Prognostic Biomarkers in Kidney Transplantation: A Systematic Review and Critical Appraisal.

SIGNIFICANCE STATEMENT: Why are there so few biomarkers accepted by health authorities and implemented in clinical practice, despite the high and growing number of biomaker studies in medical research ? In this meta-epidemiological study, including 804 studies that were critically appraised by expert reviewers, the authors have identified all prognostic kidney transplant biomarkers and showed overall suboptimal study designs, methods, results, interpretation, reproducible research standards, and transparency. The authors also demonstrated for the first time that the limited number of studies challenged the added value of their candidate biomarkers against standard-of-care routine patient monitoring parameters. Most biomarker studies tended to be single-center, retrospective studies with a small number of patients and clinical events. Less than 5% of the studies performed an external validation. The authors also showed the poor transparency reporting and identified a data beautification phenomenon. These findings suggest that there is much wasted research effort in transplant biomarker medical research and highlight the need to produce more rigorous studies so that more biomarkers may be validated and successfully implemented in clinical practice. BACKGROUND: Despite the increasing number of biomarker studies published in the transplant literature over the past 20 years, demonstrations of their clinical benefit and their implementation in routine clinical practice are lacking. We hypothesized that suboptimal design, data, methodology, and reporting might contribute to this phenomenon. METHODS: We formed a consortium of experts in systematic reviews, nephrologists, methodologists, and epidemiologists. A systematic literature search was performed in PubMed, Embase, Scopus, Web of Science, and Cochrane Library between January 1, 2005, and November 12, 2022 (PROSPERO ID: CRD42020154747). All English language, original studies investigating the association between a biomarker and kidney allograft outcome were included. The final set of publications was assessed by expert reviewers. After data collection, two independent reviewers randomly evaluated the inconsistencies for 30% of the references for each reviewer. If more than 5% of inconsistencies were observed for one given reviewer, a re-evaluation was conducted for all the references of the reviewer. The biomarkers were categorized according to their type and the biological milieu from which they were measured. The study characteristics related to the design, methods, results, and their interpretation were assessed, as well as reproducible research practices and transparency indicators. RESULTS: A total of 7372 publications were screened and 804 studies met the inclusion criteria. A total of 1143 biomarkers were assessed among the included studies from blood ( n =821, 71.8%), intragraft ( n =169, 14.8%), or urine ( n =81, 7.1%) compartments. The number of studies significantly increased, with a median, yearly number of 31.5 studies (interquartile range [IQR], 23.8-35.5) between 2005 and 2012 and 57.5 (IQR, 53.3-59.8) between 2013 and 2022 ( P < 0.001). A total of 655 studies (81.5%) were retrospective, while 595 (74.0%) used data from a single center. The median number of patients included was 232 (IQR, 96-629) with a median follow-up post-transplant of 4.8 years (IQR, 3.0-6.2). Only 4.7% of studies were externally validated. A total of 346 studies (43.0%) did not adjust their biomarker for key prognostic factors, while only 3.1% of studies adjusted the biomarker for standard-of-care patient monitoring factors. Data sharing, code sharing, and registration occurred in 8.8%, 1.1%, and 4.6% of studies, respectively. A total of 158 studies (20.0%) emphasized the clinical relevance of the biomarker, despite the reported nonsignificant association of the biomarker with the outcome measure. A total of 288 studies assessed rejection as an outcome. We showed that these rejection studies shared the same characteristics as other studies. CONCLUSIONS: Biomarker studies in kidney transplantation lack validation, rigorous design and methodology, accurate interpretation, and transparency. Higher standards are needed in biomarker research to prove the clinical utility and support clinical use.

Pharmacokinetics of nirmatrelvir/ritonavir and the drug-drug interaction with calcineurin inhibitor in renal transplant recipients.

OBJECTIVES: To describe the pharmacokinetic (PK) characteristics of nirmatrelvir/ritonavir in renal transplant recipients and explore the potential factors that related to the PK variance of nirmatrelvir/ritonavir and its interaction with calcineurin inhibitor (CNI). METHODS: Renal transplant recipients treated with CNI and nirmatrelvir/ritonavir were prospectively enrolled. Steady-state plasma concentrations of nirmatrelvir/ritonavir were determined by high-performance liquid chromatography-tandem mass spectrometry, and the PK parameters were calculated using non-compartmental analysis. Spearman correlation analysis was used for exploring influencing factors. RESULTS: A total of eight recipients were enrolled; for nirmatrelvir and ritonavir, AUC/dose was 0.24179 ± 0.14495 and 0.06196 ± 0.03767 µg·h·mL-1·mg-1. Red blood cell (RBC), hematocrit (Ht), hemoglobins (Hb), and creatinine clearance (Ccr) were negatively correlated with AUC/dose of nirmatrelvir, while Ccr, CYP3A5 genotype, and CYP3A4 genotype were related to the AUC/dose of ritonavir. Ccr was negatively correlated with the C0/dose of tacrolimus (TAC) after termination of nirmatrelvir/ritonavir (rs = -0.943, p = 0.008). CONCLUSIONS: The PK characteristics of nirmatrelvir/ritonavir vary greatly among renal transplant recipients. Factors including Ccr and CYP3A5 genotype were related to the in vivo exposure of nirmatrelvir/ritonavir. During the whole process before and after nirmatrelvir/ritonavir therapy, it is recommended to adjust the CNI basing on renal function to avoid CNI toxicity exposure.

Value of original and modified pathological scoring systems for prognostic prediction in paraffin-embedded donor kidney core biopsy.

BACKGROUND: No study has validated, compared and adapted scoring systems for prognosis prediction based on donor kidney core biopsy (CB), with less glomeruli than wedge biopsy. METHODS: A total of 185 donor kidney CB specimens were reviewed using seven scoring systems. The association between the total score, item scores, score-based grading, and allograft prognosis was investigated. In specimens with less than ten glomeruli (88/185, 47.6%), scoring systems were modified by adjusting weights of the item scores. RESULTS: The Maryland aggregate pathology index (MAPI) score-based grading and periglomerular fibrosis (PGF) associated with delayed graft function (DGF) (Grade: OR = 1.59, p < 0.001; PGF: OR = 1.06, p = 0.006). Total score, score-based grading and chronic lesion score in scoring systems associated with one-year and 3-year eGFR after transplantation. Total-score-based models had similar predictive capacities for eGFR in all scoring systems, except MAPI and Ugarte. Score of glomerulosclerosis (GS), interstitial fibrosis (IF), tubular atrophy (TA), and arteriolar hyalinosis (AH) had good eGFR predictive capacities. In specimens with less than ten glomeruli, modified scoring systems had better eGFR predictive capacities than original scoring systems. CONCLUSIONS: Scoring systems could predict allograft prognosis in paraffin-embedded CB with ten more glomeruli. A simple and pragmatic scoring system should include GS, IF, TA and AH, with weights assigned based on predictive capacity for prognosis. Replacing GS scores with tubulointerstitial scores could significantly improve the predictive capacity of eGFR. The conclusion should be further validated in frozen section.

Genotype and phenotype analysis and transplantation strategy in children with kidney failure caused by NPHP.

BACKGROUND: Nephronophthisis-related ciliopathies (NPHP-RC) have strong genotype and phenotype heterogeneity, and the transplantation strategy of Boichis syndrome is still controversial. Our purpose was to examine associations of genotype and phenotype in children with NPHP-RC and analyze the transplantation strategies of different phenotypes. METHODS: The records of children with NPHP treated at our center from 01/2018 to 03/2021 were retrospectively reviewed. Inclusion criteria were a diagnosis of NPHP, received kidney transplantation, and received whole exome sequencing (WES) or nephropathy gene panel testing. RESULTS: Twenty-nine children with NPHP were included. Nine children (31%) had NPHP1 mutations, and all presented with isolated nephropathy. Eighteen of 20 patients with non-NPHP1 mutations had compound heterozygous mutations, and 70% had extrarenal phenotype. Age at disease presentation (11.2 ± 1.94 years) and the development of kidney failure (12.4 ± 2.70 years) were later in children with NPHP1 mutations than those with non-NPHP1 mutations (5.2 ± 2.83 years and 5.7 ± 2.92 years, respectively). Four of six children with NPHP3 mutations were diagnosed with Boichis syndrome due to liver fibrosis. Isolated kidney transplantation resulted in good outcomes for patients with mild or moderate liver fibrosis without portal hypertension, while cholestasis was common postoperatively and could be resolved with ursodeoxycholic acid. CONCLUSIONS: NPHP1 mutations are the most common in children with NPHP, and the phenotype of NPHP1 mutation is significantly different from that of non-NPHP1 mutation. For NPHP patients with mild to moderate liver fibrosis without portal hypertension, timely treatment of cholestasis could prevent the rapid progression of liver function damage after isolated kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

RENAL nephrometry scoring system in bilateral Wilms tumor: predictive application.

AIM: This study aims to explore the application of RENAL nephrometry scoring system in bilateral Wilms tumor (BWT). METHODS: A retrospective review of patients with BWT from January 2010 to June 2022 was performed. Each kidney unit of the BWT was evaluated independently and scored according to RENAL nephrometry scoring system by 2 blinded reviewers, and reviewers were blinded to what surgery the patients ultimately had. Discrepancies were evaluated by a third reviewer to reach a consensus. Tumor anatomical characteristics were summarized and compared. RESULTS: 29 patients with 53 kidney units were included in the study. 53 kidney units included 12 (22.6%) low-complexity, 9 (17.0%) intermediate-complexity, and 32 (60.4%) high-complexity. 2 kidney units (3.8%) had tumor thrombus, and 14 (26.4%) had multiple lesions. A total of 42 kidney units (79.2%) underwent initial nephron-sparing surgery (NSS) and 11 (20.8%) underwent radical nephrectomy. Less complexity tumors were observed in the NSS group. Of the 42 kidney units undergoing initial NSS, 26 were performed in vivo and 16 ex vivo via autotransplantation. The latter group featured a higher complexity. During follow-up, 22 patients survived and 7 died, no statistically significant tumor complexity was observed between the two groups. CONCLUSIONS: The anatomical characteristics of BWT are complex. Despite this study did not indicate that the complexity correlates with prognosis, low-complexity tumors were candidates for NSS, and kidney autotransplantation provided a feasible procedure for high-complexity tumors. A refined system is required due to multiple lesions and tumor thrombus.

Oxidative phosphorylation regulates interleukin-10 production in regulatory B cells via the extracellular signal-related kinase pathway.

Regulatory B cells (Bregs) are immune cells that constrain autoimmune response and restrict inflammation via their expression of interleukin (IL)-10. However, the molecular mechanisms underlying Breg differentiation and IL-10 secretion remain unclear. Previous data suggest that cellular metabolism determines both the fate and function of these cells. Here, we suggest an essential role for mitochondrial oxidative phosphorylation (OXPHOS) in the regulation of IL-10 in these Bregs. We found that IL-10+ B cells from IL-10-green fluorescent protein-expressing mice had higher oxygen consumption rate than IL-10- B cells. In addition, inhibition of OXPHOS decreased the expression of IL-10 in B cells. Furthermore, suppression of OXPHOS diminished the expression of surface markers for Bregs and impaired their therapeutic effects in dextran sulphate sodium (DSS)-induced colitis. Mechanistically, mitochondrial OXPHOS was found to regulate the transcription factor HIF-1α through the extracellular signal-related kinase pathway. Taken together, this study reveals a strong correlation between mitochondrial OXPHOS and Breg phenotype/function, indicating OXPHOS as a therapeutic target in autoimmune diseases driven by Breg dysfunction.

MicroRNA profile of circulating CD4+ T cells in aged patients with atherosclerosis obliterans.

BACKGROUND: To evaluate the specificity of the expression patterns of microRNAs (miRNAs) in circulating CD4+ T cells in aged patients with atherosclerosis obliterans (ASO). METHODS: A comprehensive miRNA expression study was conducted using a miRNA microarray of CD4+ T cells isolated from peripheral blood mononuclear cells (PBMCs) of 33 patients with ASO and 24 healthy donors. A t test was used for statistical analysis, and the average linkage method was used for hierarchical clustering. The results were validated by qRT-PCR. Putative targeted pathways associated with validated miRNAs were predicted with the online software DIANA miRPath. RESULTS: We identified 44 miRNAs based on a cutoff value of a 1.3-fold change in expression between the two groups, with 18 miRNAs showing a false discovery rate (FDR) p value < 0.05. The qRT-PCR analysis validated differences in 12 miRNAs, and 6 miRNAs were proven to be differentially expressed among three age groups (age: 35-55 years; 56-75 years; 76-95 years): the miRNAs miR-21 (p: 0.0008; 0.0009; 0.0022), miR-29b (p: 0.453; < 0.0001; < 0.0001), and miR-374b (p: < 0.0001; < 0.0001; 0.2493) showed upregulated expression in patients with ASO, while miR-142-3p (p: < 0.0001; < 0.0001; < 0.0001), miR-142-5p (p: < 0.0001; < 0.0001; < 0.0001), and miR-150 (p: < 0.0001; < 0.0001; 0.0001) showed downregulated expression in patients with ASO. The validated miRNAs participated in CD4+ T cell activation, proliferation, and migration pathways. CONCLUSIONS: Circulating CD4+ T cells in aged patients with ASO may show a distinct molecular signature. This is the first time that a distinctive, validated miRNA profile from circulating CD4+ T cells in atherosclerosis has been presented. This miRNA signature may be used to help elucidate the underlying mechanism of atherosclerosis. Further clinical studies and in-depth reports will contribute to identifying predictive and therapeutic targets in these patients with atherosclerosis.

[A child with diffuse mesangial sclerosis caused by a missense mutation of TRPC6 gene].

OBJECTIVE: To explore the genetic etiology and clinical outcome of a child with steroid-resistant nephrotic syndrome and diffuse mesangial sclerosis. METHODS: Genomic DNA was extracted from peripheral blood leukocytes of the proband and his parents. Targeted capture - next generation sequencing and Sanger sequencing were carried out. Candidate variant was verified by segregation analysis in his family. RESULTS: A heterozygous missense variant of the TRPC6 gene, namely c.325G>A (p.Gly109Ser), was detected in the proband. The same variant was not detected in either parent. According to the guidelines for the interpretation of sequence variants developed by American College of Medical Genetics and Genomics, the variant was predicted as pathogenic. CONCLUSION: The missense variant of the TRPC6 gene probably underlay the diffuse mesangial sclerosis in this patient. Above finding has expanded the phenotypic spectrum of the TRPC6 gene.

COVID-19-related medical research: a meta-research and critical appraisal.

BACKGROUND: Since the start of the COVID-19 outbreak, a large number of COVID-19-related papers have been published. However, concerns about the risk of expedited science have been raised. We aimed at reviewing and categorizing COVID-19-related medical research and to critically appraise peer-reviewed original articles. METHODS: The data sources were Pubmed, Cochrane COVID-19 register study, arXiv, medRxiv and bioRxiv, from 01/11/2019 to 01/05/2020. Peer-reviewed and preprints publications related to COVID-19 were included, written in English or Chinese. No limitations were placed on study design. Reviewers screened and categorized studies according to i) publication type, ii) country of publication, and iii) topics covered. Original articles were critically appraised using validated quality assessment tools. RESULTS: Among the 11,452 publications identified, 10,516 met the inclusion criteria, among which 7468 (71.0%) were peer-reviewed articles. Among these, 4190 publications (56.1%) did not include any data or analytics (comprising expert opinion pieces). Overall, the most represented topics were infectious disease (n = 2326, 22.1%), epidemiology (n = 1802, 17.1%), and global health (n = 1602, 15.2%). The top five publishing countries were China (25.8%), United States (22.3%), United Kingdom (8.8%), Italy (8.1%) and India (3.4%). The dynamic of publication showed that the exponential growth of COVID-19 peer-reviewed articles was mainly driven by publications without original data (mean 261.5 articles ± 51.1 per week) as compared with original articles (mean of 69.3 ± 22.3 articles per week). Original articles including patient data accounted for 713 (9.5%) of peer-reviewed studies. A total of 576 original articles (80.8%) showed intermediate to high risk of bias. Last, except for simulation studies that mainly used large-scale open data, the median number of patients enrolled was of 102 (IQR = 37-337). CONCLUSIONS: Since the beginning of the COVID-19 pandemic, the majority of research is composed by publications without original data. Peer-reviewed original articles with data showed a high risk of bias and included a limited number of patients. Together, these findings underscore the urgent need to strike a balance between the velocity and quality of research, and to cautiously consider medical information and clinical applicability in a pressing, pandemic context. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/5zjyx/.

Pediatric kidney transplantation in China: an analysis from the IPNA Global Kidney Replacement Therapy Registry.

BACKGROUND: The International Pediatric Nephrology Association (IPNA) Global Kidney Replacement Therapy (KRT) Registry was established to evaluate the incidence and outcomes of kidney replacement therapy (dialysis and transplantation) provided to children worldwide. Analysis of registry data for separate regions is feasible. METHODS: Three centers located in Shanghai, Guangzhou, and Zhengzhou, which have the greatest number of pediatric kidney transplantation cases in China, participated in this analysis of transplant data. Data were registered by each center for patients under the age of 19 years who received a single-organ kidney transplant for the first time between 2011 and 2018. RESULTS: In total, 415 patients (59.8% male) aged 1.4-18.7 (median 12.1) years were followed for 0.3-97.1 (median 27.7) months. The number of kidney transplants increased from a total of 129 during 2011-2014 to 286 cases during 2015-2018. 85.8% of patients received the transplanted kidney from a pediatric (age < 19 years) donor, and deceased donors accounted for 94% of all donors. 8.0% of grafts were lost. One and 5-year patient survival rates were 97.6% and 95.5%, respectively. The major cause of death was infection (7/14). Similar graft and patient survival rates were observed for organs from pediatric and adult donors in 6-11 and 12-18 year recipient age groups, whereas recipients < 6 years showed inferior patient and graft survival. CONCLUSIONS: Pediatric kidney transplantation shows favorable short-term and medium-term outcomes in China. Our experience supports use of pediatric donors in pediatric kidney transplantation, but attention directed to the outcome of recipients aged under 6 is necessary. Graphical abstract.

Pregnancy outcomes in female patients exposed to cyclosporin-based versus tacrolimus-based immunosuppressive regimens after liver/kidney transplantation: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Pregnancy after transplantation is a challenge owing to the high risk of adverse maternal and foetal outcomes, and immunosuppressants may further impact these outcomes. There are no head-to-head randomized controlled trials comparing influences of cyclosporin and tacrolimus on pregnancy outcomes. Thus, we systematically reviewed and meta-analysed observational studies assessing the comparative influences of these two drugs on pregnancy outcomes in liver/kidney transplant recipients. METHODS: Relevant studies comparing pregnancy outcomes with tacrolimus and cyclosporin head-to-head were searched in PubMed, EMBASE and Web of Science (from 1 January 2000 to 20 March 2020). The weighted mean difference and odds ratio (OR) were calculated to compare continuous and dichotomous variables, respectively, with 95% confidence intervals (CIs). Publication bias was estimated using funnel plots. The study quality was assessed according to the modified Newcastle-Ottawa scale. RESULTS AND DISCUSSION: Overall, 10 observational studies of low quality, including a total of 1080 post-liver or kidney transplant pregnancies, were identified. Tacrolimus-treated recipients experienced a lower risk of gestational hypertension (28.0%; OR: 1.74; 95% CI: 1.27-2.39; p < 0.01). Cyclosporin-treated recipients showed a lower incidence of caesarean section (40.3%; OR: 0.62; 95% CI: 0.46-0.82; p < 0.01). Additionally, cyclosporin performed better in terms of the live birth rate (78.0%; OR: 1.38; 95% CI: 1.02-1.88; p = 0.04). No significant differences in the incidences of pre-eclampsia, gestational diabetes, preterm delivery and birth weight were observed. WHAT IS NEW AND CONCLUSION: Tacrolimus performed better in patients with gestational hypertension, while cyclosporin was associated with a lower incidence of caesarean section and a higher incidence of live birth. The findings are based on relatively low-quality evidence, but may provide a reference for clinicians in their clinical monitoring and obstetric care for post-transplant pregnancies.

Validated LC-MS/MS method for quantitation of total and free mycophenolic acid concentration and its application to a pharmacokinetic study in pediatric renal transplant recipients.

A simple and sensitive LC-MS/MS method was established to quantify total and free mycophenolic acid (MPA) plasma concentrations during immunosuppressive medication for pediatric renal transplantation. The chromatographic separation was performed with the Hypersil GOLD C18 column, using a mobile phase consisting of 0.1% formic acid in water and acetonitrile (60:40, v/v) at an isocratic flow rate of 0.4 ml/min. An Agilent 6420 triple quadrupole mass spectrometer was operated via a positive electrospray ionization interface using the transitions m/z 321.14 → 206.9 for MPA and m/z 324.15 → 209.9 for MPA-d3 (internal standard). The linearity was 0.1-50 µg/ml for total MPA and 0.0025-0.5 µg/ml for free MPA. The within-run and between-run precisions were all <5% and accuracy was within 96.23-107.63%. The validated method was successfully aspplied to a pharmacokinetic study in 28 pediatric renal recipients. The mean free fraction of MPA in our patients was 0.89% (ranging from 0.62 to 1.25%) and albumin level played a major role in the variability of free fraction of MPA, thus, in pediatric patients with hypoproteinemia, close free drug monitoring and dose adjustments should be considered to prevent toxicity.

Transplantation of a single kidney from pediatric donors less than 10 kg to children with poor access to transplantation: a two-year outcome analysis.

BACKGROUND: Access to kidney transplantation by uremic children is very limited due to the lack of donors in many countries. We sought to explore small pediatric kidney donors as a strategy to provide transplant opportunities for uremic children. METHODS: A total of 56 cases of single pediatric kidney transplantation and 26 cases of en bloc kidney transplantation from pediatric donors with body weight (BW) less than 10 kg were performed in two transplant centers in China and the transplant outcomes were retrospectively analyzed. RESULTS: The 1-year and 2-year death-censored graft survival in the en bloc kidney transplantation (KTx) group was inferior to that in the single KTx group. Subgroup analysis of the single KTx group found that the 1-year and 2-year death-censored graft survival in the group where the donor BW was between 5 and 10 kg was 97.7 and 90.0%, respectively. However, graft survival was significantly decreased when donor BW was ≤5 kg (p < 0.01), mainly because of the higher rate of thrombosis (p = 0.035). In the single KTx group, the graft length was increased from 6.7 cm at day 7 to 10.5 cm at 36 months posttransplant. The estimated glomerular filtration rate increased up to 24 months posttransplant. Delayed graft function and urethral complications were more common in the group with BW was ≤5 kg. CONCLUSIONS: Our study suggests that single kidney transplantation from donors weighing over 5 kg to pediatric recipients is a feasible option for children with poor access to transplantation.

Risk factors and outcomes of prolonged recovery from delayed graft function after deceased kidney transplantation.

OBJECTIVE: We aimed to evaluate the effect of prolonged recovery from DGF on outcomes, using a new definition of DGF recovery time, among deceased donor kidney transplant recipients with DGF, and to examine the risk factors for prolonged recovery. METHODS: From 2007 to 2016, 91 deceased donor kidney transplant recipients with DGF were retrospectively analyzed. DGF recovery time was defined as the time from transplantation to achieve a stable estimated glomerular filtration rate (eGFR). Recipients with a DGF recovery time greater than or equal to the median were assigned to the prolonged recovery group, while the others were assigned to the rapid recovery group. RESULT: The median DGF recovery time was 27 days. Donor terminal eGFR was significantly lower in the prolonged recovery group (n = 46) compared with the rapid recovery group (n = 45) (median 24.9 vs. 65.4 ml/min/1.73m2, p = 0.004). The eGFR at 1 year post-transplant in the prolonged recovery group was significantly lower than that in the rapid recovery group (50.6 ± 20.0 vs. 63.5 ± 21.4 ml/min/1.73m2, p = 0.005). The risk of adverse outcomes (acute rejection, pneumonia, graft failure, and death) was significantly greater in the prolonged recovery group (hazard ratio 2.604, 95% confidence interval 1.102-6.150, p = 0.029) compared with the rapid recovery group. CONCLUSION: Decreased donor terminal eGFR is a risk factor for prolonged recovery from DGF after deceased kidney transplantation. Prolonged DGF recovery time is associated with reduced graft function at 1-year post-transplant, and poor transplant outcome.

[Clinical features of catch-up growth after kidney transplantation in children].

OBJECTIVE: To study the clinical features of catch-up growth of body height after kidney transplantation in children and related influencing factors. METHODS: A retrospective analysis was performed from the chart review data of 15 children who underwent kidney transplantation in Guangzhou Women and Children's Medical Center from July 2017 to November 2019. According to whether the increase in height standard deviation score (ΔHtSDS) in the first year after kidney transplantation reached ≥0.5, the children were divided into a catch-up group with 8 children and a non-catch-up group with 7 children. According to whether final HtSDS was ≥-2, the children were divided into a standard group with 6 children and a non-standard group with 9 children. The features of catch-up growth of body height and related influencing factors were compared between groups. RESULTS: The data showed that median ΔHtSDS was 0.8 in the first year after transplantation, which suggested catch-up growth of body height. There was a significant difference in HtSDS between the non-catch-up and catch-up groups (P<0.05). Baseline HtSDS before transplantation was positively correlated with HtSDS at the end of follow-up (r=0.622, P<0.05) and was negatively correlated with ∆HtSDS in the first year after transplantation (r=-0.705, P<0.05). Age of transplantation and mean dose of glucocorticoid (GC) per kg body weight were risk factors for catch-up growth after kidney transplantation (OR=1.23 and 1.74 respectively; P<0.05), while baseline HtSDS and use of antihypertensive drugs were independent protective factors for catch-up growth (OR=0.08 and 0.18 respectively; P<0.05); baseline HtSDS and ΔHtSDS in the first year after kidney transplantation were influencing factors for final HtSDS (ß=0.984 and 1.271 respectively; P<0.05). CONCLUSIONS: Kidney transplantation should be performed for children as early as possible, growth retardation before transplantation should be improved as far as possible, and multiple treatment methods (including the use of GC and antihypertensive drugs) should be optimized after surgery, in order to help these children achieve an ideal body height.

Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co-administered with tacrolimus.

AIMS: Various mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in adult kidney transplant recipients co-administered with tacrolimus. However, the external predictive performance has been unclear. Thus, this study aimed to comprehensively evaluate the external predictability of published MMF popPK models in such populations and investigate the potential influencing factors. METHODS: The external predictability of qualified popPK models was evaluated using an independent dataset. The evaluation included prediction- and simulation-based diagnostics, and Bayesian forecasting. In addition, factors influencing model predictability, especially the impact of structural models, were investigated. RESULTS: Fifty full PK profiles from 45 patients were included in the evaluation dataset and 11 published popPK models were identified and evaluated. In prediction-based diagnostics, the prediction error within ±30% was less than 50% in most published models. The prediction- and variability-corrected visual predictive check and posterior predictive check showed large discrepancies between the observations and simulations in most models. Moreover, the normalized prediction distribution errors of all models did not follow a normal distribution. Bayesian forecasting demonstrated an improvement in the model predictability. Furthermore, the predictive performance of two-compartment (2CMT) models incorporating the enterohepatic circulation (EHC) process was not superior to that of conventional 2CMT models. CONCLUSIONS: The published models showed large variability and unsatisfactory predictive performance, which indicated that therapeutic drug monitoring was necessary for MMF clinical application. Further studies incorporating potential covariates need to be conducted to investigate the key factors influencing model predictability of MMF.

Prediction of mizoribine pharmacokinetic parameters by serum creatinine in renal transplant recipients.

PURPOSE: Mizoribine (MZR) is an immunosuppressive agent with extensive inter-individual differences in pharmacokinetics (PK). Here, we investigated the PK characteristics of MZR in renal transplant recipients and gave equations for prediction of some critical PK parameters. METHODS: A total of 40 renal transplant recipients participated in this prospective study and were administered MZR orally twice daily in the range of 1.1-8.9 mg kg-1 day-1. Steady-state concentrations of MZR were detected before (0 h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 h after administration by high-performance liquid chromatography method. Another 38 patients with newly detected trough concentration (C0) were enrolled to validate the obtained C0 predictive equation. RESULTS: Significant inter-individual differences in MZR PK parameters were observed. Patients with decreasing creatinine clearance rate (CCr) had significantly decreased terminal elimination rate constant (kel) and apparent total body clearance (Cl/F), while other PK parameters including apparent terminal half-life (t1/2), peak time (Tmax), peak concentration (Cmax), area under the curve (AUC0-12h), apparent volume of distribution (V/F), and mean residence time (MRT) were significantly increased. Correlation coefficients between AUC0-12h and C0/Cmax were 0.894 and 0.916, respectively (both p < 0.001). A serum creatinine (SCr)-based predictive C0 equation [C0 = (2.160 × SCr - 54.473) × Dose] was established and validated by C0 from another 38 patients. Besides, significant linear correlations between kel/t1/2 and CCr were also found (r2 = 0.668 and 0.484, respectively), and equations predicting kel/t1/2 were also obtained (kel = 0.015 + 0.002 × CCr, t1/2 = 13.601 - 0.139 × CCr). CONCLUSIONS: Renal function plays as an essential factor that contributes to great inter-individual MZR PK variation. Both C0 and Cmax are suitable for evaluating MZR exposure in the body. SCr could be applied to predict C0 and t1/2 of MZR.

Comparison of efficacy and safety between febuxostat and allopurinol in early post-renal transplant recipients with new onset of hyperuricemia.

WHAT IS KNOWN AND OBJECTIVE: Febuxostat and allopurinol are xanthine oxidase inhibitors for urate-lowering therapy. The efficacy and safety of febuxostat and allopurinol have been mostly reported in hyperuricemia patients with normal renal function. Here, we aimed to compare the effects of these two drugs in early post-renal transplant recipients, focusing on evaluating the urate-lowering effect and recovery of allograft renal function. METHODS: A retrospective cohort study was performed in early post-renal transplant recipients with new onset of hyperuricemia receiving febuxostat or allopurinol therapy. Serum uric acid (UA) and estimated glomerular filtration rate (eGFR) were detected on days 3, 7 and 15 and months 1, 3 and 6 after therapy initiation. Liver and blood functions were monitored and other adverse events were recorded. RESULTS AND DISCUSSION: A total of 48 and 33 patients were enrolled in the febuxostat and allopurinol groups, respectively. Significant UA-lowering effects were observed on day 3 in both groups. Febuxostat caused a more rapid UA decline, starting on day 3 and lasting for 1 month. The most apparent contrast was found in UA level (267.25 ± 93.66 vs 334.18 ± 96.56 µmol/L, P = 0.003) on day 7; 62.5% and 30.3% of patients achieved target UA level in febuxostat and allopurinol groups respectively on day 3 (P = 0.004), but there was no significant difference between two groups from days 15 to months 6. The median times to achieve target UA level were 3 and 5 days in febuxostat and allopurinol groups respectively (P = 0.002). The eGFR levels and recovering rates were gradually upregulated but no significant differences were found between two groups. No abnormities related to febuxostat or allopurinol were observed. WHAT IS NEW AND CONCLUSION: This is the first comprehensive evaluation of UA-lowering effects of febuxostat and allopurinol in early post-renal transplant recipients. Febuxostat caused a marginally quicker serum UA-lowering effect than allopurinol, but there was no advantage for long-term use of febuxostat. The drugs had no significant differences in impacting renal allograft function recovery, and both were well tolerated.

Transplantation for infantile nephronophthisis with loss-of-function mutation in NPHP3: Lesson from a case.

The choice of KT only or CLKT for infantile NPHP with mild liver fibrosis is understudied. A 5-year-old girl was transferred to our center for KT due to ESRD. Her primary disease was infantile NPHP with compound heterozygous NPHP3 mutations: c.458A>C(p.Q153P)/missense mutation and c.2032A>T(p. K678X)/nonsense mutation. The patient had elevated liver enzymes and biopsy-proven liver fibrosis. As liver synthesis was acceptable, only KT was performed. However, liver fibrosis progressed at 1.5 years after transplantation, manifested with portal hypertension and hypersplenism. Common causes for portal hypertension were excluded, and the progression was attributed to NPHP. AMR attacked allograft at about 2 years post-transplant. To solve both the liver and the kidney problems, CLKT was performed. Her liver and kidney function recovered initially, but she unfortunately died of pneumonia and subsequent intracranial hemorrhage two weeks later. Nonsense mutation in NPHP3 gene may be correlated with rapid progression of liver disease in infantile NPHP. More studies are required to determine the role of CLKT in these cases; however, combined transplantation may improve long-term graft and patient survival.

Up-Regulation of HMGB1 Exacerbates Renal Ischemia-Reperfusion Injury by Stimulating Inflammatory and Immune Responses through the TLR4 Signaling Pathway in Mice.

BACKGROUND/AIMS: The aim of this study was to elucidate how high-mobility group box 1 (HMGB1) exacerbates renal ischemic-reperfusion injury (IRI) by inflammatory and immune responses through the toll-like receptor 4 (TLR4) signaling pathway. METHODS: A total of 30 wild-type (WT) mice and 30 TLR4 knockout (TLR4-/-) mice were selected and then randomly assigned to the Sham, I/R or HMGB1 groups. The serum and kidney tissues of all mice were collected 24 h after the perfusion. The fully automatic biochemical detector and ELISA were applied to determine the blood urea nitrogen (BUN) and serum creatinine (Scr) levels, and TNF-α, IL-1ß, IL-6, IFN-γ and IL-10 levels, respectively. HE staining was used to evaluate kidney tissue damage, immunofluorescence and immunohistochemical staining were performed to observe CD68 and MPO cell infiltration, and flow cytometry was applied to detect immune cells. qRT-PCR and Western blotting were used to detect the expressions of TLR signaling pathway-related genes and proteins, respectively. RESULTS: Compared with the Sham group, the levels of BUN, Scr, TNF-α, IL-1ß, IL-6, IFN-γ and IL-10, kidney tissue damage score, CD68 and MPO cell infiltration, the numbers of immune cells, and the expressions of TLR signaling pathway-related genes and proteins in the I/R and HMGB1 groups were significantly up-regulated. In the I/R and HMGB1 groups, the levels of BUN and Scr, TNF-α, IL-1ß, IL-6 and IFN-γ, kidney tissue damage score, CD68 and MPO cell infiltration, immune cell numbers, and TLR signaling pathway-related gene and protein expressions in the WT mice were all higher than those in the TLR4-/- mice, but IL-10 level was significantly lower. Similarly, all aforementioned indexes but IL-10 level in the WT and TLR4-/- mice were higher in the HMGB1 group than in the I/R group. CONCLUSION: Our study indicated that the up-regulation of HMGB1 could exacerbate renal IRI by stimulating inflammatory and immune responses through the TLR4 signaling pathway.c.