Tumor necrosis factor-alpha is associated with mineral bone disorder and growth impairment in children with chronic kidney disease.

BACKGROUND: Mineral and bone disorder (MBD) and growth impairment are common complications of pediatric chronic kidney disease (CKD). Chronic inflammation detrimentally affects bone health and statural growth in non-CKD settings, but the impact of inflammation on CKD-MBD and growth in pediatric CKD remains poorly understood. This study assessed associations between inflammatory cytokines with biomarkers of CKD-MBD and statural growth in pediatric CKD. METHODS: This is a cross-sectional study of children with predialysis CKD stages II-V. Cytokines (IL-1b, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNF-α, interferon-γ), bone alkaline phosphatase (BAP), and procollagen type 1 N-terminal propeptide (P1NP) were measured at the same time as standard CKD-MBD biomarkers. Associations between cytokines, CKD-MBD biomarkers, and height z-score were assessed using linear regression analysis. RESULTS: Among 63 children, 52.4% had stage 3 CKD, 76.2% non-glomerular CKD etiology, and 21% short stature. TNF-α was the only cytokine associated with parathyroid hormone (PTH) independent of glomerular filtration rate. After stratification by low, medium, and high TNF-α tertiles, significant differences in PTH, serum phosphorus, alkaline phosphatase, BAP, P1NP, and height z-score were found. In a multivariate analysis, TNF-α positively associated with phosphorus, PTH, and alkaline phosphatase and inversely associated with height z-score, independent of kidney function, age, sex, and active vitamin D analogue use. CONCLUSIONS: TNF-α is positively associated with biomarkers of CKD-MBD and inversely associated with height z-score, indicating that inflammation likely contributes to the development of CKD-MBD and growth impairment in pediatric CKD. Prospective studies to definitively assess causative effects of inflammation on bone health and growth in children with CKD are warranted.

Interleukin-6 Contributes to the Development of Anemia in Juvenile CKD.

INTRODUCTION: Anemia is a common complication of chronic kidney disease (CKD) in children; however, the role of inflammation in its pathogenesis remains incompletely understood. METHODS: To elucidate the role of interleukin (IL)-6 in renal anemia, we induced CKD by adenine diet in juvenile wild-type (WT) and IL-6 deficient (Il6KO) mice, and examined serum IL-6 and relevant parameters in children with CKD. RESULTS: WT-CKD mice developed anemia despite increases in serum erythropoietin and displayed low serum iron and elevated serum IL-6. IL-6 deficiency resulted in a significant improvement of red blood cell count and hemoglobin in CKD mice. This effect was associated with improvement of hypoferremia by Il6 deletion, likely mediated by hepcidin. However, correction of hypoferremia by oral iron supplementation in WT-CKD mice did not fully replicate the protective effects of Il6 deletion, suggesting an additional iron-independent role for IL-6 in CKD-anemia. Indeed, Il6 deletion mitigated the severity of renal fibrosis and alleviated relative erythropoietin insufficiency in CKD mice. Cytokine profiling in a pediatric CKD cohort demonstrated that of 10 cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor (TNF)-α, and interferon-γ), only IL-6 was significantly (inversely) associated with hemoglobin when adjusted for glomerular filtration rate (GFR). The association between IL-6 and hemoglobin in children with CKD remained significant after adjustment for CKD stage, iron therapy, and hepcidin. DISCUSSION: IL-6 contributes to development of anemia in juvenile CKD, through mechanisms that include induction of hypoferremia, aggravation of renal fibrosis, and alteration of the erythropoietin axis. IL-6 appears to be a promising therapeutic target in the management of CKD-anemia.

Rituximab in post-transplant pediatric recurrent focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) recurs in 20-40 % of allografts. Plasmapheresis (TPE) has been one of the mainstays of treatment with variable results. Rituximab (RTX), a monoclonal antibody to the protein CD20, is being used for treatment of recurrent FSGS (recFSGS) but pediatric experience is limited. METHODS: We conducted a retrospective review of eight patients with recFSGS, treated with RTX (1-4 doses) after having minimal response to TPE. Complete response was defined as a decrease in urine protein creatinine ratio (Up/c) to less than 0.2 and partial response was a decrease in Up/c ratio by 50 % of baseline and in the sub-nephrotic range (U p/c <2). RESULTS: Complete response was seen in two of eight patients, and partial response was seen in four of eight patients. Two patients had no response. At last follow-up, all the partial responders had sub-nephrotic range proteinuria (Up/c ratios ranging from 0.29 to 1.6). Delayed response, up to 9 months post-RTX, was also seen in some of the patients. Significant complications such as rituximab-associated lung injury (RALI), acute tubular necrosis, and central nervous system(CNS) malignancy were also observed in our case series. CONCLUSIONS: Rituximab can be used with caution as a treatment for recFSGS. Efficacy is variable from none to complete response. Even partial reduction in proteinuria is of benefit in prolonging the life of the allograft. Long-term, multicenter studies are needed to prove its sustained efficacy in those who respond and to monitor for serious adverse effects.

Pilot study of mycophenolate mofetil for treatment of kidney disease due to congenital urinary tract disorders in children.

BACKGROUND: Congenital uropathies account for nearly half the chronic kidney disease in children. Immune-mediated injury may contribute to progressive loss of kidney function in affected patients. STUDY DESIGN: Open-label uncontrolled pilot study to determine the feasibility of treatment with the immunosuppressive drug mycophenolate mofetil (MMF) to prevent a decrease in kidney function in pediatric patients with congenital uropathies. SETTING & PARTICIPANTS: Children treated in an outpatient tertiary-care center were eligible if they had: (1) age of 3 to 16 years, (2) glomerular filtration rate (GFR) less than 50 mL/min/1.73 m(2), and (3) a congenital genitourinary tract abnormality. INTERVENTION: After a 2-month run-in period, patients were prescribed MMF, 600 mg/m(2)/dose, twice daily for a 24-month treatment period. OUTCOMES: The primary end point was feasibility based on the ability to recruit and retain subjects and lack of unanticipated adverse events. The secondary end point was change in GFR. MEASUREMENTS: Patients were monitored by using standard clinical laboratory tests, and GFR was determined by means of iothalamate clearance. RESULTS: 12 patients aged 8.9 +/- 4.8 years (10 boys, 2 girls) were treated with MMF for 18.6 +/- 8.0 months; 7 patients completed the entire treatment period. MMF dosage at the final study visit was 381 +/- 241 mg/m(2) twice daily. Gastrointestinal symptoms were the most common adverse effect. There was only 1 serious adverse event, an episode of fever and neutropenia requiring parenteral antibiotic therapy after 21 months of MMF therapy. GFR remained stable throughout the treatment period. Nutritional status, blood pressure, and serum calcium, phosphorus, and cholesterol levels were unchanged during this period. LIMITATIONS: Insufficient power to assess the safety or efficacy of MMF therapy for patients with congenital uropathies. CONCLUSION: It is feasible to study MMF as an adjunctive therapy to retard the progression of kidney disease in children with congenital uropathies. A multicenter randomized clinical trial is warranted to determine the efficacy of this novel treatment strategy.