Defining a threshold for tacrolimus intra-patient variability associated with late acute cellular rejection in paediatric kidney transplant recipients.

BACKGROUND: Late acute cellular rejection (LACR) is associated with poorer graft outcomes and non-adherence. Non-adherence to tacrolimus can be indirectly assessed by the intra-patient variability (IPV) of tacrolimus trough levels. The threshold of IPV associated with rejection is not known. METHODS: We conducted a case-control study comparing 25 patients with biopsy-proven LACR against 25 stable controls matched for age group, primary diagnosis and time post-transplant. IPV was calculated using coefficient of variance (CV) and mean absolute deviation (MAD) using tacrolimus levels in the preceding 12 months. We also assessed the percentage time for tacrolimus levels < 4 µg/L (Tac < 4) and the concentration/weight-adjusted dose (C/D) ratio as a proxy marker of tacrolimus metaboliser status. RESULTS: LACR patients had higher CV (median, IQR 44%, 36-61% v. 24%, 19-35%, p < 0.0001) and higher MAD (33%, 25-48% v. 19%, 15-26%, p < 0.0001). The MAD was less affected by outlying tacrolimus results. Receiver operating curve analysis of the MAD resulted in a sensitivity of 76% and specificity of 76% at a threshold of 26% (AUC 0.85, p < 0.05). LACR patients had more Tac < 4 (50% v. 26%, p < 0.05). There was no difference in C/D suggesting that good IPV can be maintained in fast metabolisers. Patients with LACR had significantly increased creatinine at 12-month follow-up despite treatment (108 v. 5 umol/L increase from baseline) and four patients lost their allograft. CONCLUSIONS: Monitoring of tacrolimus IPV using the MAD may be a clinical marker for LACR. A threshold IPV of 26% can potentially be used as a therapeutic target pending further validation studies.

Occult Kidney Dysfunction in Children With Transfusion-Dependent Thalassemia.

Background: Thalassemia is the commonest hemoglobinopathy in Southeast Asia. Kidney dysfunction is an underreported sequelae in children with thalassemia. We conducted a retrospective study to identify the prevalence of and predisposing factors for kidney dysfunction in children with transfusion-dependent thalassemia (TDT). Method: Abnormal kidney function was defined as children with a glomerular filtration rate (GFR) of <90 ml/min/1.73 m2 or a decline in GFR of >20 ml/min/1.73 m2 or presence of nephrotic range proteinuria within 3 years of commencing regular (every ≤6 weeks) red cell transfusion. Data analyzed were age at diagnosis of thalassemia, number of transfusion-years, iron chelation therapy, serum ferritin, and pre-transfusion hemoglobin levels. Results: Eighty-one children were studied. Mean age was 11.72 ± 5.275 years. Thirty out of 81 (37%) demonstrated abnormal kidney function. Evidence of glomerular hyperfiltration was seen in 29/81 patients (25.85%) at their last clinic visit. This fraction was doubled [48/81 (59.3%)] when the cohort was tracked back by 3 years from the last clinic encounter. Age at diagnosis (RR, 1.157; 95% CI, 1.014-1.319; p = 0.03) and duration of receiving transfusions (RR, 0.984; 95% CI, 0.974-0.994; p = 0.001) were associated with increased risk of developing abnormal kidney function. Conclusion: Abnormal kidney function in children with TDT may be overlooked by medical personnel without active screening measures. Children receiving regular red cell transfusions require systematic surveillance to enable early detection of kidney dysfunction and timely implementation of appropriate therapeutic interventions.

Case Report: Severe Hyponatremia in Infants With Urinary Tract Infection.

Introduction: Many reports on investigations and treatments in UTI, however little, have been mentioned with regard to electrolyte abnormalities. Secondary pseudohypoaldosteronism (PHA) in UTI, though less common, is a known association. Features include hyponatremia and concomitant hyperkalemia. Objectives: We aim to highlight these uncommon sequelae in UTI to avoid incorrect diagnosis and unnecessary investigations. Study Design: Clinical data of patients admitted and referred to a pediatric nephrologist at the University Malaya Medical Center between May 2019 and October 2020 were collated and elaborated. Results and Discussion: We report three infants with hyponatremia and hyperkalemia during UTI episodes. Two infants were known to have posterior urethral valve (PUV) before the onset of UTI and one infant had UTI, which led to investigations confirming the diagnosis of bladder vaginal fistula. The electrolyte derangements were temporary and resolved within 48 to 72 h of treatment with intravenous fluid and appropriate antibiotic therapy. Out of three, only one had a hormonal study, which confirms PHA. Reduced aldosterone activity could be due to absolute reduction in aldosterone titer or lack of aldosterone responsiveness at tubular (other tissues) level. In the latter, aldosterone titer is elevated. The infant in our cohort who had hormonal evaluation had the mentioned electrolyte abnormalities with a markedly elevated aldosterone titer. This demonstrated defective action of the hormone at the level of mineralocorticoid receptor. Although the remaining two infants had no confirmatory hormonal study, all of them recovered within 48 h of hospital admission, after receiving appropriate management for the primary problem, which was UTI. We observed a slower recovery of hyponatremia in relation to hyperkalemia, but none of these infants required salt replacement upon discharge. Conclusion: Infants with severe UTI and deranged electrolytes should be screened for structural abnormality and vice versa. Not all infants require hormonal screening, but those who required prolonged salt replacement or showed involvement of other systems warrant further evaluation.

Adrenal Insufficiency in Children With Nephrotic Syndrome on Corticosteroid Treatment.

Background: Adrenal insufficiency can result from impaired functions at all levels of hypothalamic-pituitary-adrenal (HPA) axis. We here studied risk factors associated with adrenal insufficiency in children receiving prolonged exogenous steroid treatment for nephrotic syndrome. Method:We performed low-dose Synacthen tests (LDSTs, 0.5 µg/m2) in children with steroid-sensitive nephrotic syndrome 4-6 weeks after discontinuation of the corticosteroid therapy. We measured early morning serum cortisol levels at baseline and at intervals of 10, 20, 30, and 60 min following the stimulation test. We defined normal HPA axis stimulation responses as those with peak cortisol cut-off values >550 nmol/L. Result:We enrolled 37 children for this study research. All children enrolled had normal early morning cortisol levels. However, 13 (35.1%) demonstrated HPA axis suppression (by LDST) 4-+6 weeks after discontinuation of oral prednisolone. Nephrotic syndrome diagnosed before 5 years of age (OR, 0.75; 95% CI, 0.57-0.99; p = 0.043), and steroid-dependence [OR, 5.58; 95% confidence interval (CI), 1.06-29.34; p = 0.042] were associated with increased risk of developing adrenal suppression after steroid discontinuation. Conclusion:HPA axis suppression, may go unnoticed without proper screening. A normal early morning cortisol level (275-555 nmol/L) does not exclude adrenal insufficiency in children with steroid-sensitive nephrotic syndrome. Further screening with LDSTs, particularly in children younger than 5 years at diagnosis, may be warranted.