Background
Hyperparathyroidism persists in up to 50% of pediatric kidney transplant recipients. The aims of this study were to describe the evolution of parathyroid hormone (PTH) in the first year ...after transplantation and to identify factors associated with hyperparathyroidism.
Methods
This retrospective study included children who underwent kidney transplantation at the University Hospitals of Ghent, Leuven, Rotterdam, or Amsterdam. Data from 149 patients were collected before and up to 12 months after transplantation. Severe hyperparathyroidism was defined as PTH 2-fold above the reference value. Factors associated with hyperparathyroidism and severe hyperparathyroidism were identified using multivariate logistic regression analysis.
Results
Before transplantation, 97 out of 137 patients (71%) had hyperparathyroidism. The probability of hyperparathyroidism and severe hyperparathyroidism declined from 0.49 and 0.17 to 0.29 and 0.09 at 3 and 12 months after transplantation, respectively. BMI SDS (
β
: 0.509;
p
= 0.011; 95% CI: 1.122–2.468), eGFR (
β
: − 0.227;
p
= 0.030; 95% CI: 0.649–0.978), and pre-transplant hyperparathyroidism (
β
: 1.149;
p
= 0.039; 95% CI: 1.062–9.369) were associated with hyperparathyroidism 12 months after transplantation. Pre-transplant hyperparathyroidism (
β
: 2.115;
p
= 0.044; 95% CI: 1.055–65.084), defined as intact parathormone (iPTH) levels > 65 ng/l (6.9 pmol/l) or 1-84 PTH > 58 ng/l (6.2 pmol/l), was associated with severe hyperparathyroidism at 3 months. Only eGFR (
β
: − 0.488;
p
= 0.010; 95% CI: 0.425–0.888) was inversely associated with severe hyperparathyroidism at 9 months after transplantation.
Conclusions
Allograft function remains the main determinant of severe hyperparathyroidism after transplantation. Our findings emphasize the importance of BMI and pre-transplant PTH control.
Background
Multiple clinical, demographic, and genetic factors affect the pharmacokinetics of tacrolimus in children, yet in daily practice, a uniform body-weight based starting dose is used. It can ...take weeks to reach the target tacrolimus pre-dose concentration.
Objectives
The objectives of this study were to determine the pharmacokinetics of tacrolimus immediately after kidney transplantation and to find relevant parameters for dose individualization using a population pharmacokinetic analysis.
Methods
A total of 722 blood samples were collected from 46 children treated with tacrolimus over the first 6 weeks after renal transplantation. Non-linear mixed-effects modeling (NONMEM
®
) was used to develop a population pharmacokinetic model and perform a covariate analysis. Simulations were performed to determine the optimal starting dose and to develop dosing guidelines.
Results
The data were accurately described by a two-compartment model with allometric scaling for bodyweight. Mean tacrolimus apparent clearance was 50.5 L/h, with an inter-patient variability of 25%. Higher bodyweight, lower estimated glomerular filtration rate, and higher hematocrit levels resulted in lower total tacrolimus clearance. Cytochrome P450 3A5 expressers and recipients who received a kidney from a deceased donor had a significantly higher tacrolimus clearance. The model was successfully externally validated. In total, these covariates explained 41% of the variability in clearance. From the significant covariates, the cytochrome P450 3A5 genotype, bodyweight, and donor type were useful to adjust the starting dose to reach the target pre-dose concentration. Dosing guidelines range from 0.27 to 1.33 mg/kg/day.
Conclusion
During the first 6 weeks after transplantation, the tacrolimus weight-normalized starting dose should be higher in pediatric kidney transplant recipients with a lower bodyweight, those who express the cytochrome P450 3A5 genotype, and those who receive a kidney from a deceased donor.
Improved management of growth impairment might have resulted in less growth retardation after pediatric kidney transplantation (KT) over time. We aimed to analyze recent longitudinal growth data ...after KT in comparison to previous eras, its determinants, and the association with transplant outcome in a large cohort of transplanted children using data from the European Society for Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry.
A total of 3492 patients transplanted before 18 years from 1990 to 2012 were included. Height SD scores (SDS) were calculated using recent national or European growth charts. We used generalized equation models to estimate the prevalence of growth deficit and linear mixed models to calculate adjusted mean height SDS.
Mean adjusted height post-KT was -1.77 SDS. Height SDS was within normal range in 55%, whereas 28% showed moderate, and 17% severe growth deficit. Girls were significantly shorter than boys, but catch-up growth by 5 years post-KT was observed in both boys and girls. Children <6 years were shortest at KT and showed the greatest increase in height, whereas there was no catch-up growth in children transplanted >12.
Catch-up growth post-KT remains limited, height SDS did not improve over time, resulting in short stature in nearly half of transplanted children in Europe.
Because little is known about long-term treatment-related nephrotoxicity, the aim was to determine risk factors for renal impairment long after childhood cancer treatment.
Data from 763 adult ...childhood cancer survivors (414 men) were obtained during regular visits at the late-effects clinic between 2003 and 2009. Median follow-up time was 18.3 years (range=5.0-58.2). Glomerular function was assessed by estimated GFR (using the Modification of Diet in Renal Disease formula), urinary albumin creatinine ratio, and tubular function by urinary β2-microglobulin creatinine ratio. The association with treatment factors was analyzed with covariance analysis for estimated GFR and logistic regression for urinary albumin and urinary β2-microglobulin creatinine ratios.
Survivors treated with nephrectomy and abdominal irradiation had significantly lower estimated GFR than survivors not treated with nephrectomy/abdominal irradiation (estimated mean=90 ml/min per 1.73 m(2) versus 106, P<0.001). Estimated GFR was significantly lower in survivors after treatment with high-dose ifosfamide (88 versus 98, P=0.02) and high-dose cisplatin (83 versus 101, P=0.004) compared with survivors not treated with these regimen. Nephrectomy combined with abdominal radiotherapy (odds ratio=3.14, 95% confidence interval=1.02; 9.69) and high-dose cisplatin (odds ratio=5.19, 95% confidence interval=1.21; 22.21) was associated with albuminuria. High-dose ifosfamide (odds ratio=6.19, 95% confidence interval=2.45; 15.67) was associated with increased urinary β2-microglobulin creatinine ratio. Hypertension was present in 23.4% of survivors and 31.4% of renal tumor survivors.
Treatment with unilateral nephrectomy, abdominal radiotherapy, cisplatin, and ifosfamide was associated with lower estimated GFR. Persisting tubular damage was related to ifosfamide treatment.
Background
Amlodipine is a widely used antihypertensive agent for the treatment of paediatric hypertension, but the commercially available tablets are not suitable to treat young patients, who need ...lower, flexible dosages and a liquid formulation.
Objective
To determine the pharmacokinetic properties of amlodipine and the acceptability of a standardised, extemporaneous oral solution.
Method
A newly developed liquid formulation of amlodipine was administered to hypertensive children between the age of 6 months and 11 years. Using a limited sampling strategy, population PK analysis was performed using nonlinear mixed effects modelling.
Results
Nine children, with a median age of 2.9 years (IQR 1.8–8.4), receiving stable amlodipine therapy in a median dose of 0.15 mg kg
−1
day
−1
(IQR 0.11–0.18), were switched to study medication. The population pharmacokinetic model was able to accurately predict the clearance of amlodipine in the study population. Based on the final model, clearance was reduced by 31.2% (RSE: 10%) in females. Patient reported outcomes on taste from a five-point hedonic scale were available for five patients, who scored the taste from positive to slightly negative.
Conclusion
The results from the PK study and the acceptability assessment show that the amlodipine oral solution presented in this study offers an appropriate treatment option for young children.
CYP3A enzymes are involved in the metabolism of calcineurin inhibitor tacrolimus as well as vitamin D. In this review, we summarize the clinical aspects of CYP3A-mediated metabolism of tacrolimus and ...vitamin D with emphasis on the influence of single-nucleotide polymorphisms on tacrolimus disposition. We describe the utility of 4β hydroxycholesterol as a marker of CYP3A activity. Then, we discuss the possible interaction between calcineurin inhibitors and vitamin D in solid organ transplant recipients. Also, we review other mechanisms which may contribute to side effects of calcineurin inhibitors on bone. Lastly, suggestions for future research and clinical perspectives are discussed.
In clinical practice, discriminating between glomerular and nonglomerular causes of hematuria is often difficult. Dysmorphic red blood cells (dRBC) in the urinary sediment are claimed to be ...effective, but the cutoff points in the literature vary. This follow-up study aimed to determine the diagnostic value of dRBC.
We investigated 134 hematuria patients in the departments of nephrology and urology. To diagnose the origin of hematuria, urological and/or nephrological examination was performed and the %dRBC identified by microscopy. Follow-up was performed after 3.5 years.
The cause of hematuria was proven in 68 patients (35% glomerular; 65% nonglomerular). Patients with glomerular disease had significantly more albuminuria and dRBC than patients with nonglomerular disease, but the %dRBC ranged from 1 to 50% and no optimal cutoff could be identified. Logistic regression analysis showed that %dRBC had a predicted probability to diagnose glomerular disease of 77.9% (area under the curve, AUC, 0.85). When %dRBC was combined with other risk factors such as serum creatinine, sex, age, dipstick erythrocyte or proteinuria score and number of casts, the predictive probability increased to 90.6% (AUC 0.97). Follow-up of the included patients showed no benefit of dRBC to identify patients at risk for glomerular disease.
The diagnostic value of routinely collected urinary dRBC to diagnose glomerular disease in patients presenting with hematuria is modest. However, including dRBC with other variables, such as age and erythrocyte score on dipstick testing may increase the sensitivity, but needs to be confirmed in another, preferably larger, population.
The prognostic significance of histopathologic (sub)classes in the current classification of lupus nephritis (LN) is controversial. We analyzed clinical and histopathologic predictors of renal ...outcome in LN outside the framework of the classification.
Variables (50 histopathologic and ten clinical) were tested in mixed, linear, and Cox regression models for their association with renal flare, ESRD, and eGFR during follow-up (1, 5, and 10 years) in 105 patients with LN who underwent biopsy from 1987 to 2011. The Cockcroft-Gault (normalized to a body surface area of 1.73 m
) and Schwartz formulas were used to calculate eGFR for adults and children, respectively.
During median follow-up of 9.9 years (25th-75th percentile, 5.9-13.8), 47 patients experienced a renal flare and 21 progressed to ESRD. Renal flare was predicted by fibrinoid necrosis (hazard ratio HR, 1.04 per %; 95% confidence interval 95% CI, 1.00 to 1.07) and nonwhite race (HR, 2.23; 95% CI, 1.23 to 4.04). ESRD was predicted by fibrinoid necrosis (HR, 1.08 per %; 95% CI, 1.02 to 1.13), fibrous crescents (HR, 1.09 per %; 95% CI, 1.02 to 1.17), interstitial fibrosis/tubular atrophy (IF/TA) ≥25% (HR, 3.89; 95% CI, 1.25 to 12.14), eGFR at baseline (HR, 0.98 per ml/min per 1.73 m
; 95% CI, 0.97 to 1.00), and nonwhite race (HR, 7.16; 95% CI, 2.34 to 21.91). A higher mean eGFR during follow-up was associated with normal glomeruli (+0.2 ml/min per 1.73 m
per %; 95% CI, 0.1 to 0.4). Like ESRD, a lower eGFR during follow-up was associated with fibrous crescents, IF/TA≥25%, and nonwhite race, as well as with cellular/fibrocellular crescents (-0.4 ml/min per 1.73 m
per %; 95% CI, -0.6 to -0.2) and age (-0.8 ml/min per 1.73 m
per year; 95% CI, -1.2 to -0.4).
The LN classification should include an index of evidence-based prognosticators. Awaiting validation of a formal index, we suggest that at least fibrinoid necrosis, fibrous crescents, and IF/TA warrant explicit independent scoring to assess the risk of progressive renal dysfunction in conjunction with clinical findings.
In this retrospective study 351 children (<16.0 years) with end-stage renal disease (ESRD) accepted for renal replacement therapy (RRT) in the four Dutch pediatric centers were analyzed for the ...period 1987-2001. The data were compared with a previous study performed in 1979-1986. Eighty patients were of non-Dutch origin. An annual ESRD incidence of 5.8 patients per million of the child population (p.m.c.p.) was calculated, without significant changes with time. The final prevalence in Dutch children under 15 years of ESRD was 38.7 p.m.c.p. The most frequent primary renal disease leading to ESRD was urethral valves, with a significant increase vs. the previous observation period (14% vs. 6%). The distribution of primary renal diseases was similar in patients of non-Dutch origin and in Dutch patients. Peritoneal dialysis was the most frequent dialysis procedure initially applied (62% vs. 26% in the earlier observation period). Thirteen percent of all first transplantations (n=278) were pre-emptive and 19% from living donors. Five-year graft survival after a living-donor and a cadaver graft was 80% and 73%, respectively. Overall patient survival after 10 years on RRT was 94%.
The aim of this study was to investigate (a) the extent to which age at first renal replacement therapy, achievement of developmental milestones, satisfaction of psychological needs, and coping were ...related to subjective well-being and medication adherence among young adult kidney transplant recipients; and (b) the relationship between subjective well-being and immunosuppressive medication adherence.
A cross-sectional, interview study was conducted among renal transplant patients aged 20 to 30 years. In addition to sociodemographic and medical characteristics, concepts measured were: subjective well-being (Positive And Negative Affect Schedule; Satisfaction With Life Scale), medication adherence (Basel Assessment of Adherence to Immunosuppressive Medication Scale), dispositional coping (Brief COPE), achievement of developmental milestones (Course of Life Questionnaire), and satisfaction of psychological needs (Basic Psychological Needs Scale).
Sixty-two patients participated (66% men; mean age, 26 years). Sixty-five percent were classified as nonadherent in the past month. In contrast, subjective self-rated overall adherence was high. None of the variables measured were related to nonadherence. Higher feelings of competence and autonomy, and timely achievement of social and psychosexual developmental milestones were related to higher subjective well-being. Well-being and adherence did not differ according to age at diagnosis or first renal replacement therapy.
Two thirds of participants were classified as nonadherent which conflicts with participants' own high rating of medication adherence. This emphasizes the need for continued adherence support among young adult transplant recipients; however, no targets for interventions were found in this study. Potential targets for interventions aimed at improving well-being include competence and autonomy.
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