Atypical Hemolytic Uremic Syndrome Occurring After Receipt of mRNA-1273 COVID-19 Vaccine Booster: A Case Report.

Atypical hemolytic uremic syndrome (aHUS) is a subtype of thrombotic microangiopathy (TMA) characterized by a dysregulation of the alternative complement pathway. Here, we report a previously healthy 38-year-old woman in whom aHUS developed after a COVID-19 vaccine booster. One day after receipt of a booster dose of mRNA-1273 vaccine, she felt ill. Because of persistent headache, nausea, and general malaise, she went to her general practitioner, who referred her to the hospital after detecting hypertension and acute kidney injury. A diagnosis of TMA was made. Her treatment consisted of blood pressure control, hemodialysis, plasma exchange, and respiratory support. Kidney biopsy confirmed the diagnosis of acute TMA. The patient was referred for treatment with eculizumab, and kidney function improved after initiation of this therapy. Genetic analysis revealed a pathogenic C3 variant. SARS-CoV-2 infection as a trigger for complement activation and development of aHUS has been described previously. In addition, there is one reported case of aHUS occurring after receipt of the adenovirus-based COVID-19 vaccine ChAdOx1 nCoV-19, but, to our knowledge, this is the first case of aHUS occurring after a booster dose of an mRNA COVID-19 vaccine in a patient with an underlying pathogenic variant in complement C3. Given the time frame, we hypothesize that the vaccine probably was the trigger for development of aHUS in this patient.

Natural History of Bone Disease following Kidney Transplantation.

BACKGROUND: Knowledge of the effect of kidney transplantation on bone is limited and fragmentary. The aim of this study was to characterize the evolution of bone disease in the first post-transplant year. METHODS: We performed a prospective, observational cohort study in patients referred for kidney transplantation under a steroid-sparing immunosuppressive protocol. Bone phenotyping was done before, or at the time of, kidney transplantation, and repeated at 12 months post-transplant. The phenotyping included bone histomorphometry, bone densitometry by dual-energy x-ray absorptiometry, and biochemical parameters of bone and mineral metabolism. RESULTS: Paired data were obtained for 97 patients (median age 55 years; 72% male; 21% of patients had diabetes). Bone turnover remained normal or improved in the majority of patients (65%). Bone histomorphometry revealed decreases in bone resorption (eroded perimeter, mean 4.6% pre- to 2.3% post-transplant; P<0.001) and disordered bone formation (fibrosis, 27% pre- versus 2% post-transplant; P<0.001). Whereas bone mineralization was normal in all but one patient pretransplant, delayed mineralization was seen in 15% of patients at 1 year post-transplant. Hypophosphatemia was associated with deterioration in histomorphometric parameters of bone mineralization. Changes in bone mineral density were highly variable, ranging from -18% to +17% per year. Cumulative steroid dose was related to bone loss at the hip, whereas resolution of hyperparathyroidism was related to bone gain at both spine and hip. CONCLUSIONS: Changes in bone turnover, mineralization, and volume post-transplant are related both to steroid exposure and ongoing disturbances of mineral metabolism. Optimal control of mineral metabolism may be key to improving bone quality in kidney transplant recipients. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evolution of Bone Histomorphometry and Vascular Calcification Before and After Renal Transplantation, NCT01886950.

Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial.

Importance: Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression. Objective: To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor. Design, Setting, and Participants: Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022). Interventions: Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos. Main Outcomes and Measures: The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome. Results: Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%). Conclusion and Relevance: Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication. Trial Registration: ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.

Patterns of renal osteodystrophy 1 year after kidney transplantation.

BACKGROUND: Renal osteodystrophy is considered common, but is not well characterized in contemporary kidney transplant recipients. This study reports extensively on bone phenotype by bone histomorphometry, bone densitometry and novel bone biomarkers 1 year after kidney transplantation. METHODS: A transiliac bone biopsy and dual-energy X-ray absorptiometry scans were performed in 141 unselected kidney transplant recipients in this observational cohort study. Blood and 24-h urine samples were collected simultaneously. RESULTS: The median age was 57 ± 11 years, 71% were men and all were of Caucasian ethnicity. Bone turnover was normal in 71% of patients, low in 26% and high in just four cases (3%). Hyperparathyroidism with hypercalcaemia was present in 13% of patients, of which only one had high bone turnover. Delayed bone mineralization was detected in 16% of patients, who were characterized by hyperparathyroidism (137 versus 53 ρg/mL), a higher fractional excretion of phosphate (40 versus 32%) and lower levels of phosphate (2.68 versus 3.18 mg/dL) and calcidiol (29 versus 37 ng/mL) compared with patients with normal bone mineralization. Osteoporosis was present in 15-46% of patients, with the highest prevalence at the distal skeleton. The proportion of osteoporotic patients was comparable across categories of bone turnover and mineralization. CONCLUSIONS: The majority of kidney transplant recipients, including patients with osteoporosis, have normal bone turnover at 1-year post-transplant. Low bone turnover is seen in a substantial subset, while high bone turnover is rare. Vitamin D deficiency and hypophosphataemia represent potential interventional targets to improve bone health post-transplant.

Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients.

The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.

Prospective randomized study of conversion from tacrolimus to cyclosporine A to improve glucose metabolism in patients with posttransplant diabetes mellitus after renal transplantation.

Tacrolimus (TAC) increases the risk of posttransplant diabetes (PTDM) compared with cyclosporine A (CYC). The present 12-month, multicenter, investigator-driven, prospective, randomized study was designed to assess whether conversion from tacrolimus to CYC can reverse PTDM after renal transplantation. Predominantly white patients with PTDM according to the 2005 American Diabetes Association criteria were randomized to either replacement of TAC with CYC or continuation of their TAC-based regimen after stratification for type of glucose-lowering therapy, steroid therapy, and hepatitis C status. At 12 months, 14 of 41 patients with complete data in the CYC arm (34%; 95%CI 19%-49%) were free of diabetes, whereas this was the case in only 4 of 39 patients (10%; 95%CI 3%-20%) in the TAC arm (P = .01). At 12 months, 39% of patients in the CYC arm were off glucose-lowering medication vs 13% of patients in the TAC arm (P = .01). The CYC group decreased glycated hemoglobin level during the 12-month follow-up, resulting in significantly lower levels compared with the TAC group (6.0 ± 0.9% vs 7.1 ± 1.7% at 12 months; P = .002). In conclusion, replacement of TAC with CYC significantly improves glucose metabolism and has the potential to reverse diabetes during the first year after conversion. (EU Clinical Trials Register No. 2006-001765-42).

Relationship between In Vivo CYP3A4 Activity, CYP3A5 Genotype, and Systemic Tacrolimus Metabolite/Parent Drug Ratio in Renal Transplant Recipients and Healthy Volunteers.

CYP3A5 genotype is a major determinant of tacrolimus clearance, and has been shown to affect systemic tacrolimus metabolite/parent ratios in healthy volunteers, which may have implications for efficacy and toxicity. In a cohort of 50 renal transplant recipients who underwent quantification of CYP3A4 activity using the oral midazolam drug probe, we confirmed that CYP3A5 genotype is the single most important determinant of tacrolimus metabolite/parent ratio [CYP3A5 expressors displayed 2.7- and 2-fold higher relative exposure to 13-desmethyltacrolimus (DMT) and 31-DMT, respectively; P < 0.001]. There was, however, no relationship between CYP3A4 activity and tacrolimus metabolite/parent ratios. Additional analyses in 16 healthy volunteers showed that dual pharmacological inhibition of CYP3A4 and P-glycoprotein using itraconazole resulted in increased tacrolimus metabolite/parent ratios (+65%, +112%, and 25% for 13-, 15-, and 31-DMT, respectively; P < 0.01). This finding was confirmed in a cohort of nine renal transplant recipients who underwent tacrolimus pharmacokinetic assessments before and during CYP3A4 inhibition (58% increase in overall metabolite/tacrolimus ratio; P = 0.017).

Pretransplant 4ß-hydroxycholesterol does not predict tacrolimus exposure or dose requirements during the first days after kidney transplantation.

AIMS: The CYP3A metric 4ß-hydroxycholesterol (4ßOHC) has been shown to correlate with tacrolimus steady-state apparent oral clearance (CL/F). Recently, pretransplant 4ßOHC was shown not to predict tacrolimus CL/F after transplantation in a cohort of renal recipients (n = 79). The goal of the current study was determine whether these findings could be validated in a substantially larger cohort. METHODS: In a retrospective analysis of 279 renal recipients, tacrolimus trough concentrations (C0), daily dose, haematocrit and other relevant covariates were registered every day for the first 14 days after transplantation. 4ßOHC and cholesterol were quantified on plasma collected immediately pretransplant using liquid chromatography tandem-mass spectrometry. Patients were genotyped for CYP3A5*1 and CYP3A4*22. RESULTS: A total of 3551 tacrolimus C0 concentrations were registered. In a linear mixed model for the 14-day period, determinants of tacrolimus C0 were CYP3A5 genotype, haematocrit, age and weight (overall R2  = 0.179). Determinants of daily dose were CYP3A5 genotype, age, methylprednisolone dose, tacrolimus formulation, ALT and estimated glomerular filtration rate (overall R2  = 0.242). Considering each of the first 5 days separately, 4ßOHC had a limited effect on tacrolimus C0 on day 3 only (-1.00 ng ml-1 per ln, P = 0.035) but not on any other day, and no effect on dose or C0/dose. During the first 5 days, haematocrit and age, which were previously established as determinants of tacrolimus disposition under steady-state conditions, never explained more than 17.7% of between-subject variability in tacrolimus C0/dose. CONCLUSIONS: The CYP3A metric 4ßOHC cannot be used to predict tacrolimus dose requirements in the first days after transplantation.

Tubulointerstitial expression and urinary excretion of connective tissue growth factor 3 months after renal transplantation predict interstitial fibrosis and tubular atrophy at 5 years in a retrospective cohort analysis.

Connective tissue growth factor (CTGF) is an important mediator of renal allograft fibrosis, and urinary CTGF (CTGFu) levels correlate with the development of human allograft interstitial fibrosis. We evaluated the predictive value of CTGF protein expression in 160 kidney transplant recipients with paired protocol biopsies at 3 months and 5 years after transplantation. At month 3 and year 1, CTGFu was measured using ELISA, and biopsies were immunohistochemically stained for CTGF, with semiquantitative scoring of tubulointerstitial CTGF-positive area (CTGFti). Predictors of interstitial fibrosis and tubular atrophy (IF/TA) severity at 5 years were donor age [OR 1.05 (1.02-1.08), P = 0.001], female donor [OR 0.40 (0.18-0.90), P = 0.026], induction therapy [OR 2.76 (1.10-6.89), P = 0.030], and CTGFti >10% at month 3 [OR 2.72 (1.20-6.15), P = 0.016]. In subgroups of patients with little histologic damage at 3 months [either ci score 0 (n = 119), IF/TA score ≤1 (n = 123), or absence of IF/TA, interstitial inflammation, and tubulitis (n = 45)], consistent predictors of progression of chronic histologic damage by 5 years were donor age, induction therapy, CTGFti >10%, and CTGFu. These results suggest that, even in patients with favorable histology at 3 months, significant CTGF expression is often present which may predict accelerated accumulation of histologic damage.

Proteinuria as a Noninvasive Marker for Renal Allograft Histology and Failure: An Observational Cohort Study.

Proteinuria is routinely measured to assess renal allograft status, but the diagnostic and prognostic values of this measurement for renal transplant pathology and outcome remain unclear. We included 1518 renal allograft recipients in this prospective, observational cohort study. All renal allograft biopsy samples with concomitant data on 24-hour proteinuria were included in the analyses (n=2274). Patients were followed for ≥7 years post-transplantation. Compared with proteinuria <0.3 g/24 h, the hazard ratios for graft failure were 1.14 (95% confidence interval [95% CI], 0.81 to 1.60; P=0.50), for proteinuria 0.3-1.0 g/24 h, 2.17 (95% CI, 1.49 to 3.18; P<0.001), for proteinuria 1.0-3.0 g/24 h, and 3.01 (95% CI, 1.75 to 5.18; P<0.001), for proteinuria >3.0 g/24 h, independent of GFR and allograft histology. The predictive performance of proteinuria for graft failure was lower at 3 months after transplant (area under the receiver-operating characteristic curve [AUC] 0.64, P<0.001) than at 1, 2, and 5 years after transplant (AUC 0.73, 0.71, and 0.77, respectively, all P<0.001). Independent determinants of proteinuria were repeat transplantation, mean arterial pressure, transplant glomerulopathy, microcirculation inflammation, and de novo/recurrent glomerular disease. The discriminatory power of proteinuria for these intragraft injury processes was better in biopsy samples obtained >3 months after transplant (AUC 0.73, P<0.001) than in those obtained earlier (AUC 0.56, P<0.01), with 85% specificity but lower sensitivity (47.8%) for proteinuria >1.0 g/24 h. These data support current clinical guidelines to routinely measure proteinuria after transplant, but illustrate the need for more sensitive biomarkers of allograft injury and prognosis.

Clinical determinants of calcineurin inhibitor disposition: a mechanistic review.

The calcineurin inhibitors (CNIs) tacrolimus and cyclosporine are widely used immunosuppressive drugs characterized by high pharmacokinetic and pharmacodynamic variability, both between and within patients. CNIs are highly lipophilic, poorly soluble, undergo extensive first-pass metabolism and are cleared by the liver. In both gut and liver, CNIs are substrates for the cytochrome P450 (CYP) enzymes 3A4 and 3A5 as well as the P-glycoprotein (P-gp) transporter, whose functions are determined by a complex interplay between genetic polymorphisms, the inductive or inhibitory effects of many drugs, herbs, food constituents and endogenous substances such as uremic toxins in case of end-stage renal disease. The current literature is reviewed for all common clinical determinants of variability in CNI disposition such as food intake, diarrhea and other intestinal pathology, anemia, hypoalbuminemia, hyperlipidemia, liver and kidney disease, aging, ethnicity, formulation and time post-transplant, focusing on the underlying mechanisms. Drugs and herb- and food constituents mainly interact with CNIs at the gut level by affecting bioavailability, with interactions generally being much more pronounced in case of oral compared with intravenous co-administration. Cyclosporine disposition is less susceptible to these interactions compared with tacrolimus, possibly because cyclosporine is itself a moderately strong CYP3A4- and strong P-gp inhibitor, blunting the effect of additional inhibitors. P-gp also has a major role in limiting distribution of CNI to tissues such as the brain, placenta, lymphocytes and kidney. Inactivating polymorphisms and inhibition of P-gp have the potential to significantly increase CNI exposure in these tissues with possible implications for toxicity and efficacy.

Comparative performance of oral midazolam clearance and plasma 4ß-hydroxycholesterol to explain interindividual variability in tacrolimus clearance.

AIMS: We compared the CYP3A4 metrics weight-corrected midazolam apparent oral clearance (MDZ Cl/F/W) and plasma 4ß-hydroxycholesterol/cholesterol (4ß-OHC/C) as they relate to tacrolimus (TAC) Cl/F/W in renal transplant recipients. METHODS: For a cohort of 147 patients, 8 h area under the curve (AUC) values for TAC and oral MDZ were calculated besides measurement of 4ß-OHC/C. A subgroup of 70 patients additionally underwent intravenous erythromycin breath test (EBT) and were administered the intravenous MDZ probe. All patients were genotyped for common polymorphisms in CYP3A4, CYP3A5 and P450 oxidoreductase, among others. RESULTS: MDZ Cl/F/W, 4ß-OHC/C/W, EBT and TAC Cl/F/W were all moderately correlated (r = 0.262-0.505). Neither MDZ Cl/F/W nor 4ß-OHC/C/W explained variability in TAC Cl/F/W in CYP3A5 expressors (n = 29). For CYP3A5 non-expressors (n = 118), factors explaining variability in TAC Cl/F/W in a MDZ-based model were MDZ Cl/F/W (R2  = 0.201), haematocrit (R2  = 0.139), TAC formulation (R2  = 0.107) and age (R2  = 0.032; total R2  = 0.479). In the 4ß-OHC/C/W-based model, predictors were 4ß-OHC/C/W (R2  = 0.196), haematocrit (R2  = 0.059) and age (R2  = 0.057; total R2  = 0.312). When genotype information was ignored, predictors of TAC Cl/F/W in the whole cohort were 4ß-OHC/C/W (R2  = 0.167), MDZ Cl/F/W (R2  = 0.045); Tac QD formulation (R2  = 0.036), and haematocrit (R2  = 0.032; total R2  = 0.315). 4ß-OHC/C/W, but not MDZ Cl/F/W, was higher in CYP3A5 expressors because it was higher in CYP3A4*1b carriers, which were almost all CYP3A5 expressors. CONCLUSIONS: A MDZ-based model explained more variability in TAC clearance in CYP3A5 non-expressors. However, 4ß-OHC/C/W was superior in a model in which no genotype information was available, likely because 4ß-OHC/C/W was influenced by the CYP3A4*1b polymorphism.

Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit.

AIMS: The long-term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose-corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated in vivo. METHODS: Sixty-five tacrolimus- and 10 cyclosporine-treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8-h area under the concentration-time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes. RESULTS: Tacrolimus clearance decreased gradually throughout the entire first year but only in CYP3A5*3/*3 homozygous recipients (25.6 ± 11.1 l h(-1) at day 7; 17 ± 9.1 l h(-1) at month 12; P < 0.001). In mixed model analysis, decreasing CYP3A4 activity, measured by apparent oral MDZ clearance (924 ± 443 ml min(-1) at day 7 vs. 730 ± 344 ml min(-1) at month 1; P < 0.001), explained 55.4% of the decline in tacrolimus clearance in the first month. CYP3A4 activity decreased by 18.9 ml min(-1) for every milligram of methylprednisolone dose tapering within the first month; beyond this point it remained stable. A gradual rise in haematocrit throughout the entire first year explained 31.7% of the decrease in tacrolimus clearance in the first month and 23.6% of the decrease between months 1 and 12. Cyclosporine clearance did not change over time. CONCLUSIONS: The maturation of tacrolimus disposition in the first year after renal transplantation observed in CYP3A5*3/*3 homozygous patients can partly be explained by a (steroid tapering-related) decline in CYP3A4 activity and a progressive increase in haematocrit.

Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients.

AIM: In a cohort of 298 de-novo renal recipients treated with a standard tacrolimus loading dose of 0.2 mg/kg, the combined effects of the CYP3A5*1, POR*28, and CYP3A4*22 genotypes on early tacrolimus exposure (C0), dose requirements, and achievement of the therapeutic target, C0, were examined. The incidence of clinical events (e.g. acute rejection, diabetes mellitus) was compared between genotypes. RESULTS: Fast metabolizers (CYP3A5*1/POR*28T carriers) had two-fold to three-fold higher tacrolimus dose requirements compared with slow metabolizers (CYP3A5*3/*3/CYP3A4*22 carriers) and needed significantly more time to achieve the target tacrolimus C0 of a minimum 10 ng/ml (3.3±1.7 vs. 1.34±0.75 days; P<0.0001). No differences in acute rejection incidence and time to first rejection were observed. Slow metabolizers more frequently had tacrolimus C0 above the target range early after transplantation (70 vs. 13% on day 3); however, this did not translate into a higher incidence of post-transplantation diabetes mellitus or graft dysfunction. Multivariate analyses identified the CYP3A5*1/POR*28/CYP3A4*22 genotype combination as the single strongest determinant of tacrolimus dose requirements throughout the first year, explaining between 24-40% of its variability, whereas recipient age, hematocrit, and delayed graft function were additional nongenetic determinants of tacrolimus dose. CONCLUSION: Combining the CYP3A5*1, POR*28 and CYP3A4*22 genotypes allows partial differentiation of early tacrolimus dose requirements and the time to reach therapeutic target concentrations after transplantation, but without obvious clinical implications. Larger prospective studies need to address the clinical relevance of early combined genotype-based tacrolimus dosing in de-novo renal recipients.

Genetic polymorphisms in IL-2, IL-10, TGF-ß1, and IL-2RB and acute rejection in renal transplant patients.

Acute rejection (AR) remains a concern for kidney transplantation. Cytokines are key mediators in the induction and effector phases of all immune and inflammatory responses. Single nucleotide polymorphisms (SNPs) in cytokines and their receptors may relate to AR. We investigated the relation between AR and SNPs in the genes encoding for IL-2(-330G>T), IL-10(-592C>A and -1082G>A), TGF-ß1(915G>C), and IL-2RB(rs228942 C>A and rs228953 C>T) in 325 renal transplant patients during the first year after transplantation. The overall incidence of AR was 15.4%. In multivariate analysis, only the use of induction therapy was correlated with AR (odds ratio 1.9; 95% confidence interval 1.1-3.7; p = 0.04). No statistically significant associations between the SNPs studied and AR were observed. SNPs in the investigated cytokines and their receptors were not associated with the risk of AR. Genotyping patients for these SNPs is unlikely to aid the clinician in adjusting the immunosuppressive therapy for individual patients.

Impact of POR*28 on the pharmacokinetics of tacrolimus and cyclosporine A in renal transplant patients.

BACKGROUND: The P450 oxidoreductase (POR)*28 variant allele has been associated with altered cytochrome P450 3A enzyme activities. Both CYP3A5 and CYP3A4 are involved in the metabolism of calcineurin inhibitors and recent data show that POR*28 may explain part of the variability observed in tacrolimus (Tac) pharmacokinetics. The aim of this study was to investigate the impact of the POR*28 allele on Tac and cyclosporine A (CsA) immunosuppressive therapies. METHODS: Kidney transplant recipients receiving either Tac (n = 184) or CsA (n = 174), participating in a prospective multicenter trial, were genotyped for POR*28, CYP3A4*22, and CYP3A5*3. RESULTS: CYP3A5 expressers that were carriers of at least 1 POR*28 allele had a 16.9% decrease in dose-adjusted predose concentrations when compared CYP3A5 expressers that carried the POR*1/*1 genotype (P = 0.03), indicating an increased CYP3A5 activity for POR*28 carriers. In CYP3A5, nonexpressers carrying 2 POR*28 alleles, a 24.1% (confidence interval95% = -39.4% to -4.9%; P = 0.02) decrease in dose-adjusted predose concentrations was observed for Tac, suggesting higher CYP3A4 activity. For CsA, POR*28/*28 patients not expressing CYP3A5 and not carrying the CYP3A4*22 decrease-of-function allele showed 15% lower CsA dose-adjusted predose concentrations (P = 0.01), indicating also increased CYP3A4 activity. In both cohorts (ie, Tac and CsA), the POR*28 allele was neither associated with the incidence of delayed graft function nor with biopsy-proven acute rejection. These results were further confirmed in 2 independent cohorts. CONCLUSIONS: Our results show that the POR*28 allele is associated with increased in vivo CYP3A5 activity for Tac in CYP3A5 expressers, whereas POR*28 homozygosity was associated with a significant higher CYP3A4 activity in CYP3A5 nonexpressers for both Tac and CsA.

Impact of Immunosenescence in Older Kidney Transplant Recipients: Associated Clinical Outcomes and Possible Risk Stratification for Immunosuppression Reduction.

The number of older individuals receiving a kidney transplant as replacement therapy has significantly increased in the past decades and this increase is expected to continue. Older patients have a lower rate of acute rejection but an increased incidence of death with a functioning graft. Several factors, including an increased incidence of infections, post-transplant malignancy and cardiovascular comorbidity and mortality, contribute to this increased risk. Notwithstanding, kidney transplantation is still the best form of kidney replacement therapy in all patients with chronic kidney disease, including in older individuals. The best form of immunosuppression and the optimal dose of these medications in older recipients remains a topic of discussion. Pharmacological studies have usually excluded older patients and when included, patients were highly selected and their numbers insignificant to draw a reasonable conclusion. The reduced incidence of acute rejection in older recipients has largely been attributed to immunosenescence. Immunosenescence refers to the aging of the innate and adaptive immunity, accumulating in phenotypic and functional changes. These changes influences the response of the immune system to new challenges. In older individuals, immunosenescence is associated with increased susceptibility to infectious pathogens, a decreased response after vaccinations, increased risk of malignancies and cardiovascular morbidity and mortality. Chronic kidney disease is associated with premature immunosenescent changes, and these are independent of aging. The immunosenescent state is associated with low-grade sterile inflammation termed inflammaging. This chronic low-grade inflammation triggers a compensatory immunosuppressive state to avoid further tissue damage, leaving older individuals with chronic kidney disease in an immune-impaired state before kidney transplantation. Immunosuppression after transplantation may further enhance progression of this immunosenescent state. This review covers the role of immunosenescence in older kidney transplant recipients and it details present knowledge of the changes in chronic kidney disease and after transplantation. The impact of immunosuppression on the progression and complications of an immunosenescent state are discussed, and the future direction of a possible clinical implementation of immunosenescence to individualize/reduce immunosuppression in older recipients is laid out.

A Machine Learning-Driven Virtual Biopsy System For Kidney Transplant Patients.

In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate between donor-inherited lesions and those acquired post-transplantation. However, many centers do not perform such biopsies since they are invasive, costly and may delay the transplant procedure. We aim to generate a non-invasive virtual biopsy system using routinely collected donor parameters. Using 14,032 day-zero kidney biopsies from 17 international centers, we develop a virtual biopsy system. 11 basic donor parameters are used to predict four Banff kidney lesions: arteriosclerosis, arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, and the percentage of renal sclerotic glomeruli. Six machine learning models are aggregated into an ensemble model. The virtual biopsy system shows good performance in the internal and external validation sets. We confirm the generalizability of the system in various scenarios. This system could assist physicians in assessing organ quality, optimizing allograft allocation together with discriminating between donor derived and acquired lesions post-transplantation.