The real world experience of pediatric primary hyperoxaluria patients in the PEDSnet clinical research network.

The rarity of primary hyperoxaluria (PH) challenges our understanding of the disease. The purpose of our study was to describe the course of clinical care in a United States cohort of PH pediatric patients, highlighting health service utilization. We performed a retrospective cohort study of PH patients < 18 years old in the PEDSnet clinical research network from 2009 to 2021. Outcomes queried included diagnostic imaging and testing related to known organ involvement of PH, surgical and medical interventions specific to PH-related renal disease, and select PH-related hospital service utilization. Outcomes were evaluated relative to cohort entrance date (CED), defined as date of first PH-related diagnostic code. Thirty-three patients were identified: 23 with PH type 1; 4 with PH type 2; 6 with PH type 3. Median age at CED was 5.0 years (IQR 1.4, 9.3 years) with the majority being non-Hispanic white (73%) males (70%). Median follow-up between CED and most recent encounter was 5.1 years (IQR 1.2, 6.8). Nephrology and Urology were the most common specialties involved in care, with low utilization of other sub-specialties (12%-36%). Most patients (82%) had diagnostic imaging used to evaluate kidney stones; 11 (33%) had studies of extra-renal involvement. Stone surgery was performed in 15 (46%) patients. Four patients (12%) required dialysis, begun in all prior to CED; four patients required renal or renal/liver transplant.    Conclusion: In this large cohort of U.S. PH children, patients required heavy health care utilization with room for improvement in involving multi-disciplinary specialists. What is Known: • Primary hyperoxaluria (PH) is rare with significant implications on patient health. Typical involvement includes the kidneys; however, extra-renal manifestations occur. • Most large population studies describe clinical manifestations and involve registries. What is New: • We report the clinical journey, particularly related to diagnostic studies, interventions, multispecialty involvement, and hospital utilization, of a large cohort of PH pediatric patients in the PEDSnet clinical research network. • There are missed opportunities, particularly in that of specialty care, that could help in the diagnosis, treatment, and even prevention of known clinical manifestations.

Diagnostic Code-Based Screening for Identifying Children with Primary Hyperoxaluria.

PURPOSE: We evaluated the utility of diagnostic codes to screen for patients with primary hyperoxaluria (PH) and evaluate their positive predictive value (PPV) in identifying children with this rare condition in PEDSnet, a clinical research network of pediatric health systems that shares electronic health records data. MATERIALS AND METHODS: We conducted a cross-sectional study of children who received care at 7 PEDSnet institutions from January 2009 through January 2021. We developed and applied screening criteria using diagnostic codes that generated 3 categories of the hypothesized probability of PH. Tier 1 had specific diagnostic codes for PH; tier 2 had codes for hyperoxaluria, oxalate nephropathy, or oxalosis; and tier 3 had a combination of ≥2 codes for disorder of carbohydrate metabolism and ≥1 code for kidney stones. We reviewed the electronic health records of patients with possible PH to confirm PH diagnosis and evaluate the accuracy and timing of diagnostic codes. The PPV of the codes was compared across tiers, time, PH type, and site. RESULTS: We identified 341 patients in the screen; 33 had confirmed PH (9.7%). Tier 1 had the highest proportion of PH; however, the PPV was only 20%. The degree to which an institution accurately represented point of care diagnoses in the data extraction process was predictive of higher PPV. The PPV of diagnostic codes was highest for PH3 (100%) and lowest for PH1 (22.8%). CONCLUSIONS: Diagnostic codes for PH have poor PPV. Findings suggest that one should be careful in research using large databases in which source validation is not possible.

Isosorbide dinitrate in nephronophthisis treatment.

Nephronophthisis is a progressive disease that affects development of the renal tubules and leads to end stage renal disease. Many affected children have isolated renal disease; however, there can be additional manifestations including heart defects, liver fibrosis, brain malformations, and situs inversus. There is no way to slow or modify the disease. We describe a patient who presented at birth with cholestatic jaundice and decreased kidney function, found by exome sequencing to have two NPHP3 variants. Her clinical status deteriorated rapidly, and two disease-modifying agents were given in hopes of slowing disease progression, the arginine vasopressin type II receptor antagonist tolvaptan to stabilize her renal function and isosorbide dinitrate to manage her poorly controlled hypertension. Tolvaptan therapy initiated at 82 days of life had limited effect on the rate of decline in renal function and was insufficient to abrogate the need for dialysis; however, isosorbide dinitrate therapy led to a dramatic improvement in blood pressure control and allowed for the discontinuation of multiple anti-hypertensive agents. This is the first report of the use of tolvaptan and isosorbide dinitrate for nephronophthisis management. We suggest that isosorbide dinitrate may represent a disease-modifying agent in nephronophthisis treatment.

Continuous Infusion Vancomycin Through the Addition of Vancomycin to the Continuous Renal Replacement Therapy Solution in the PICU: A Case Series.

OBJECTIVES: To describe our experience with achieving therapeutic serum vancomycin concentrations in pediatric continuous renal replacement therapy by using continuous infusion vancomycin by mixing vancomycin into the continuous renal replacement therapy solution. DESIGN: Retrospective chart review. SETTING: A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA. PATIENTS: Pediatric patients receiving continuous renal replacement therapy from April 1, 2009, through December 31, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were a total of 21 patients who received continuous renal replacement therapy during the study period. Of these, 11 (52.3%) received vancomycin in the continuous renal replacement therapy solution. The median (range) concentration of vancomycin added to the continuous renal replacement therapy solution was 25 mg/L (18-35 mg/L). The mean vancomycin plateau level was 22.8 ± 3.3 mg/L. All patients achieved a serum vancomycin plateau level that was greater than 15 mg/L. There were no adverse events related to the addition of vancomycin to the continuous renal replacement therapy solution. CONCLUSIONS: The addition of vancomycin to the continuous renal replacement therapy solution(s) is an effective modality that is used for delivering vancomycin continuous infusion and for ensuring therapeutic vancomycin serum plateau levels in the setting of pediatric continuous renal replacement therapy. Further studies are required to evaluate whether this delivery method can lead to improved patient outcomes.

Distinguishing characteristics of pediatric patients with primary hyperoxaluria type 1 in PEDSnet.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of metabolism that causes oxalate deposition, leading to recurrent calcium oxalate kidney stones, chronic kidney disease and systemic oxalosis, which produces a broad range of serious life-threatening complications. Patients with PH1 have delayed diagnosis due to the rarity of the disease and the overlap with early-onset kidney stone disease not due to primary hyperoxaluria. OBJECTIVE: The objective of this study was to determine the clinical features of individuals <21 years of age with PH1 that precede its diagnosis. We hypothesized that a parsimonious set of features could be identified that differentiate patients with PH1 from patients with non-primary hyperoxaluria-associated causes of early-onset kidney stone disease. STUDY DESIGN: We determined the association between clinical characteristics and PH1 diagnosis in a case-control study conducted between 2009 and 2021 in PEDSnet, a clinical research network of eight US pediatric health systems. Each patient with genetically confirmed PH1 was matched by sex and PEDSnet institution to up to 4 control patients with kidney stones without PH of any type. We obtained patient characteristics and diagnostic test results occurring before to less than 6 months after study entrance from a centralized database query and from manual chart review. Differences were examined using standardized differences and multivariable regression. RESULTS: The study sample included 37 patients with PH1 and 147 controls. Patients with PH1 were younger at diagnosis (median age of 3 vs 13.5 years); 75 % of children with PH1 were less than 8 years-old. Patients with PH1 were more likely to have combinations of nephrocalcinosis on ultrasound or CT (43 % vs 3 %), lower eGFR at diagnosis (median = 52 mL/min/1.73 m2 vs 114 mL/min/1.73 m2), and have normal mobility. Patients with PH1 had higher proportion of calcium oxalate monohydrate kidney stones than controls (median = 100 % vs 10 %). There were no differences in diagnosis of failure to thrive, stone size, or echocardiography results. CONCLUSIONS: Children with PH1 are characterized by presentation before adolescence, nephrocalcinosis, decreased eGFR at diagnosis, and calcium oxalate monohydrate stone composition. If externally validated, these characteristics could facilitate earlier diagnosis and treatment of children with PH1.

Two decades of pediatric kidney transplantation in a multi-ethnic cohort.

This study evaluated a 20-yr experience in kidney transplantation in children from a predominantly Hispanic community. A retrospective analysis was carried out in children who received kidney transplants from 1985 to 2005. Of 124 kidney transplants, 81 (65%) were from LD. Racial distribution was Hispanic (48%), followed by AA (24%) and Caucasian (26%). First yr allograft survival was similar in LD and DD and significantly better in LD until seven yr post transplant. eGFR <60 mL/min/1.73 m(2) at one yr post transplant was associated with a median allograft survival of 3.3 yr, compared to 16 yr in those with eGFR > or = 60 mL/min/1.73 m(2) (p < 0.0001). Graft loss in the first five yr was from non-adherence, recurrence of disease, and infections. Those of AA race were more likely to receive a DD and have low socioeconomic status and the poorest median allograft survival compared to Hispanics and Caucasians (6 vs. > or =15 yr; p < 0.001). In conclusion, this predominantly Hispanic cohort emphasizes the disadvantaged profile of AAs compared to other racial groups. Strategies to improve supportive services and living donations in minority populations need to be developed. Long-term renal allograft survival is achievable if GFR is maintained >60 mL/min/1.73 m(2).

Renal manifestations in toddlers with Takayasu's arteritis and malignant hypertension.

Three children under the age of 3 years presented with malignant hypertension, proteinuria, and acute kidney injury. Takayasu's arteritis was diagnosed on the basis of clinical symptoms of weight loss and low grade fever in conjunction with elevated sedimentation rate and radiographic evidence of aortic and renal artery stenosis. One patient had a renal biopsy which showed arteriolar sclerosis and focal glomerulosclerosis. All three patients required multiple antihypertensive agents, ultimately including angiotensin receptor blockers and/or angiotensin converting enzyme inhibitors. The vasculitis was treated with pulse corticosteroids followed by cyclophosphamide in one patient and mycophenolate mofetil as maintenance therapy in all. Follow-up has ranged from 2 to 8 years. Although global renal function has normalized in each patient, two have unilateral non-function of one kidney. The last patient has persistent aortic and renal artery stenosis with complex collateralization requiring ongoing medical and anticipated surgical management.