given his cardiac history, blood cultures were collected from three sites. Broad-spectrum antibiotics were initiated when he subsequently developed fever. Renal pathology on biopsy showed diffuse proliferative immune complex-mediated glomerulonephritis. Transesophageal echocardiogram visualized a vegetation on the pulmonary valve. Bordetella holmesii was ultimately cultured from the prior and current hospitalization. A serum sample detecting microbial cell-free DNA sequencing confirmed Bordetella holmesii at very high levels. After completing 6 weeks of intravenous antibiotics with concurrent angiotensin receptor blockade, his kidney function recovered with improvement in hypocomplementemia and proteinuria. This case report highlights the early recognition and comprehensive evaluation of a rare organism causing IE-associated GN, which allowed for renal recovery and preserved cardiac function.

Case Report: Uroenteric Fistula in a Pediatric-en-bloc Kidney Transplant Manifests as Deceptive Watery Diarrhea and Normal Anion Gap Acidosis.

Introduction: The diagnosis of a post-surgical uroenteric fistula can be challenging and may be delayed for months after symptoms begin. A normal anion gap metabolic acidosis has been reported in up to 100% of patients after ureterosigmoidostomy, and bladder substitution using small bowel and/or colonic segments. Here, we describe a rare case of a pediatric patient who developed a uroenteric fistula from the transplant ureters into the small bowel, after an en-bloc kidney transplantation resulting in profound acidosis and deceptive watery diarrhea. Case Presentation: The patient is an 8-year-old girl with end stage kidney disease (ESKD) secondary to focal segmental glomerulosclerosis. Through a right retroperitoneal approach, she underwent a right native nephrectomy and a pediatric deceased donor en-bloc kidney transplant including two separate ureters. One month later, she had a renal allograft biopsy for suspected rejection. During the week after the biopsy, she experienced abdominal pain followed by watery diarrhea and metabolic acidosis requiring continuous bicarbonate/acetate infusions. An extensive gastro-intestinal evaluation for the cause of the diarrhea including endoscopy was inconclusive. The urine output decreased to <500 ml daily; although, the kidney function remained normal. After 2 weeks of unexplained watery diarrhea a magnetic resonance urogram with contrast was performed which demonstrated extravasation of urine from both ureters with fistulization into the small bowel. She underwent corrective surgery which identified the fistulous tract, which was resected and both ureters were re-implanted. The diarrhea and acidosis resolved, and she has maintained normal renal allograft function for over 1 year. Conclusion: An important aspect in the early diagnosis of a uroenteric fistula is the sudden onset of severe hyperchloremic metabolic acidosis that results when urine is diverted into the intestinal tract. The mechanism is similar to that described in cases of urinary diversions and/or bladder augmentation using the intestine. Important diagnostic tools are the measurements of solute excretion and pH in the urine as compared to the "watery diarrhea" or bowel output. Summary: We describe a case of a uroenteric fistula in a pediatric-en-bloc kidney transplant patient that went undiagnosed for almost 3 weeks due to the deceptive nature of the watery diarrhea which was actually urine. A uroenteric fistula should be considered in the differential diagnosis of diarrhea and hyperchloremic metabolic acidosis as a complication of kidney transplant. The simultaneous comparison of stool and urine pH and solute excretions may lead to the diagnosis, appropriate imaging and surgical intervention.

Conversion to permanent vascular access is associated with improved markers of hemodialysis efficacy in children: Pediatric nephrology research consortium study.

BACKGROUND AND OBJECTIVES: Arteriovenous fistulae (AVF) and grafts (AVG) are preferred permanent vascular access (PVA) for chronic hemodialysis (HD) patients. Our objective was to examine the change in markers of HD efficacy after successful establishment of a PVA among children who started HD with a tunneled cuffed catheter (TCC). MATERIALS AND METHODS: Retrospective chart reviews were completed on patients from 20 pediatric dialysis centers. All patients used TCC prior to AVF/AVG, and each patient acted as his/her own control. Data on markers of HD efficacy (single-pool Kt/V, urea reduction ratio (URR), serum albumin and hematocrit (Hct)) were collected at the creation of AVF/AVG and for 2 years thereafter. Statistical methods included hypothesis testing and statistical modeling after adjusting for relevant demographic variables. RESULTS: First PVA was created in 98 individual children: 87 (89%) were AVF and 11 (11%) were AVG. The mean TCC vintage prior to AVF/AVG was 10.4 ± 17.3 months. At 1-year follow-up, Kt/V improved by 0.15 ± 0.06 (p = 0.02) and URR improved by 4.54 ± 1.17% (p < 0.0001). Furthermore, PVA was associated with improved serum albumin by 0.31 ± 0.07 g/dL (p < 0.0001) and Hct by 2.80 ± 0.65% (p < 0.0001) at 1 year. These HD efficacy markers remained statistically significant at 2nd-year follow-up. These observations were further supported by the adjusted models. Conversion to AVF was associated with statistically significant improvement in all four markers of HD efficacy at 1-year follow-up. This trend was not demonstrated for subjects who were converted to AVG. CONCLUSION: Switching to PVA was associated with improved markers of HD efficacy, single-pool Kt/V, URR, serum albumin, and Hct. This improvement was mostly demonstrated at 1 year and maintained for the 2nd year. The potential differential impact of the type of PVA on the trajectory of markers of HD efficacy should be further investigated.

The old becomes new: advances in imaging techniques to assess nephron mass in children.

Renal imaging is widely used in the assessment of surrogate markers of nephron mass correlated to renal function. Autopsy studies have tested the validity of various imaging modalities in accurately estimating "true" nephron mass. However, in vivo assessment of nephron mass has been largely limited to kidney volume determination by ultrasonography (US) in pediatric populations. Practical limitations and risks create challenges in incorporating more precise 3D volumetric imaging, like magnetic resonance imaging (MRI), and computed tomography (CT) technologies, compared to US for routine kidney volume assessment in children. Additionally, accounting for structural anomalies such as hydronephrosis when estimating renal parenchymal area in congenital anomalies of the kidney and urinary tract (CAKUT) is important, as it correlates with chronic kidney disease (CKD) progression. 3D imaging using CT and MRI has been shown to be superior to US, which has traditionally relied on 2D measurements to estimate kidney volume using the ellipsoid calculation. Recent innovations using 3D and contrast-enhanced US (CEUS) provide improved accuracy with low risk. Indexing kidney volume to body surface area in children is an important standard that may allow early detection of CKD progression in high-risk populations. This review highlights current understanding of various imaging modalities in assessing nephron mass, discusses applications and limitations, and describes recent advances in the field of imaging and kidney disease. Although renal imaging has been a long-standing, essential tool in assessing kidney disease, innovation and new applications of established technologies provide important tools in the study and management of kidney disease in children.

Predictors of time to first cannulation for arteriovenous fistula in pediatric hemodialysis patients: Midwest Pediatric Nephrology Consortium study.

BACKGROUND: Permanent vascular access (PVA) is preferred for long-term hemodialysis. Arteriovenous fistulae (AVF) have the best patency and the lowest complication rates compared to arteriovenous grafts (AVG) and tunneled cuffed catheters (TCC). However, AVF need time to mature. This study aimed to investigate predictors of time to first cannulation for AVF in pediatric hemodialysis patients. METHODS: Data on first AVF and AVG of patients at 20 pediatric dialysis centers were collected retrospectively, including demographics, clinical information, dialysis markers, and surgical data. Statistical modeling was used to investigate predictors of outcome. RESULTS: First PVA was created in 117 children: 103 (88%) AVF and 14 (12%) AVG. Mean age at AVF creation was 15.0 ± 3.3 years. AVF successfully matured in 89 children (86.4%), and mean time to first cannulation was 3.6 ± 2.5 months. In a multivariable regression model, study center, age, duration of non-permanent vascular access (NPVA), and Kt/V at AVF creation predicted time to first cannulation, with study center as the strongest predictor (p < 0.01). Time to first cannulation decreased with increasing age (p = 0.03) and with increasing Kt/V (p = 0.01), and increased with duration of NPVA (p = 0.03). Secondary failure occurred in 10 AVF (11.8%). Time to first cannulation did not predict secondary failure (p = 0.29), but longer time to first cannulation tended towards longer secondary patency (p = 0.06). CONCLUSIONS: Study center is the strongest predictor of time to first cannulation for AVF and deserves further investigation. Time to first cannulation is significantly shorter in older children, with more efficient dialysis treatments, and increases with longer NPVA duration.

Clinical predictors of chronic kidney disease in congenital lower urinary tract obstruction.

Congenital lower urinary tract obstruction is associated with oligohydramnios and significant perinatal mortality and long-term chronic kidney disease. The counseling of families facing this diagnosis, especially when prenatal intervention is proposed, is fraught with ambiguity. This review aims to equip the provider with the current evidence behind the conventional and novel biomarkers predictive of chronic kidney disease. The relevant clinical predictors are categorized by when they are identified, antenatally or postnatally, and as either anatomic or chemical. They are considered for their prognostic value and the challenges in obtaining them, specifically the risk to the fetus in the case of prenatal biomarkers. Serum creatinine in infancy is the traditional chemical biomarker of kidney function and continues to be a consistent predictor of future serum creatinine. ß-2 microglobulin may provide earlier information regarding fetal glomerular and tubular function and is also predictive of long-term serum creatinine. Renal parenchymal area is an anatomic surrogate of nephron mass that is used in both prenatal and postnatal settings. Understanding the anatomic and chemical biomarkers is essential for future refinement of the staging algorithm used to distinguish which patients may benefit from early in utero intervention.

Risk Assessment of Severe Congenital Anomalies of the Kidney and Urinary Tract (CAKUT): A Birth Cohort.

Recent advances in the early diagnosis of fetal CAKUT with an increase in fetal surgical interventions have led to a growing number of neonatal survivors born with severe renal dysfunction. This, in turn, has required the development of multi-disciplinary treatment paradigms in the individualized management of these infants with advanced stage kidney disease from birth. Early multi-modal management includes neonatal surgical interventions directed toward establishing adequate urine flow, respiratory support with the assessment of pulmonary hypoplasia, and establishing metabolic control to avoid the need for dialysis intervention. The development of specialized imaging to assess for residual renal mass with non-invasive 3-dimensional techniques are rapidly evolving. The use of non-radioactive imaging offers improved safety and allows for early prognostic-based planning including anticipatory guidance for progression to end stage renal disease (ESRD). The trajectory of kidney function during the neonatal period as determined by peak and nadir serum creatinine (SCr) and cystatin C (CysC) during the first months of life provides a guide toward individualized prospective management. This is a single center experience based on a birth cohort of 42 subjects followed prospectively from birth for an average of 6.1 ± 2.8 years at the University of Miami/Holtz Children's Hospital during the past decade. There was an 8:1 male: female ratio. The birth cohort was divided into 3 subgroups according to CKD Stages at the current age: CKD 1-2 (Group 1) (eGFR ≥ 60 ml/min/1.73 m2) (N = 15), CKD stage 3-5 (Group 2) (eGFR ≤ 59 ml/min/1.73 m2) (N = 12), and ESRD-Dialysis and/or Transplantation (Group 3) (N = 15). A neonatal CysC >3.0 mg/L predicted progression to ESRD while a nadir SCr >0.6 mg/dL predicted progression to CKD 3-5 with the highest specificity and sensitivity by ROC-AUC analysis (P < 0.0001). Medical management was directed toward nutritional support with novel formula designs, early introduction of growth hormone and strict control of mineral bone disorder. One of the central aspects of the management was to avoid dialysis for as long as feasible with a primary goal toward pre-emptive transplantation.

Correction to: Predictors of patency for arteriovenous fistulae and grafts in pediatric hemodialysis patients.

The original version of this article unfortunately contained a mistake. The name of Vimal Chadha was presented incorrectly. The corrected author list is given above.

Cinacalcet as rescue therapy for refractory hyperparathyroidism in young children with advanced chronic kidney disease.

BACKGROUND: Studies in the use of the calcimimetic, cinacalcet, in pediatric chronic kidney disease (CKD) are few and limited to older children with secondary hyperparathyroidism (sHPT), a major morbid complication contributing to poor growth, bone deformities, and cardiovascular disease. Our objectives were to determine a safe and effective dosing regimen of cinacalcet in the treatment of infants and young children with sHPT that was refractory to standard care and to examine their growth during treatment. METHODS: Ten young pediatric patients with advanced CKD were studied retrospectively during 11 courses of treatment with cinacalcet. All had severe sHPT with intact parathyroid hormone (iPTH) levels ≥ 500 pg/ml and were refractory to standard therapy with phosphate binders and active vitamin D analogs at high doses for > 30 days. The cinacalcet dose was advanced by 50% every 2-4 weeks to achieve a decline in the iPTH to a goal of 150-300 pg/ml. Linear growth was assessed at 6-month intervals by change in z-scores (△SDS) for length before and during cinacalcet therapy. RESULTS: Median age at initiation of cinacalcet was 18 months (IQR 6, 36) with an average starting dose of 0.7 ± 0.2 mg/kg/day. Median effective dose required to reach iPTH goal of 150-300 pg/ml was 2.8 mg/kg/day (IQR 2.0, 3.1), and time to goal was 112 days (IQR 56, 259) with a median overall decline in iPTH of 82% from baseline by 6 months (p < 0.0001). No subject experienced a clinical adverse event, although 4 had biochemical asymptomatic hypocalcemia. Linear growth improved significantly during cinacalcet therapy (△SDS - 0.62 ± 1.2 versus + 0.91 ± 1.4; p < 0.005). By multiple regression analysis, the primary determinants of growth were concurrent treatment with growth hormone and age < 2 years (R2 = 89.6%; p < 0.001). A shorter treatment time required to achieve iPTH goals also was associated with improved growth (r = - 0.75; p < 0.01). CONCLUSIONS: Cinacalcet may be used effectively and safely in infants and small children with refractory sHPT in advanced CKD using a cautious dosing regimen. Cinacalcet successfully brings iPTH to target level and supports growth when other treatments have been ineffective.

Association of infections and venous thromboembolism in hospitalized children with nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) results in hypercoagulability and increased risk of infection. Furthermore, infection increases the risk of venous thromboembolism (VTE). Our objective was to determine the prevalence of infection, VTE, and the associated outcomes among a cohort of hospitalized children with NS. METHODS: All children with NS admitted to 17 pediatric hospitals across North America from 2010 to 2012 were included. Prevalence of infection and VTE was determined. Wilcoxon rank-sum and logistic regression were performed. RESULTS: Seven-hundred thirty hospitalizations occurred among 370 children with NS. One-hundred forty-eight children (40%) had ≥ 1 infection (211 episodes) and 11 (3%) had VTE. Those with VTE had infection more frequently (p = 0.046) and were younger at NS diagnosis (3.0 vs. 4.0 years; p = 0.008). The most common infectious pathogen identified was Streptococcus pneumoniae. The median hospital length of stay for those with infection [10 vs 5 days (p < 0.0001)] or VTE [22 vs 6 days (p < 0.0001)] was longer than those without either complication. Of those with infection, 13% had an intensive care unit (ICU) stay compared with 3.3% of those without infection. Median ICU stay was 4 days in those with VTE compared to 0 days in those without (p < 0.001). By logistic regression, only the number of ICU days was associated with VTE (OR 1.074, 95% CI 1.013-1.138). CONCLUSIONS: Hospitalized children with NS have high rates of infection. Presence of VTE was associated with infection. Both were associated with longer hospitalizations and ICU stays.

Predictors of patency for arteriovenous fistulae and grafts in pediatric hemodialysis patients.

BACKGROUND: Hemodialysis (HD) guidelines recommend permanent vascular access (PVA) in children unlikely to receive kidney transplant within 1 year of starting HD. We aimed to determine predictors of primary and secondary patency of PVA in pediatric HD patients. METHODS: Retrospective chart reviews were performed for first PVAs in 20 participating centers. Variables collected included patient demographics, complications, interventions, and final outcome. RESULTS: There were 103 arterio-venous fistulae (AVF) and 14 AV grafts (AVG). AVF demonstrated superior primary (p = 0.0391) and secondary patency (p = 0.0227) compared to AVG. Primary failure occurred in 16 PVA (13.6%) and secondary failure in 14 PVA (12.2%). AVF were more likely to have primary failure (odds ratio (OR) = 2.10) and AVG had more secondary failure (OR = 3.33). No demographic, clinical, or laboratory variable predicted primary failure of PVA. Anatomical location of PVA was predictive of secondary failure, with radial having the lowest risk compared to brachial (OR = 12.425) or femoral PVA (OR = 118.618). Intervention-free survival was predictive of secondary patency for all PVA (p = 0.0252) and directly correlated with overall survival of AVF (p = 0.0197) but not AVG. Study center demonstrated statistically significant effect only on intervention-free AVF survival (p = 0.0082), but not number of complications or interventions, or outcomes. CONCLUSIONS: In this multi-center pediatric HD cohort, AVF demonstrated primary and secondary patency advantages over AVG. Radial PVA was least likely to develop secondary failure. Intervention-free survival was the only predictor of secondary patency for AVF and directly correlated with overall access survival. The study center effect on intervention-free survival of AVF deserves further investigation.

Cardioprotective Effects of Paricalcitol Alone and in Combination With FGF23 Receptor Inhibition in Chronic Renal Failure: Experimental and Clinical Studies.

BACKGROUND: In uremic animals, vitamin D receptor (VDR) agonists like paricalcitol (Pc) attenuate cardiac hypertrophy, but this effect has not been replicated consistently in humans with chronic kidney disease. Elevated fibroblast growth factor 23 (FGF23) levels cause cardiac hypertrophy with activation of the myocardial calcineurin/nuclear factor of activated T cell (NFAT) axis and may antagonize the cardioprotective effects of VDR agonist therapy. We hypothesized that the effectiveness of Pc may depend on the prevailing circulating levels of FGF23 and could be potentiated by the combined administration of a pan-FGF23 receptor (FGFR) blocker agent (PD173074). METHODS: In rats with 5/6 nephrectomy treated with Pc or PD173074 or both agents concurrently, myocardial mRNA expression of renin-angiotensin system, VDR, FGFR4, and calcineurin/NFAT target genes was determined. In adolescents on hemodialysis, we analyzed sequential echocardiograms, blood pressures and serial FGF23 measurements, and their relations to the cumulative administered dose of parenteral Pc. RESULTS: The ratio of Pc dose/plasma levels of FGF23 correlated inversely (P < 0.005) with the cardiac mass in uremic rats and in hemodialysis patients, independently of hypertension. Despite persistently elevated FGF23 levels and myocardial FGFR4 activation, Pc suppressed upregulated myocardial calcineurin/NFAT target genes, and the effects were amplified by coadministration of PD173074. CONCLUSIONS: The beneficial effects of Pc on uremic cardiac hypertrophy are counterbalanced by the increased FGF23 levels. Blockade of FGF23-mediated signaling increased the Pc-induced suppression of the myocardial calcineurin/NFAT system. Higher doses of Pc should be considered in the treatment of patients with uremic cardiomyopathy.

Prenatal renal parenchymal area as a predictor of early end-stage renal disease in children with vesicoamniotic shunting for lower urinary tract obstruction.

BACKGROUND: Vesicoamniotic shunting (VAS) and other bladder drainage techniques for fetal lower urinary tract obstruction (LUTO) have been proven to ameliorate pulmonary hypoplasia and increase survival in patients with an initial poor prognosis. Currently there are limited prognostic tools available during gestation to evaluate and predict postnatal renal function. OBJECTIVE: The aim was to describe the prenatal growth of the renal parenchymal area (RPA) in patients with LUTO and determine its application as a predictor of renal function at one year of life. STUDY DESIGN: The study population comprised a retrospective cohort of all infants who survived the fetal VAS to birth. Renal growth and size were measured using imageJ software to calculate the RPA in sequential prenatal ultrasounds. The parenchymal area was measured from the image of each kidney with the greatest longitudinal length. These measurements were further correlated and analyzed as a predictor of end-stage renal disease (ESRD) within the first year of life. RESULTS: Etiologies of LUTO in the 15 male fetuses included eight posterior urethral valves, four Eagle-Barrett/prune belly syndrome, two urethral atresia, and one megacystis microcolon intestinal hypoperistalsis syndrome. All patients had patent shunts, in place, at birth. Furthermore, ultrasonographic parameters such as oligohydramnios, keyhole sign, and bladder wall thickness showed no statistical difference between groups. Renal parenchymal growth correlated with postnatal renal function in both the ESRD (r = 0.409, p = 0.018) and the non-ESRD (r = 0.657, p < 0.001) groups. Most notably, RPA during the 3rd trimester predicted ESRD with the best cut-off point determined to be 8 cm2 (sensitivity, 0.714; specificity, 0.882; and positive likelihood ratio, 6.071) (Table). DISCUSSION: Despite definitive VAS for LUTO, postnatal morbidity and mortality remain high, emphasizing the role of renal dysplasia in postnatal renal failure, in spite of urinary diversion. Renal growth statistically differs between groups in the 3rd trimester of gestation; RPA development appears stagnant in patients that developed ESRD within the first year of life. In contrast, patients that did not develop ESRD continued to have renal parenchymal growth in a linear fashion. This suggests that prenatal RPA may be predictive of postnatal ESRD. CONCLUSIONS: RPA measurement during the prenatal period could play an important role as a non-invasive tool to predict postnatal renal function and to anticipate postnatal clinical interventions.