COVID-19 in pediatric kidney transplantation: The Improving Renal Outcomes Collaborative.

There are limited data on the impact of COVID-19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID-19 in pediatric KT patients. Twenty-two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS-CoV-2 by PCR. Testing indications included symptoms and/or potential exposures to COVID-19 (N = 134, 47.7%) and/or testing per hospital policy (N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID-19-positive patients, 16 were managed as outpatients, six received non-ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID-19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID-19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID-19 disease and excellent short-term outcomes.

Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.

A novel deletion in the RCA gene cluster causes atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a complex complement-mediated disease that progresses to end-stage renal failure (ESRF) in 50% of cases. Dysregulation of the alternative pathway (AP) of the complement cascade manifests as microangiopathic anaemia and thrombocytopenia. Multiple genes in the AP have been implicated in disease pathogenesis. Here, we report the clinical presentation of an affected patient that was inconsistent with genotype-phenotype data for carriers of CD46 mutations. Tests of AP function in this patient suggested additional genetic factors, and in-depth studies revealed a de novo heterozygous deletion that creates a novel CFH/CFHR1 fusion protein.

The Improving Renal Outcomes Collaborative: Blood Pressure Measurement in Transplant Recipients.

BACKGROUND AND OBJECTIVES: Hypertension is highly prevalent in pediatric kidney transplant recipients and contributes to cardiovascular death and graft loss. Improper blood pressure (BP) measurement limits the ability to control hypertension in this population. Here, we report multicenter efforts from the Improving Renal Outcomes Collaborative (IROC) to standardize and improve appropriate BP measurement in transplant patients. METHODS: Seventeen centers participated in structured quality improvement activities facilitated by IROC, including formal training in quality improvement methods. The primary outcome measure was the proportion of transplant clinic visits with appropriate BP measurement according to published guidelines. Prospective data were analyzed over a 12-week pre-intervention period and a 20-week active intervention period for each center and then aggregated as of the program-specific start date. We used control charts to quantify improvements across IROC centers. We applied thematic analysis to identify patterns and common themes of successful interventions. RESULTS: We analyzed data from 5392 clinic visits. At baseline, BP was measured and documented appropriately at 11% of visits. Center-specific interventions for improving BP measurement included educating clinic staff, assigning specific team member roles, and creating BP tracking tools and alerts. Appropriate BP measurement improved throughout the 20-week active intervention period to 78% of visits. CONCLUSIONS: We standardized appropriate BP measurement across 17 pediatric transplant centers using the infrastructure of the IROC learning health system and substantially improved the rate of appropriate measurement over 20 weeks. Accurate BP assessment will allow further interventions to reduce complications of hypertension in pediatric kidney transplant recipients.

Renal pathology in the pediatric transplant patient.

Renal transplantation is a therapeutic goal for children with advanced chronic kidney disease. There are many causes of renal dysfunction in children with allografts--the transplanted kidney can develop a variety of morphologic alterations leading to dysfunction. Evaluation of the kidney biopsy is one of the best methods of determining the cause of graft dysfunction. Rejection is a major cause of renal allograft failure in children. The morphologic hallmarks of acute antibody-mediated and cell-mediated rejection and chronic allograft nephropathy have been codified in classification strategies that are useful in adults and children. Viral infection and Epstein-Barr virus-driven posttransplant lymphoproliferative disease also occur in the pediatric transplanted kidney. Drug toxicity from immunosuppressive agents also causes characteristic morphologic alterations in the renal allograft. As the survival of pediatric heart and liver transplant patients improves, the incidence of immunosuppression therapy-related disease in the native kidney in these patients will likely become more important clinically. In addition to renal lesions related to the allograft state, glomerular disease can recur or occur de novo in renal allografts. Here, we describe the pathology of the more common morphologic lesions in kidneys of children with a renal allograft.

Early renal benefit of rapamycin combined with reduced calcineurin inhibitor dose in pediatric heart transplantation patients.

BACKGROUND: Calcineurin inhibitors such as cyclosporine are effective in preventing rejection in recipients of solid organ transplants. Unfortunately, the prolonged use of calcineurin inhibitors may result in progressive renal injury. METHODS: We studied the renal function of 15 pediatric heart transplant recipients who were taking calcineurin inhibitors. Their renal function was studied before and after rapamycin was introduced to their immunosuppression regimen. With the introduction of rapamycin, the patients were given a lower dose of calcineurin inhibitors, and the calcineurin inhibitor was discontinued in 5 patients. RESULTS: Renal function improved significantly in the patients by 30 days after these changes in the calcineurin inhibitor dose were instituted. Mean levels of blood urea nitrogen and mean serum creatinine decreased, and mean creatinine clearance increased. Pre-rapamycin, the patients' mean level of blood urea nitrogen was 27.1 +/- 12.4 mg/dl and post-rapamycin they decreased to 18.6 +/- 11.1 mg/dl (p = 0.014). Similarly, creatinine decreased from 1.0 +/- 0.5 mg/dl to 0.8 +/- 0.3 mg/dl (p = 0.019). Their creatinine clearance increased from 88 +/- 28 ml/min/1.73 mol/liter2 to 105 +/- 27 ml/min/1.73 mol/liter2 (p = 0.008). The patients' lipid levels did not change after they were prescribed rapamycin. Biopsy-negative rejection developed in 2 patients. CONCLUSIONS: The introduction of rapamycin to the immunosuppressive regimen of patients taking calcineurin inhibitors, with a concomitant reduction of the calcineurin inhibitor dose, may improve renal function within 30 days, without a significant increase in rejection.

Systemic Hypertension: Management in Children and Adolescents.

Recognition of systemic hypertension in children and adolescents requires careful blood pressure measurement using proper technique to compare with appropriate normative data. Selected use of ambulatory blood pressure monitoring can identify children with "white coat" hypertension, thus avoiding unnecessary diagnostic testing and treatment in these children. Nonpharmacologic therapies including dietary sodium restriction, weight loss, and exercise may benefit children and adolescents with borderline hypertension and mild essential hypertension. These therapies may be important adjunctive agents in children requiring antihypertensive therapy as well. Historically, pharmacologic management of hypertension in children has been limited by a lack of controlled studies and age-appropriate formulations. Recent clinical trials have provided new information regarding a number of antihypertensive agents in this age group.