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Background: When applying Pierce U25 formula for estimating glomerular filtration rate (eGFR), we observed a higher proportion of eGFR < 90 mL/min/1.73 m2 (chronic kidney disease (CKD) stage 2). We compared agreement and accuracy of the Pierce U25 (ages 2–25), Pottel (ages 2–100), and CKD-EPI (ages 18–100) formulae to GFR measurements. Methods: Post hoc analysis of the three eGFRs compared to 367 99m technetium-diethylene-triamine penta-acetic acid (99Tc DTPA) GFR measurements (240 patients) using 3 sampling points and Brockner/Mørtensen correction (body surface area calculation based on ideal weight) on simultaneous serum creatinine and cystatin C measurements. Results: Overall, the U25 formula performed well with a Spearman r of 0.8102 (95% confidence interval 0.7706 to 0.8435, p < 0.0001) while diagnostic accuracy was low in patients with normal mGFR. The U25 formula reclassified 29.5% of patients with normal mGFR as CKD stage 2; whereas the average of the modified Schwartz formula based on serum creatinine and the Filler formula based on cystatin C, only over-diagnosed CKD stage 2 in 8.5%, 24.5% within 10% and 62.7% within 30%. We therefore combined both. The average Schwartz/Filler eGFR had 36.5% of results within 10%, 84.7% within 30%, and normal mGFR accuracy was 26.8%, 63.9% for 10% and 30%, respectively, outperforming the CKD-EPI and Pottel formulae. Conclusions: The Pierce U25 formula results correlated well with mGFR < 75 mL/min/1.73 m2. Over the entire GFR range, accuracy was better for patients with a higher mGFR, when averaging the combined Schwartz/Filler formulae. More work is needed to prospectively confirm our findings in other centers. [ABSTRACT FROM AUTHOR]

The article discusses the use of different formulas to estimate glomerular filtration rate (GFR) in pediatric kidney transplant recipients. The authors compare various formulas based on cystatin C and creatinine with measured GFR in a pediatric cohort. They find that the U25 CKiD formula provides the most accurate estimation of GFR in this population. However, the availability of cystatin C is limited globally. The authors suggest that further research and collaboration are needed to improve the estimation of GFR in pediatric patients. [Extracted from the article]

The article focuses on the need for validating estimated glomerular filtration rate (eGFR) formulae in diverse populations, particularly in underrepresented groups such as African children. Topics include the historical development of eGFR formulae, the limitations of existing approaches when applied to different demographics, and the importance of global collaboration to improve GFR estimation methods across various populations.

Background: The COVID-19 pandemic has led to increased utilization of telemedicine services. Methods: A retrospective analysis of all referral-based ambulatory telemedicine services in Ontario from November 2019 to June 2021 was collected from the Ontario Health Insurance Plan (OHIP) billing database. Only fee-for-service billings were included in the present analysis. Coincident COVID-19 cases were obtained from Public Health Ontario. Comparisons were made based on age bracket, sex, telemedicine and in-person care. Results: Billings for telemedicine services in Ontario increased from $1.7 million CAD in November 2019 to $64 million CAD in April 2020 and the proportions reached a mean peak of 72% in April 2020 and declined to 46% in June 2021. A positive correlation was found between the use of telemedicine and COVID-19 cases (p = 0.05). The age group with the highest proportion of telemedicine use was the 10–20-year-olds, followed by the 20–50-year-olds (61 ± 9.0%, 55 ± 7.3%, p = 0.01). Both age groups remained above 50% telemedicine services at the end of the study period. There seemed to be higher utilization by females (females 54.2 ± 8.0%, males 47.9 ± 7.7%, ANCOVA p = 0.05) for all specialties, however, after adjusting for male to female ratio m:f of 0.952:1.0 according to the 2016 census, this was no longer significant. Conclusions: The use of telemedicine services remained at a high level across groups, particularly the 10–50-year-olds. There were clear age preferences for using telemedicine. Studying these differences may provide insights into how the delivery of non-hospital-based medicine has changed during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Acute and chronic kidney disease continues to confer significant morbidity and mortality in the clinical setting. Despite high prevalence of these conditions, few validated biomarkers exist to predict kidney dysfunction. In this study, we utilized a novel kidney multiplex panel to measure 21 proteins in plasma and urine to characterize the spectrum of biomarker profiles in kidney disease. Blood and urine samples were obtained from age-/sex-matched healthy control subjects (HC), critically-ill COVID-19 patients with acute kidney injury (AKI), and patients with chronic or end-stage kidney disease (CKD/ESKD). Biomarkers were measured with a kidney multiplex panel, and results analyzed with conventional statistics and machine learning. Correlations were examined between biomarkers and patient clinical and laboratory variables. Median AKI subject age was 65.5 (IQR 58.5–73.0) and median CKD/ESKD age was 65.0 (IQR 50.0–71.5). Of the CKD/ESKD patients, 76.1% were on hemodialysis, 14.3% of patients had kidney transplant, and 9.5% had CKD without kidney replacement therapy. In plasma, 19 proteins were significantly different in titer between the HC versus AKI versus CKD/ESKD groups, while NAG and RBP4 were unchanged. TIMP-1 (PPV 1.0, NPV 1.0), best distinguished AKI from HC, and TFF3 (PPV 0.99, NPV 0.89) best distinguished CKD/ESKD from HC. In urine, 18 proteins were significantly different between groups except Calbindin, Osteopontin and TIMP-1. Osteoactivin (PPV 0.95, NPV 0.95) best distinguished AKI from HC, and β2-microglobulin (PPV 0.96, NPV 0.78) best distinguished CKD/ESKD from HC. A variety of correlations were noted between patient variables and either plasma or urine biomarkers. Using a novel kidney multiplex biomarker panel, together with conventional statistics and machine learning, we identified unique biomarker profiles in the plasma and urine of patients with AKI and CKD/ESKD. We demonstrated correlations between biomarker profiles and patient clinical variables. Our exploratory study provides biomarker data for future hypothesis driven research on kidney disease. [ABSTRACT FROM AUTHOR]

A study published in the journal Pediatric Transplantation explores the use of urinary CXCL10/creatinine ratio as a biomarker for kidney transplantation. The study analyzed urine samples from 72 pediatric kidney transplant recipients and found that urinary CXCL10/creatinine ratio was significantly higher in samples with allograft rejection compared to those without rejection. However, the authors note that further research is needed before this biomarker can be implemented in clinical practice. The study highlights the importance of identifying and validating new biomarkers for kidney allograft function. [Extracted from the article]

Background: The severity of X-linked hypophosphataemic rickets (XLH) may be affected by genotype and sex. However, burosumab, a fully humanized monoclonal antibody against fibroblast growth factor 23, has the same pediatric dose recommendation for both sexes (0.8 mg/kg every 2 weeks). Patients and methods: In a retrospective cohort study, we describe the burosumab response differences by sex in children with XLH. Results: We treated 10 children (5 females, mean age at initiation 4.2 ± 3.5 years) with XLH with burosumab. Initial mean serum phosphate was 0.69 ± 0.18 mmol/L in males and 0.86 ± 0.22 mmol/L in females (p = 0.108). The mean ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 0.55 ± 0.11 mmol/L in males and 0.76 ± 0.23 mmol/L in females (p = 0.06). The mean starting dose of burosumab was 0.83 ± 0.19 mg/kg subcutaneously every 14 days (males: 0.79 ± 0.19 mg/kg; females: 0.87 ± 0.21 mg/kg, n.s.). Two weeks after starting burosumab, serum phosphate differed significantly between males (0.90 ± 0.21 mmol/L) and females (1.27 ± 0.25 mmol/L) (p = 0.018). All males required a dose increase to try to normalize serum phosphate. On day 140 after starting, the average dose in males increased further to 1.24 ± 0.41 mg/kg to achieve a phosphate of 0.87 ± 0.11 mmol/L while females had a normal phosphate and alkaline phosphatase on the starting dose. After a mean of 458 ± 79 days, the mean burosumab dose/kg in males was 1.68 ± 0.61 mg/kg, mean serum phosphate was 1.08 ± 0.23 mmol/L, mean TmP/GFR was 1.01 ± 0.20, mean alkaline phosphatase had normalized to 303.6 ± 40.7U/L, and mean 1.25(OH)2 vitamin D level was 186.4 ± 16.6 nmol/L. Conclusions: Our findings may suggest a sex difference in response to burosumab in XLH patients. Our data suggest that males may require higher doses. [ABSTRACT FROM AUTHOR]

The authors discuss barriers for clinical trials including the ethical approach to acquiring high level evidence for optimal decision making, lack of funding, paucity of partners, low interest from pharmaceutical industry, regulatory issues, under-recognition of children's rights and autonomy and attitudes of patients/caregivers and providers. Topics include differences between pediatric subspecialties, examples of some pediatric nephrology studies, and ethical considerations and harms.

Background: The diagnosis of hypertension and hypertension-induced target organ injury by the 2022 American Heart Association (AHA) ambulatory blood pressure threshold as compared with 2014 AHA and 2016 European Society of Hypertension (ESH) thresholds has not been evaluated. Methods: In a cross-sectional study (n = 291, aged 5–18 years, at a tertiary care outpatient clinic), we compared 2022 AHA with 2014 AHA and ESH thresholds (revised with 2018 adult ESH thresholds where applicable) to diagnose ambulatory hypertension (AH), and detect ambulatory arterial stiffness index (AASI) and left ventricular target organ injury (LVTOI). Results: The 2022 AHA threshold diagnosed significantly more AH (53%) than the 2014 AHA (42%, p < 0.01) and ESH (36%, p < 0.001) thresholds. The 2022 AHA threshold demonstrated only a moderate agreement with the 2014 AHA (kappa (k) = 0.77) and ESH (k = 0.66) thresholds to diagnose AH. Adjusted logistic regression analysis found that only the 2022 AHA threshold predicted elevated AASI significantly (odds ratio 2.40, 95% CI 1.09, 5.25, p = 0.02; AUC 0.61, p < 0.01). In those with elevated AASI, more participants had AH by the 2022 AHA threshold (72%) than the 2014 AHA (46%, p = 0.02) and ESH (48%, p = 0.03) thresholds. AH defined by the 2022 AHA threshold continued to maintain higher odds, larger AUC, and higher sensitivity to identify LVTOI than the 2014 AHA and ESH thresholds; however, the difference did not reach a statistically significant level. Conclusions: AH defined by the 2022 AHA threshold diagnoses more children with hypertension and identifies more children with hypertension-induced target organ injury than the 2014 AHA and ESH thresholds. [ABSTRACT FROM AUTHOR]

An editorial is presented on assessing kidney length in children and adolescents being overweight or obese. Topics include overweight and obese children which being a very interesting finding demonstrating the importance of external validation; and resulting in underestimation of kidney length and kidney volumes in overweight and obese patients overestimating it in thin patients.

Background: Manganese (Mn) and Selenium (Se) deficiencies are noted in adult patients with chronic kidney disease (CKD). However, levels of these trace elements have not been well studied in the paediatric CKD population. We determined the Mn and Se levels in a single-institution cohort of paediatric patients with CKD. Methods: Ancillary cross-sectional study to a prospective longitudinal randomized control trial on zinc supplementation, which included 42 children and adolescents aged 0 to 19 years with CKD stages I to IV not on dialysis, who had 1–6 trace element measurements. Cystatin C estimated glomerular filtration rate (eGFR) was calculated using the Filler formula. Plasma Mn and Se levels were measured, and anthropomorphic data/blood parameters were collected from electronic health records. The trial was registered on clinicaltrials.gov, NCT02126293. Results: There were 96 Mn and Se levels in 42 patients (age 12.5 ± 4.6 years). The median Mn concentration was 12.61 nmol/L [10.08, 16.42] with a trend towards lower values with lower eGFR (p = 0.0367 one-sided). Mn z-scores were significantly lower than the general paediatric reference population. The mean Se level was 1.661 ± 0.3399 µmol/L with a significant positive correlation with eGFR (p = 0.0159, r = 0.366). However, only 4 patients with low eGFR had abnormally low Se levels. Conclusions: This single-institution study of children with CKD demonstrates a significant decrease in Se levels with decreasing eGFR, but no significant difference between mean Se z-scores of our cohort and the reference population. There was no significant relationship between Mn levels and eGFR however the mean Mn z-score was significantly lower than the theoretical mean. Trial registration: clinicaltrials.gov, NCT02126293, https://clinicaltrials.gov/ct2/show/NCT02126293. Date: April 30, 2014. [ABSTRACT FROM AUTHOR]

Background: Sodium-23 magnetic resonance imaging (23Na MRI) allows non-invasive assessment of tissue sodium concentration ([Na+]). Age and chronic kidney disease (CKD) are associated with increased tissue [Na+] in adults, but limited information is available pertaining to children and adolescents. We hypothesized that pediatric CKD is associated with altered tissue [Na+] compared to healthy controls. Methods: This was a case–control exploratory study on healthy children and adults and pediatric CKD patients. Study participants underwent an investigational visit, blood/urine biochemistry, and leg 23Na MRI for tissue [Na+] quantification (whole leg, skin, soleus muscle). CKD was stratified by etiology and patients' tissue [Na+] was compared against healthy controls by computing individual Z-scores. An absolute Z-score > 1.96 was deemed to deviate significantly from the mean of healthy controls. Pearson correlation was used to compute the associations between tissue [Na+] and kidney function. Results: A total of 36 pediatric participants (17 healthy, 19 CKD) and 19 healthy adults completed the study. Healthy adults had significantly higher tissue [Na+] compared with pediatric groups; conversely, no significant differences were found between healthy children/adolescents and CKD patients. Four patients with glomerular disease and one kidney transplant recipient due to atypical hemolytic-uremic syndrome had elevated whole-leg [Na+] Z-scores. Reduced whole-leg [Na+] Z-scores were found in two patients with tubular disorders (Fanconi syndrome, proximal–distal renal tubular acidosis). All tissue [Na+] measures were significantly associated with proteinuria and hypoalbuminemia. Conclusions: Depending on etiology, pediatric CKD was associated with either increased (glomerular disease) or reduced (tubular disorders) tissue [Na+] compared with healthy controls. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

The article comments on a paper by Chloe Braun and colleagues on the estimation of glomerular filtration rate in pediatric and adult patients with acute kidney injury (AKI). Topics mentioned include the proposed formula for estimating baseline creatinine by age and sex, the link between serum creatinine and muscle mass, and the use of electronic health records with rule-based algorithms for immediate detection of AKI.

Introduction: Growth retardation is a common problem in pediatric patients with chronic kidney disease. It is unknown if the growth of children on peritoneal dialysis (PD) can be augmented by more dialysis. Methods: We studied the effect of various peritoneal adequacy parameters on delta height standard deviation scores (SDSs) and growth velocity z-scores in 53 children (27 males) on PD, who underwent 2 longitudinal adequacy tests at 9-month intervals. None of the patients were on growth hormone. Intraperitoneal pressure and standard KDOQI guidelines were compared to the outcome measures delta height SDS and height velocity z-scores, using univariate and multivariate tests. Results: At the time of the second PD adequacy test, their mean age was 9.2 ± 5.3 years; mean fill volume was 961 ± 254 mL/m2; and median total infused dialysate volume was 5.26 L/m2/day (range 2.03–15.32 L). The median total weekly Kt/V was 3.79 (range 0.9–9.5), and the median total creatinine clearance was 56.6 (range 7.6–133.48) L/week, higher than previous pediatric studies. The delta height SDS was a median of −0.12 (range −2 to +3.95)/year. The mean height velocity z-score was −1.6 ± 4.0. The only relationships discovered were between the delta height SDS and age, bicarbonate, and intraperitoneal pressure, but not for Kt/V or creatinine clearance. Conclusion: Our findings highlight the importance of normalization of bicarbonate concentrations to improve height z-score. [ABSTRACT FROM AUTHOR]

Background: Long-term peritoneal dialysis (PD), especially with nonphysiological solutions, is afflicted with the severe complication of encapsulating peritoneal sclerosis (EPS). Physiologic PD solutions have been introduced to reduce pH trauma. Data on peritoneal biopsies in pediatrics with long-term PD using physiological solutions are scant. Case Report: We report an adolescent who had been on 10-h continuous hourly cycles using mostly 2.27% Physioneal™ for 5 years. There were two episodes of peritonitis in October 2017 (Klebsiella oxytoca) and May 2018 (Klebsiella pneumoniae), which were treated promptly. This adolescent, who lost two kidney transplants from recurrent focal and segmental glomerulosclerosis, underwent a peritoneal membrane biopsy at the time of a third PD catheter placement, 16 months after the second renal transplant. Laparoscopically, the peritoneum appeared grossly normal, but fibrosis and abundant hemosiderin deposition were noted on histology. The thickness of the peritoneum was 200–900 (mean 680) µm; normal for age of 14 years is 297 [IQR 229, 384] μm. The peritoneum biopsy did not show specific EPS findings, as the mesothelial cells were intact, and there was a lack of fibrin exudation, neo-membrane, fibroblast proliferation, infiltration, or calcification. Conclusions: While the biopsy was reassuring with respect to the absence of EPS, significant histopathological changes suggest that avoiding pH trauma may not ameliorate the effects of glucose exposure in long-term PD. [ABSTRACT FROM AUTHOR]

Background Sodium-23 magnetic resonance imaging (23Na MRI) allows the measurement of skin sodium concentration ([Na+]). In patients requiring dialysis, no data are available relating to the clinical outcomes associated with skin sodium accumulation or the determinants of increasing deposition. Methods This was an exploratory, observational study of adult hemodialysis (HD) and peritoneal dialysis (PD) patients. Participants underwent skin [Na+] quantification with leg 23Na MRI at the study's beginning. Outcomes of interest were all-cause mortality and composite all-cause mortality plus major adverse cardiovascular events. Cumulative total and event-free survival were assessed using the Kaplan–Meier survival function after stratification into skin [Na+] quartiles. Cox proportional hazards regression was used to model the association between skin [Na+] and outcomes of interest. Multiple linear regression was used to model the predictors of skin [Na+]. Results A total of 52 participants (42 HD and 10 PD) underwent the study procedures. The median follow-up was 529 days (interquartile range: 353–602). Increasing skin [Na+] quartiles were associated with significantly shorter overall and event-free survival (log-rank χ2(1) = 3.926, log-rank χ2(1) = 5.685; P for trend <0.05 in both instances). Skin [Na+] was associated with all-cause mortality {hazard ratio (HR) 4.013, [95% confidence interval (95% CI) 1.988–8.101]; P < 0.001} and composite events [HR 2.332 (95% CI 1.378–3.945); P < 0.01], independently of age, sex, serum [Na+] and albumin. In multiple regression models, dialysate [Na+], serum albumin and congestive heart failure were significantly associated with skin [Na+] in HD patients (R2adj = 0.62). Conclusions Higher skin [Na+] was associated with worse clinical outcomes in dialysis patients and may represent a direct therapeutic target. [ABSTRACT FROM AUTHOR]

Objective: In previous studies, smaller renal volumes were reported in prematurely born infants, however, these renal volumes were not corrected for body surface area, the main determinant of renal size. Given the rapid growth of the renal cortex after premature birth, the authors hypothesized that corrected volumes would not differ from healthy controls. Methods: Ambispective cohort study with prospective follow-up of prematurely born babies in a large specialized center and retrospectively recruited healthy control group. Children were assessed for renal length and renal volumes at age 5 by three independent ultrasonographers. Detailed anthropometry, blood pressure and renal function were also obtained. Age independent z-scores were calculated for all parameters and compared using descriptive statistics. Results: Eighty-nine premature study participants (median 32 weeks gestational age) and 33 healthy controls (median 38 weeks gestational age) were studied. Study participants did not differ in age, sex, Afro-Colombian descent, height, blood pressure, serum creatinine, or new Schwartz eGFR. Premature study participants had a significantly lower weight (17.65 § 2.93 kg) than controls (19.05 § 2.81 kg, p = 0.0072) and lower body surface area. The right renal volumes were significantly smaller (39.4 vs 43.4 mL), but after correction for body surface area, the renal volume and renal length z-scores were identical for both kidneys (mean right kidney -0.707 vs -0.507; mean left kidney -0.498 vs -0.524, respectively). Conclusion: Renal volumes need to be corrected to body surface area. After correction for body surface area, 5-year-old healthy and prematurely born children have comparable renal volumes. [ABSTRACT FROM AUTHOR]

Use of sodium-glucose co-transporter 2 inhibitors in solid organ transplant recipients with pre-existing type 2 or post-transplantation diabetes mellitus: a systematic review. The ongoing need to improve long-term patient survival of pediatric solid organ recipients Abbreviations CNS congenital nephrotic syndrome MRI magnetic resonance imaging PTLD post-transplant lymphoproliferative disease SGLT2i sodium-glucose cotransporter 2 inhibitors SOT Solid organ transplantation INTRODUCTION Solid organ transplantation (SOT) is the therapy of choice for end-stage organ disease in children and adolescents. Salonen et al.[6] reported survival of all pediatric SOT recipients (kidney, liver and heart) in Finland. [Extracted from the article]

The agreement between the traditionally‐used ambulatory blood pressure (ABP)‐load thresholds in children and recently‐recommended pediatric American Heart Association (AHA)/European Society of Hypertension (ESH) ABP thresholds for diagnosing ambulatory hypertension (AH), white coat hypertension (WCH), and masked hypertension (MH) has not been evaluated. In this cross‐sectional study on 450 outpatient participants, the authors evaluated the agreement between previously used ABP‐load 25%, 30%, 40%, 50% thresholds and the AHA/ESH thresholds for diagnosing AH, WCH, and MH. The American Academy of Pediatrics thresholds were used to diagnose office hypertension. The AHA threshold diagnosed ambulatory normotension/hypertension closest to ABP load 50% in 88% (95% CI 0.79, 0.96) participants (k 0.67, 95% CI 0.59, 0.75) and the ESH threshold diagnosed ambulatory normotension/hypertension closest to ABP load 40% in 86% (95% CI 0.77, 0.94) participants (k 0.66, 95% CI 0.59, 0.74). In contrast, the AHA/ESH thresholds had a relatively weaker agreement with ABP load 25%/30%. Therefore, the diagnosis of AH was closest between the AHA threshold and ABP load 50% (difference 3%, 95% CI ‐2.6%, 8.6%, p =.29) and between the ESH threshold and ABP load 40% (difference 4%, 95% CI ‐2.1%, 10.1%, p =.19) than between the AHA/ESH and ABP load 25%/30% thresholds. A similar agreement pattern persisted between the AHA/ESH and various ABP load thresholds for diagnosing WCH and MH. The AHA and ESH thresholds diagnosed AH, WCH, and MH closest to ABP load 40%/50% than ABP load 25%/30%. Future outcome‐based studies are needed to guide the optimal use of these ABP thresholds in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Polyuria is a common problem in patients with tubular diseases, especially for those with CKD and high-output Fanconi syndrome. There are currently no guidelines on how to treat debilitating polyuria, in children or adults, and vasopressin is usually not effective. Case-diagnosis/treatment: A 13-year-old female with idiopathic Fanconi syndrome and an eGFR of 69 mL/min/1.73 m2 was severely affected by polyuria of 5 L per day (voiding at least 11 times during the day and up to 8 times at night), impacting her mood (measured by the RCADS-child) and academic performance at school. In the absence of guidelines and with literature discouraging the use of indomethacin in this condition, we attempted indomethacin treatment at a dose of 2 mg/kg divided in two doses with substantial success. Urine output dropped to 2.5L and this was accompanied by a substantial decrease of her sodium wasting from 24.6 to 7.7 mmol/kg/day. Over the course of 18 months, the patient's eGFR dropped temporarily to 60 mL/min/1.73 m2 and was 68 mL/min/1.73 m2 at last follow-up. However, a sodium-23 (23Na) MRI of her thigh revealed ongoing moderate sodium decrease in her skin and substantial Na+ decrease in her muscle when compared to age-matched peers with normal kidney function. Conclusions: Indomethacin may be a safe and effective treatment option for polyuria in idiopathic Fanconi syndrome. [ABSTRACT FROM AUTHOR]

Acute kidney disease predicts chronic kidney disease in pediatric non-kidney solid organ transplant patients. Impaired kidney function >90 days determines long-term kidney outcomes Keywords: acute kidney disease; acute kidney injury; children; transplantation EN acute kidney disease acute kidney injury children transplantation 1 3 3 08/16/22 20220901 NES 220901 Abbreviations AKD acute kidney disease AKI acute kidney injury CKD chronic kidney disease ESKD end-stage chronic kidney disease GFR glomerular filtration rate IDMS isotope-dilution mass spectrometry RAAS renin-angiotensin-aldosterone system INTRODUCTION Some organs of the human body have evolved to a degree that organoids, the functioning units of more complex organs, can only develop until a certain time in the development. Footnotes 1 Editorial for "Acute Kidney Disease Predicts Chronic Kidney Disease in Pediatric Non-Kidney Solid Organ Transplant Patients" by Mital Patel et al. [Extracted from the article]

Background: Pre‐emptive kidney transplantation for end‐stage kidney disease in children has many advantages and may lead to the consideration of marginal parent donors. Methods: Using the example of the transplant of a kidney with medullary sponge disease from a parent to the child, we review the ethical framework for working up such donors. Results: The four principles of health ethics include autonomy (the right of the patient to retain control over his/her own body); beneficence (healthcare providers must do all they can do to benefit the patient in each situation); non‐maleficence ("first do no harm"—providers must consider whether other people or society could be harmed by a decision made, even if it is made for the benefit of an individual patient) and justice (there should be an element of fairness in all medical decisions). Highly motivated donors may derive significant psychological benefit from their donation and may thus be willing to incur more risk. The transplantation team and, ideally, an independent donor advocate team must make a judgment about the acceptability of the risk‐benefit ratio for particular potential donors, who must also make their own assessment. The transplantation team and donor advocate team must be comfortable with the risk‐benefit ratio before proceeding. Conclusions: An independent donor advocacy team that focuses on the donor needs is needed with sufficient multidisciplinary ethical, social, and psychological expertise. The decision to accept or reject the donor should be within the authority of the independent donor advocacy team and not the providers or the donor. [ABSTRACT FROM AUTHOR]

Adolescents and young adults (AYAs) with CKD or end-stage kidney disease (ESKD) have unique medical, dental, psychosocial, neurocognitive, and academic needs and require close interdisciplinary collaboration to optimize their care. The etiology of CKD in AYAs is diverse compared to older adults. With their continuously improved survival, AYAs must start preparation for health-care transition (HCT) from pediatric- to adult-focused health care in the pediatric setting and it must continue at the adult-focused setting, given that their brain maturation and self-management skill acquisition occur until their mid-20s. While the growth and physical maturation of most visible body parts occur before 18 years of age, the prefrontal cortex of the brain, where reasoning, impulse control, and other higher executive functions reside, matures around 25 years of age. The HCT process must be monitored using patient- and caregiver-measuring tools to guide interventions. The HCT process becomes more complex when patients and/or caregivers have a language barrier, different cultural beliefs, or lower literacy levels. In this article, we discuss the unique comorbidities of pediatric-onset CKD/ESKD, provide information for a planned HCT preparation, and suggest interdisciplinary coordination as well as cultural and literacy-appropriate activities to achieve optimal patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Telemedicine is increasingly utilized as an alternative to in person consultation. Current pandemic conditions are providing additional impetus to virtual care delivery. We compared both adolescent and caregiver (parent or guardian) attitudes towards telemedicine (here as tertiary center to remote health care location) as a crucial determinant of longer-term effectiveness.Methods: This qualitative research study analyzed transcribed structured telephone interviews with both 11-18 year-old pediatric nephrology patients and their caregivers and performed a quantitative analysis of patient demographics, disease factors and distance to tertiary center vs. telemedicine center.Results: The study was conducted in a medium-sized tertiary pediatric nephrology centre with a large catchment area of over 0.5 million square kilometers and 629,000 children and adolescents under 18 years of age. Eleven dyads of adolescents and caregivers were enrolled. Five adolescents were male. The mean age of the adolescents was 14.4 ± 2.5 years (range 11.2-18.0). The median distance to our tertiary center was 191 km (range 110-1378 km). Four adolescents lived more than 500 km from our tertiary center. The 11 adolescents had a total of 334 in person visits (mean 30 ± 25) and 86 telemedicine visits (mean 8 ± 7). A ratio of 2:1 telemedicine to in-person visits was favored; with caregivers more in favor of remote care than adolescents. Qualitative analysis found that experiences with telemedicine were distinguished by consultation-specific factors and contextual factors. Contextual factors (travel/cost savings) were valued for telemedicine by adolescents and caregivers. Consultation-specific factors, such as the ability to show the doctor physical symptoms, were more valued during in-person consultations, especially by adolescents. The overall visit type preference was related to the nature of the consultation. For regular check-ups, and for adolescents with less complex needs, participants felt that telemedicine offered a comparable experience to in-person visits. Adolescents with more complex conditions preferred in-person visits.Conclusions: Indiscriminate transfer to chronic care predicated on mainly telemedicine approach is not compatible with user expressed attitudes (especially among adolescents). Accurately mapping models of care to these attitudes is an essential determinant of effective management and longer-term engagement with potentially life-long health challenges. [ABSTRACT FROM AUTHOR]

Background: Pediatric nephrologists use kidney length and kidney volume z-scores to longitudinally assess normal nephron endowment. However, most radiologists only report kidney length. Agreement between kidney length and kidney volume z-scores in children has been understudied. This study aims to assess agreement between kidney length and kidney volume z-scores in children. Methods: This novel cross-sectional cohort study prospectively followed prematurely born babies from a large specialized prematurity follow-up center. A healthy control group matched the cases by age and sex and was recruited from schools. Children were assessed for kidney length and kidney volumes at age 5 by three independent ultrasonographers. All measurements were performed in triplicate. Detailed anthropometry, blood pressure, and kidney function were also obtained. Age-independent z-scores were calculated for all parameters according to Scholbach and Weitzel and compared using descriptive statistics. Results: We studied 89 premature patients (median 32 weeks gestational age) and 33 healthy controls (median 38 weeks gestational age). There were 732 determinations of kidney length, width, and thickness. The mean z-score of the right kidney length was 0.65 ± 0.08 (SEM) compared with 0.88 ± 0.08 of the left kidney length (p = 0.0003, two-sided paired t test). The squared correlation coefficient for kidney volume to kidney length was 0.32 (p < 0.0001). Bland and Altman analysis revealed considerable bias with − 1.36 ± 0.76 standard deviations and 95% limits of agreement from − 2.83 to − 0.16. Conclusion: Reporting only kidney length results in significant overestimation of age-independent z-scores. Based on our findings, consideration to measuring all kidney dimensions may be more appropriate. [ABSTRACT FROM AUTHOR]

Aim: Review of current knowledge on assessing renal function in term and preterm neonates. Methods: Literature review and analysis of own data. Results: Prematurity, genetic, environmental and maternal factors may alter peak nephron endowment and life‐long renal function. Nephrogenesis continues until 34‐36 weeks of gestation, but it is altered with premature delivery. Variability of nephron endowment has a substantial impact on the clearance of renally excreted drugs. Postnatally, glomerular function rate (GFR) increases daily, doubles by two weeks, and slowly reaches full maturity at 18 months of age. Ideally, renal function biomarkers should be expressed as age‐independent z‐scores, and evidence suggests indexing these values to post‐conceptual age rather than chronological age. Newborn and maternal serum creatinine correlate tightly for more than 72 hours after delivery, rendering this biomarker unsuitable for the assessment of neonatal renal function. Cystatin C does not cross the placenta and may be the preferred biomarker in the neonate. Here, we provide preliminary data on the natural evolution of the cystatin C eGFR in infancy. Conclusion: Cystatin C may be superior for GFR estimation in neonates, but the best approach to drug dosing of renally excreted drugs remains to be established. [ABSTRACT FROM AUTHOR]

Background The impact of diagnosing pediatric hypertension based on all three-24-hour, day and night ambulatory blood pressure (ABP) thresholds (combined ABP threshold) vs. conventionally used 24-hour ABP threshold is not known. Methods In this cross-sectional, retrospective study from a tertiary care outpatient clinic, we evaluated the diagnosis of hypertension based on the 24-hour European Society of Hypertension (ESH) and combined ESH ABP thresholds in untreated children with essential hypertension. The American Academy of Pediatrics (AAP) and Fourth Report thresholds were used to classify office blood pressure (OBP). Results In 159 children, aged 5–18 years, the 24-hour ESH and combined ESH thresholds classified 82% (95th confidence interval (CI) 0.68, 0.97) ABP similarly with the area under the curve (AUC) of 0.86 (95th CI 0.80, 0.91). However, the AUC of the 2 ABP thresholds was significantly higher in the participants with office hypertension than office normotension, with OBP classified by the AAP (AUC 0.93, 95th CI 0.84, 0.98 vs. 0.80, 95th CI 0.71, 0.88) or Fourth Report (AUC 0.93, 95th CI 0.83, 0.98 vs. 0.81, 95th CI 0.73, 0.88) threshold. With OBP classified by the either OBP threshold, the combined ESH threshold diagnosed significantly more masked hypertension (MH) (difference 15%, 95th CI 4.9, 24.7; P = 0.00); however, the diagnosis of white coat hypertension (WCH) by the 2 ABP thresholds did not differ significantly (difference 4%, 95th CI 1.8, 10; P = 0.16). Conclusions In children with essential hypertension, the 24-hour and combined ESH thresholds have a stronger agreement for diagnosing WCH than MH. [ABSTRACT FROM AUTHOR]

Aim: To evaluate whether renal length z‐scores predict renal dysfunction in children with a solitary functioning kidney (SFK). Methods: In a single‐centre retrospective cohort of children with SFK, we correlated body mass index z‐scores, extracellular volume and lean body mass to renal length z‐scores. We grouped these z‐scores to other markers of renal dysfunction (proteinuria, hypertension, extracellular volume and abnormal estimated glomerular function rate [eGFR]) and analysed renal length z‐score with multivariate analysis, receiver‐operated characteristics (ROC) plots and Youden's index to determine an appropriate cut‐off. Results: 111 children had a median follow‐up 5.08 years, eGFR 80.8 mL/min/1.73 m2, and age at last follow‐up 7.4 (3.8‐13.4 years). The median renal length z‐scores of those without any renal dysfunction (n = 37, 25.1%) were greater (+3.66, interquartile range 3.02‐4.47) than those with renal dysfunction (median 3.11, interquartile range 1.76‐4.11, P =.0107, Mann‐Whitney test). Using a cut‐off of z‐score of >+1.911, the odds ratio for having no renal dysfunction was 0.07 (95% CI 0.002‐0.459, P =.0010). However, accuracy of the renal length z‐score was poor (ROC curve 0.6488). Conclusion: In this cohort of children with SKF, using the renal length z‐score as a biomarker of renal dysfunction at 7 years of age is not recommended. [ABSTRACT FROM AUTHOR]

The article comments on the study "Large Inter-Assay Difference of Serum Creatinine in the Pediatric Population: A Threat to Accurate Staging of Chronic Kidney Disease," by K. Lao and colleagues. Topics noted include the use of creatinine in estimating glomerular filtration rate, the factors that affect the levels of serum creatinine, the difference between the Abbott enzymatic method and the Abbott Jaffe method, and the need to standardize the calibration procedure in creatinine measurement.

The incidence of nephrolithiasis is increasing worldwide. Understanding how gut microbiome influences oxalate homeostasis has the potential to offer new strategies to prevent nephrolithiasis. The literature was reviewed to gather the evidence on the association between gut microbiome, hyperoxaluria and nephrolithiasis, and to identify the therapeutic interventions focused on the gut microbiome that could decrease hyperoxaluria and prevent nephrolithiasis. Gut microbiome is constituted by a plethora of microbiota including Oxalobacter formigenes (Oxf) and lactobacilli. Oxf can degrade dietary oxalate and induce enteral oxalate secretion. Animal studies suggested an association between oral Oxf supplementation and a decrease in hyperoxaluria. However, human studies have showed inconsistent results. Oral supplementation of lactobacilli did not show benefit in decreasing the hyperoxaluria. Antibiotic exposure, by affecting the gut microbiome, has been associated with an increase in nephrolithiasis. In vivo studies suggest fecal transplantation as a potential treatment option for reducing nephrolithiasis, but needs further evaluation in clinical studies. The current evidence suggests an association between gut microbiome and nephrolithiasis. However, the strategies focused on modulating gut microbiome for decreasing hyperoxaluria and preventing nephrolithiasis need further research. Judicious use of antibiotics in those predisposed to nephrolithiasis offers a preventative strategy for decreasing nephrolithiasis. [ABSTRACT FROM AUTHOR]

Background: Aortic dilatation is a cardiovascular complication in pediatric renal transplant recipients and may have an increased risk of aortic dissection, aortic rupture, and death. Studies failed to show an association between blood pressure and aortic dilatation; however, 24‐hours ambulatory blood pressure monitoring (ABPM) was not performed. There was also no comparison between preemptive transplantation and dialysis. Methods: After ethics approval, a retrospective cross‐sectional study was performed on all prevalent pediatric renal transplant recipients from a single tertiary care center. The presence of aortic dilatation was determined using standard echocardiographic measurements, and those with other risk factors for aortic dilatation were excluded. Associations between 24‐hours ABPM, renal function, dialysis history, and aortic dimensions were determined. Results: We enrolled 37 participants with the following characteristics: 46% female, mean age 14.5 ± 3.7 years, 16% preemptive transplantation, and median end‐stage renal disease (ESRD) combined vintage (time from ESRD onset to echocardiogram) 597 days (range 289‐1290 days). We found 16/37 patients (43%) with aortic dilatation at any level, mostly mild. There was no association between 24‐hours ABPM measurements and aortic dilatation. None of the preemptively transplanted children had aortic dilatation. Conclusion: This study confirms a high prevalence of aortic dilatation among pediatric renal transplant recipients, which appears to be independent of hypertension on 24‐hour ABPM. Patients with preemptive renal transplantation did not have aortic dilatation, suggesting that the effects of dialysis may contribute to the high prevalence of this complication. Pediatric cardiologists need to carefully assess aortic dimensions in these at‐risk patients. [ABSTRACT FROM AUTHOR]

Background: Bartter syndrome subtypes are a group of rare renal tubular diseases characterized by impaired salt reabsorption in the tubule, specifically the thick ascending limb of Henle's loop. Clinically, they are characterized by the association of hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II. Bartter syndrome type II is caused by mutations in the renal outer medullary potassium channel (ROMK) gene (KCNJ1), can present in the newborn period and typically requires lifelong therapy.Case Presentation: We describe a case of a prematurely born female infant presenting with antenatal polyhydramnios, and postnatal dehydration and hyponatremia. After 7 weeks of sodium supplementation, the patient demonstrated complete resolution of her hyponatremia and developed only transient metabolic alkalosis at 2 months of age but continues to be polyuric and exhibits hypercalciuria, without development of nephrocalcinosis. She was found to have two pathogenic variants in the KCNJ1 gene: a frameshift deletion, p.Glu334Glyfs*35 and a missense variant, p. Pro110Leu. While many features of classic ROMK mutations have resolved, the child does have Bartter syndrome type II and needs prolonged pediatric nephrology follow-up.Conclusion: Transient neonatal hyponatremia warrants a multi-system workup and genetic variants of KCNJ1 should be considered. [ABSTRACT FROM AUTHOR]

Background: The incidence of nephrolithiasis in children and adolescents is increasing and appears to double every 10 years. The most important role of the pediatric nephrologist is to diagnose and modify various metabolic and non-metabolic risk factors, as well as prevent long-term complications especially in the case of recurrent nephrolithiasis. Objective: The purpose of this review is to summarize the existing literature on the etiology and management of pediatric nephrolithiasis. Results: The incidence of kidney stones is increasing; dietary and environmental factors are probably the main causes for this increased incidence. In most pediatric patients, the etiology for the kidney stones can be identified. Metabolic factors, such as hypercalciuria and hypocitraturia, urinary tract infection, and urinary stasis, constitute leading causes. Herein, we review the etiologies, diagnostic work-up, and treatment options for the most prevalent causes of kidney stones. The detrimental effects of excessive dietary sodium, reduced fluid intake, and the benefits of plant-based over animal-based protein consumption on urinary crystal formation are discussed. We also review the long-term complications. Conclusions: Pediatric nephrologists have an important role in the diagnostic work-up and prevention of recurring nephrolithiasis. [ABSTRACT FROM AUTHOR]

In the original publication of this article [1], the institutional author's name needs to be revised from The Paediatric Chairs of Canada Mark Bernstein to The Paediatric Chairs of Canada. [ABSTRACT FROM AUTHOR]

Background: Neonatal asphyxia caused kidney injury and severe hypertension in a newborn. An unusually dilatated ascending aorta developed. Dialysis and pharmacological treatment led to partial recovery of the ascending aortic diameters. It was hypothesized that the aortic dilatation may be associated with aortic stiffening, peripheral resistance, and cardiovascular changes. Mathematical modeling was used to better understand the potential causes of the hypertension, and to confirm our clinical treatment within the confines of the model's capabilities. Methods: The patient's systolic arterial blood pressure showed hypertension. Echocardiographic exams showed ascending aorta dilatation during hypertension, which partially normalized upon antihypertensive treatment. To explore the underlying mechanisms of the aortic dilatation and hypertension, an existing lumped parameter hemodynamics model was deployed. Hypertension was simulated using realistic literature informed parameter values. It was also simulated using large parameter perturbations to demonstrate effects. Simulations were designed to permit examination of causal mechanisms. The hypertension inducing effects of aortic stiffnesses, vascular resistances, and cardiac hypertrophy on blood flow and pressure were simulated. Sensitivity analysis was used to stratify causes. Results: In agreement with our clinical diagnosis, the model showed that an increase of aortic stiffness followed by augmentation of peripheral resistance are the prime causes of realistic hypertension. Increased left ventricular elastance may also cause hypertension. Ascending aortic pressure and flow increased in the simultaneous presence of left ventricle hypertrophy and augmented small vessel resistance, which indicate a plausible condition for ascending aorta dilatation. In case of realistic hypertension, sensitivity analysis showed that the treatment of both the large vessel stiffness and small vessel resistance are more important in comparison to cardiac hypertrophy. Conclusion and Discussion: Large vessel stiffness was found to be the prime factor in arterial hypertension, which confirmed the clinical treatment. Treatment of cardiac hypertrophy appears to provide significant benefit but may be secondary to treatment of large vessel stiffness. The quantitative grading of pathophysiological mechanisms provided by the modeling may contribute to treatment recommendations. The model was limited due to a lack of data suitable to permit model identification. [ABSTRACT FROM AUTHOR]

The article presents the discussion on adaptation of neonatal function being a complex process where nephrons being slowly recruited in the order of the formation. Topics include renal development interrupted by premature delivery affecting nephron endowment; and recruitment of more nephrons, improving isosthenuria, handling of sodium, altering or halting nephrogenesis, and hypoxic-ischemic processes.

Abdominal compartment syndrome (ACS) is an infrequently encountered life-threatening disorder characterised by elevated abdominal pressure with evidence of new organ dysfunction. It is rarely reported in paediatrics. We describe an extremely unusual presentation of a 13-year-old boy with long-standing constipation who developed ACS complicated by refractory septic shock and multiorgan failure. He was treated with emergent decompressive laparotomy and supportive critical care. This case highlights the need for early diagnosis and timely management of ACS to improve its outcome. [ABSTRACT FROM AUTHOR]

Introduction: Small molecular weight toxin clearance is the main method of assessment of hemodialysis efficiency. Middle molecules including cystatin C (CysC) and Beta‐2 microglobulin (β2‐M) are understudied. We hypothesized that lowering of predialysis CysC and β2‐M serum concentrations would be affected by switching to more frequent hemodialysis. Methods: Predialysis CysC and β2‐M serum concentrations were measured from serum samples of the Frequent Hemodialysis Network (FHN) Daily and Nocturnal Trials. The differences between predialysis concentrations at baseline (while on conventional thrice weekly dialysis) and those after 12‐months of study (on more frequent dialysis) were compared separately by trial (Nocturnal, Daily). We tested the associations between predialysis serum CysC and β2‐M concentrations and outcomes. Findings: Forty‐nine percent and 52% of the patients from the FHN Daily and Nocturnal Trials respectively were included in this ancillary study. Predialysis serum CysC concentrations remained unchanged after intensifying hemodialysis dose by either modality. There was significant lowering of the serum β2‐M concentrations in the frequent Daily Trial hemodialysis group at 12 months in all patients and in patients without residual renal function at baseline (−3.8 ± 12.62 μg/mL, P = 0.004; −5.9 ± 12.99 μg/mL, P = 0.02, respectively). There were no significant differences between the baseline and the 12‐months predialysis β2‐M serum concentrations in the two control groups (Daily 3× and Nocturnal 3× groups). No association between the changes in the two biomarkers between baseline and 12‐months and in changes in left ventricular mass, physical‐health composite scores, hospitalization rate, and death were found. The numbers of hospitalizations and deaths were small. Discussion: β2‐M may be a better biomarker of dialysis dose than CysC. Reduction in the concentration of potentially toxic long‐lived proteins of the size of β‐2M is one potential long‐term benefit of more intensive dialysis that may be explored. [ABSTRACT FROM AUTHOR]

Background: Galloway-Mowat syndrome (GAMOS) (OMIM #251300) is a severe autosomal recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies caused by WDR73 as well as OSGEP, TP53RK, TPRKB, or LAGE3 mutations.Objective: We report on the hitherto undescribed urological and nephrological complications of the homozygous c.974G>A (p.Arg325Gln) OSGEP mutations in a 7-year-old Caucasian girl.Case diagnosis: The patient came to the attention of pediatric nephrology at the age of 3 years and 11 months, when she presented with status epilepticus due to profound hypomagnesemia (0.31 mmol/L, normal 0.65-1.05). A 24-h urine demonstrated a magnesium loss of 0.6 mmol/kg/day with associated proteinuria suggesting renal tubulopathy. Subsequently, she developed recurrent urinary tract infections (UTIs) and was diagnosed with neurogenic bladder dysfunction. The patient continued to have UTIs associated with seizures and sequential cultures growing multi-drug-resistant organisms despite of antibiotic prophylaxis. In addition, the proteinuria (median microalbumin/creatinine ratio 647 mg/mmol) increased, and she developed partial Fanconi syndrome. At age 7, she developed a large bladder calculus (3.3 × 3.2 cm) and three left non-obstructing renal calculi associated with elevated urinary cystine, hypercalciuria, and ongoing hypomagnesemia and required surgical intervention. Glomerular filtration rate (GFR) remained normal and she never developed frank nephrotic syndrome (average albumin 31 g/L).Conclusions: It is unclear if patients with OSGEP mutations with tubular symptoms rather than nephrotic syndrome should be considered a different entity. Nephrological and urological complications of OSGEP mutations can be challenging and require a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

Importance: Changes in kidney function are typically followed by the sequential estimation of glomerular filtration rate (eGFR). Formulae for eGFR work well on a population basis, but there are well-known conditions where they do not work.Objective: The purpose of this review is to summarize the existing literature on special populations in the pediatric age range and provide recommendations on how to estimate GFR in these populations.Findings: The reliability of creatinine depends on muscle mass, while cystatin C (not widely available) is limited by inflammation and changes in protein catabolism. Various dietary factors can alter eGFR. Renal function in neonates changes drastically every day, and there are currently no satisfactory reference intervals for routine pediatric use. Gender effects and conditions such as wasting disease and obesity require alternative ways to obtain eGFR. In oncology patients, chemotherapy may negatively affect renal function, and nuclear GFR measurements may be necessary. For body builders, high muscle mass may lead to underestimation of eGFR using creatinine.Conclusions and relevance: Clinicians should be aware of special populations that may yield misleading eGFRs with conventional creatinine-based formulae, and that the alternative methods may be more appropriate for some populations. [ABSTRACT FROM AUTHOR]

Immunosuppressive drugs for solid organ transplantation are critical dose drugs with a narrow therapeutic index. Many of the most commonly used innovator drugs are off patent and have been replicated by generic counterparts, often at substantial cost-savings to the patient. However, serious adverse events caused by the transition from innovator to generic medications, specifically in pediatric solid organ transplant recipients, have questioned these autosubstitutions. The purpose of this review is to summarize the criteria set forth by the regulatory bodies, and to examine how major immunosuppressive drugs conform to these recommendations. Regulatory bodies have established inconsistent criteria to demonstrate bioequivalence between innovator and generic medications, causing approved generic variations to have varying levels of equivalence with the innovator drugs. In order to minimize the risk for under-immunosuppression, the following recommendations have been concluded. Brand prescribing of cyclosporine and tacrolimus are recommended due to evidence of adverse events after conversion to generic formulations and differences in dissolution parameters. Mycophenolate mofetil (MMF) shows better bioequivalence between innovator and generic formulations, however caution should be advised when switching between formulations. The institution of ‘innovator only’ policies may be appropriate at this time in order to minimize the risk of under-immunosuppressing patients until the evidence of more stringent bioequivalence has been established. [ABSTRACT FROM AUTHOR]