Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

Delivery of a nutritional prescription by enteral tube feeding in children with chronic kidney disease stages 2-5 and on dialysis-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce.

The nutritional prescription (whether in the form of food or liquid formulas) may be taken orally when a child has the capacity for spontaneous intake by mouth, but may need to be administered partially or completely by nasogastric tube or gastrostomy device ("enteral tube feeding"). The relative use of each of these methods varies both within and between countries. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, has developed clinical practice recommendations (CPRs) based on evidence where available, or on the expert opinion of the Taskforce members, using a Delphi process to seek consensus from the wider community of experts in the field. We present CPRs for delivery of the nutritional prescription via enteral tube feeding to children with chronic kidney disease stages 2-5 and on dialysis. We address the types of enteral feeding tubes, when they should be used, placement techniques, recommendations and contraindications for their use, and evidence for their effects on growth parameters. Statements with a low grade of evidence, or based on opinion, must be considered and adapted for the individual patient by the treating physician and dietitian according to their clinical judgement. Research recommendations have been suggested. The CPRs will be regularly audited and updated by the PRNT.

Energy and protein requirements for children with CKD stages 2-5 and on dialysis-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce.

Dietary management in pediatric chronic kidney disease (CKD) is an area fraught with uncertainties and wide variations in practice. Even in tertiary pediatric nephrology centers, expert dietetic input is often lacking. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, was established to develop clinical practice recommendations (CPRs) to address these challenges and to serve as a resource for nutritional care. We present CPRs for energy and protein requirements for children with CKD stages 2-5 and those on dialysis (CKD2-5D). We address energy requirements in the context of poor growth, obesity, and different levels of physical activity, together with the additional protein needs to compensate for dialysate losses. We describe how to achieve the dietary prescription for energy and protein using breastmilk, formulas, food, and dietary supplements, which can be incorporated into everyday practice. Statements with a low grade of evidence, or based on opinion, must be considered and adapted for the individual patient by the treating physician and dietitian according to their clinical judgment. Research recommendations have been suggested. The CPRs will be regularly audited and updated by the PRNT.

The dietary management of calcium and phosphate in children with CKD stages 2-5 and on dialysis-clinical practice recommendation from the Pediatric Renal Nutrition Taskforce.

In children with chronic kidney disease (CKD), optimal control of bone and mineral homeostasis is essential, not only for the prevention of debilitating skeletal complications and achieving adequate growth but also for preventing vascular calcification and cardiovascular disease. Complications of mineral bone disease (MBD) are common and contribute to the high morbidity and mortality seen in children with CKD. Although several studies describe the prevalence of abnormal calcium, phosphate, parathyroid hormone, and vitamin D levels as well as associated clinical and radiological complications and their medical management, little is known about the dietary requirements and management of calcium (Ca) and phosphate (P) in children with CKD. The Pediatric Renal Nutrition Taskforce (PRNT) is an international team of pediatric renal dietitians and pediatric nephrologists, who develop clinical practice recommendations (CPRs) for the nutritional management of various aspects of renal disease management in children. We present CPRs for the dietary intake of Ca and P in children with CKD stages 2-5 and on dialysis (CKD2-5D), describing the common Ca- and P-containing foods, the assessment of dietary Ca and P intake, requirements for Ca and P in healthy children and necessary modifications for children with CKD2-5D, and dietary management of hypo- and hypercalcemia and hyperphosphatemia. The statements have been graded, and statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs based on the clinical judgment of the treating physician and dietitian. These CPRs will be regularly audited and updated by the PRNT.

Racial-ethnic differences in health-related quality of life among adults and children with glomerular disease.

INTRODUCTION: Disparities in health-related quality of life (HRQOL) have been inadequately studied in patients with glomerular disease. The aim of this study was to identify relationships between race/ethnicity, socioeconomic status, disease severity, and HRQOL in an ethnically and racially diverse cohort of patients with glomerular disease. METHODS: Cure Glomerulonephropathy (CureGN) is a multinational cohort study of patients with biopsy-proven glomerular disease. Associations between race/ethnicity and HRQOL were determined by the following: 1. Missed school or work due to kidney disease; 2. Responses to Patient Reported Outcomes Measurement Information System (PROMIS) questionnaires. We adjusted for demographics, socioeconomic status, and disease characteristics using multivariable logistic and linear regression. RESULTS: Black and Hispanic participants had worse socioeconomic status and more severe glomerular disease than White or Asian participants. Black adults missed work or school most frequently due to kidney disease (30% versus 16-23% in the other three groups, p=0.04), and had the worst self-reported global physical health (median score 44.1 versus 48.0-48.2, p<0.001) and fatigue (53.8 versus 48.5-51.1, p=0.002), compared to other racial/ethnic groups. However, these findings were not statistically significant with adjustment for socioeconomic status and disease severity, both of which were strongly associated with HRQOL in adults. Among children, disease severity but not race/ethnicity or socioeconomic status were associated with HRQOL. CONCLUSIONS: Among patients with glomerular disease enrolled in CureGN, the worse HRQOL reported by Black adults was attributable to lower socioeconomic status and more severe glomerular disease. No racial/ethnic differences in HRQOL were observed in children.

Glomerular permeability activity: prevalence and prognostic value in pediatric patients with idiopathic nephrotic syndrome.

BACKGROUND: A circulating factor that increases in vitro glomerular permeability to albumin (P alb ) has been isolated from patients with recurrence of focal segmental glomerulosclerosis in their renal allografts. The prevalence and prognostic significance of permeability activity has not been examined in children with idiopathic nephrotic syndrome (INS). METHODS: P alb activity level was determined in sera from 26 children with new-onset INS before the initiation of therapy by using an in vitro assay. Permeability factor was considered present if P alb was greater than 0.5. The following clinical and laboratory data for patients were tabulated: demographic information, serum albumin and cholesterol concentrations, calculated glomerular filtration rate, age at disease onset, response to corticosteroid treatment, and long-term outcome. RESULTS: Patients ranged in age from 2 to 18 years, and 19 patients (73%) were male. Mean P alb was 0.45 +/- 0.04 (SEM). P alb in patients with a steroid-responsive course (n = 17) did not differ from that of patients with steroid-resistant disease (n = 9). Percentages with P alb greater than 0.5 did not differ between patients with steroid-responsive and steroid-resistant disease (47% and 33%, respectively). P alb was determined after 41 +/- 5 months in 6 patients with steroid-responsive INS. These patients had normal serum creatinine concentrations, and 4 of 6 patients were in prolonged remission. P alb at the onset of INS before therapy was 0.51 +/- 0.09 (P alb > 0.5 in 2 patients) and was not changed at follow-up (P alb = 0.40 +/- 0.12; P alb > 0.5 in 2 patients). CONCLUSION: Permeability activity, defined as P alb greater than 0.5, is present in pretreatment serum samples from nearly half the children with INS. The presence of permeability activity does not predict clinical response to steroid treatment, renal histopathologic characteristics, or clinical outcome at up to 5 years of follow-up.

Peritoneal transport kinetics of proteins in children on chronic peritoneal dialysis.

OBJECTIVE: This study describes a modified 4-hour peritoneal equilibration test (PET) for analyzing peritoneal transport characteristics of proteins with different molecular weights and predicting daily peritoneal protein losses in children on chronic peritoneal dialysis (PD). DESIGN: Cross-sectional study. SETTING: A single regional pediatric dialysis unit in a teaching hospital. PATIENTS: 9 stable pediatric dialysis patients; 4 were on continuous ambulatory PD, 5 were on continuous cycling PD. MAIN OUTCOME MEASURES: Serum and dialysate concentrations of IgG, albumin, beta2-microglobulin, and transferrin were determined during a PET. Changes in dialysate-to-plasma (D/P) ratios were determined hourly. Agreement between PET-derived and measured daily peritoneal protein losses was examined. RESULTS: The D/P ratio decreased with increased molecular radius (p < 0.0001). Many children had low plasma levels of IgG, albumin, and transferrin, but elevated levels of beta2-microglobulin. The D/P ratio increased linearly during the PET for all measured proteins, regardless of molecular weight. There was close correlation between 4-hour PET protein losses and 24-hour losses during routine PD. CONCLUSIONS: Proteins are lost through the peritoneum according to their size, demonstrating linear transport kinetics during a 4-hour PET. The PET-derived data predicted daily protein losses in children on chronic PD. This approach might help to eliminate inaccuracies due to incomplete dialysate collection.

Surveillance renal transplant biopsies and subclinical rejection at three months post-transplant in pediatric recipients.

UNLABELLED: Subclinical acute rejection (SCR) has been increasingly recognized in adult renal transplant recipients with the advent of surveillance biopsies. However, in children, surveillance biopsies are not routinely performed at most centers. Therefore, the incidence, predisposing factors, treatment, and clinical outcomes of SCR remain unclear in children. From August 2004 to December 2005, we performed 36 protocol biopsies at three months post-transplantation. All patients had received induction therapy with basiliximab and were maintained on prednisone, MMF, and tacrolimus. Sixteen cases of SCR were detected by biopsy (44%). Age, gender, race, donor source, or serum creatinine did not discriminate between children with SCR and those with normal biopsies. All cases of SCR were treated with high doses of methylprednisolone. At one yr post-transplant, renal function was similar in children with SCR to those with normal surveillance biopsies (p = 0.62). Because of the high incidence of SCR, the maintenance dose of MMF was increased by 50% in 20 children transplanted after December 2005. This resulted in a significant decline in the incidence of SCR from 44 to 15% (p < 0.05). However, the incidence of polyomavirus (BK) viremia also increased significantly in these children (p < 0.005). CONCLUSION: A high incidence of SCR was found on surveillance biopsies at three months post-transplant and could not be predicted by age, gender, race, donor source, or serum creatinine. The occurrence of SCR declined significantly by increasing the dose of MMF, but resulted in an increase in BK viremia. We conclude that surveillance biopsies provide valuable information in the management of pediatric renal transplant recipients. Increasing immunosuppression to avoid SCR should be weighed against the risk for infection.