A Systematic Review and Meta-analysis of Rituximab-Associated Infections Among Children and Adolescents With Glomerular Disease: Focus on the Risk of Infections.

OBJECTIVE: This systematic review and meta-analysis aimed to explore rituximab (RTX) associated infectious complications in children with glomerular disease. METHODS: We performed an electronic search of PubMed, International Scientific Information (ISI), Scopus, and EMBASE between January 2010 and July 2021. Infection rates and total drug-related adverse events were the outcomes. Statistical heterogeneity was evaluated by using the I2 statistic. When there was statistical evidence of heterogeneity (I2 > 50%, p > 0.1), a random-effect model was adopted. Data analysis was performed with Stata17.0 software. RESULTS: A total of 7 studies with 668 patients (136 with lupus nephritis [LN] and 532 with nephrotic syndrome were included in the meta-analysis. The pooled risk ratio showed that the administration of RTX was significantly associated with lower risk of infectious complications in patients with LN and nephrotic syndrome (0.72 [95% CI 0.58, 0.85]) when compared with population data of patients without glomerular disease (p = 0.2). There was no significant difference between the LN and nephrotic syndrome groups in terms of total serious adverse events or the occurrence of infections. There was significant heterogeneity among the reported studies (Q = 42.39, p < 0.001, I2 = 81%). CONCLUSION: Administration of RTX in children with glomerular disease is associated with a lower rate of infections when compared with population data of patients without LN or nephrotic syndrome. Additional high-quality randomized controlled trials with long-term follow-up are needed to identify the long-term potential complications. Trial registration PROPERO ID: CRD42021274869 (https://www.crd.york.ac/prospero/display_record.php?).

Validity of the Adrogué-Madias Formula for the Management of Acute Dysnatremias in Critically Ill Children: A Prospective Multicenter Analysis.

OBJECTIVE: Current conventional formulas do not predict the expected changes in serum sodium after administration of various fluids to correct serum sodium abnormalities. The Adrogué-Madias formula is currently the preferred and widely used fluid prescription for adult patients with dysnatremias, but its therapeutic efficacy has not been validated in pediatric patients. METHODS: In this prospective study, we used the Adrogué-Madias formula for calculating the appropriate rate of various fluids administration to correct serum sodium abnormalities in 7 critically ill children with acute dysnatremias. RESULTS: After administration of various intravenous fluids using the Adrogué-Madias formula, the anticipated as well as the achieved sodium concentrations were almost similar. CONCLUSIONS: This study demonstrates that the use of the Adrogué-Madias quantitative formula allows to calculate the appropriate rate of administration of various fluids. The calculated fluid administration resulted in the subsequent actual laboratory values and clinical changes.

Urine KIM-1 as a Potential Biomarker of Acute Renal Injury After Circulatory Collapse in Children.

OBJECTIVES: Serum creatinine (SCr) is a late marker of acute kidney injury (AKI) due to the lag time between initiating injury and loss of function. We assessed the ability of urinary interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) to predict AKI in critically ill children with circulatory collapse. METHODS: Serum creatinine, estimated creatinine clearance (eCrCL), urine IL-18, KIM-1, and NGAL values were measured in 86 children with circulatory collapse on the day of admission, and the results were compared with those obtained 6 days later. Acute kidney injury was defined as a decrease in eCrCL of greater than 25% within the first 48 hours of enrollment. Areas under the curve (AUC) for receiver operating characteristic curve were calculated for the early detection of AKI. RESULTS: Mean SCr concentration did not differ significantly during the first 6 days of hospital admission. In contrast, mean urine concentrations of IL-18, KIM-1, and NGAL rose significantly from day of admission to the sixth day of hospital stay (P < 0.001). Urinary KIM-1 emerged as having the strongest performance for the early detection of AKI, followed by NGAL, IL-18, and eCrCL. Urinary KIM-1 displayed the highest AUC of 0.81 (95% confidence interval [CI], 0.76-0.93; P < 0.001) for the early detection of AKI after circulatory collapse, followed by NGAL (0.77% CI, 0.70-0.84) and IL-18 (0.69% CI, 0.48-0.64). CONCLUSIONS: Of a panel of 3 promising urinary biomarkers, KIM-1 demonstrated the best performance in predicting AKI in children with circulatory collapse before a change in SCr or eCrCL becomes apparent.

Prevention of Chemotherapy-Induced Nephrotoxicity in Children with Cancer.

Children with cancer treated with cytotoxic drugs are frequently at risk of developing renal dysfunction. The cytotoxic drugs that are widely used for cancer treatment in children are cisplatin (CPL), ifosfamide (IFO), carboplatin, and methotrexate (MTX). Mechanisms of anticancer drug-induced renal disorders are different and include acute kidney injury (AKI), tubulointerstitial disease, vascular damage, hemolytic uremic syndrome (HUS), and intrarenal obstruction. CPL nephrotoxicity is dose-related and is often demonstrated with hypomagnesemia, hypokalemia, and impaired renal function with rising serum creatinine and blood urea nitrogen levels. CPL, mitomycin C, and gemcitabine treatment cause vascular injury and HUS. High-dose IFO, streptozocin, and azacitidine cause renal tubular dysfunction manifested by Fanconi syndrome, rickets, and osteomalacia. AKI is a common adverse effect of MTX, interferon-alpha, and nitrosourea compound treatment. These strategies to reduce the cytotoxic drug-induced nephrotoxicity should include adequate hydration, forced diuresis, and urinary alkalization. Amifostine, sodium thiosulfate, and diethyldithiocarbamate provide protection against CPL-induced renal toxicity.

Practical considerations to drug dosing in children with acute kidney injury.

Medication dosing for children with acute kidney injury (AKI) needs to be individualized based on pharmacokinetic and pharmacodynamic principles of the prescribed drugswhenever possible to optimize therapeutic outcome and to minimize toxicity. The pediatric RIFLE criteria should be prospectively utilized to identify patients at highest risk of developing AKI. Serum creatinine and urine output along with volume status should be utilized to guide drug dosing when urinary biomarkers including kidney injury molecule 1, interleukin-18, or neutrophil gelatinase-associated lipocalin are not readily available. Because of the presence of a positive fluid balance in early stages of AKI, the dosing regimen for many drugs, especially antimicrobial agents, should be initiated at a larger loading dose based on the expected volume of distribution to achieve target serum concentrations.When possible, therapeutic drug monitoring should be utilized for those medications where serum drug concentrations can be obtained in a clinically relevant time frame. For these medications, close monitoring of serum drug concentrations is highly recommended. This review addresses drug-dosing strategies in pediatric patients with AKI including the roles of therapeutic drug monitoring and newer kidney injury biomarkers.

Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus.

BACKGROUND: Congenital nephrogenic diabetes insipidus (NDI) is characterized by massive polyuria and polydipsia due to defects in the vasopressin-sensitive signaling system expression of the acuaporin-2 (AQP2) water channel of the kidney collecting duct principal cells. Current conventional treatment regimen including hydration, diuretics and nonsteroidal anti-inflammatory drugs can only partially reduce polyuria. Recent experimental studies have suggested that treatment with sildenafil, a selective phosphodiesterase inhibitor, may enhance cyclic guanosine monophosphate (cGMP)-mediated apical trafficking of AQP2 and may be effective in increasing water reabsorption in patients with congenital NDI. PATIENT AND METHODS: A 4-year old boy with X-linked NDI resistant to conventional therapy was treated with sildenafil for 10 days after a 2-day washout period between the 2 treatment regimens. Aliquots of the 24-hour urine collections before and after treatment were analyzed for urine volume, osmolality, cGMP and AQP2 determinations. Blood samples were also obtained for sodium and osmolality measurements. The primary endpoint was 24-hour urine volume after 10 days of sildenafil and conventional treatments. RESULTS: Compared to conventional therapy, treatment with sildenafil resulted in substantial reduction in 24-hour urine volume (1,764 vs. 950 ml) and serum sodium (148 vs. 139) mEq/l, and increased urine osmolality (104 vs. 215 mOsm/l), and AQP2 excretion (5 vs. 26 fmol/mg creatinine). The patient tolerated sildenafil well and experienced no adverse effects. CONCLUSIONS: Sildenafil citrate should be considered an alternative agent in the treatment of X-linked NDI resistant to conventional therapy.