Consequences of Nephrotic Proteinuria and Nephrotic Syndrome after Kidney Transplant.

Proteinuria is the main predictor of kidney graft loss. However, there is little information regarding the consequences of nephrotic proteinuria (NP) and nephrotic syndrome (NS) after a kidney transplant. We aimed to describe the clinical and histopathological characteristics of kidney recipients with nephrotic-range proteinuria and compare the graft surveillance between those who developed NS and those who did not. A total of 204 patients (18.6% of kidney transplants in the study period) developed NP, and 68.1% of them had NS. Of the 110 patients who underwent a graft biopsy, 47.3% exhibited ABMR, 21.8% the recurrence of glomerulonephritis, 9.1% IFTA, and 7.3% de novo glomerulonephritis. After a median follow-up of 97.5 months, 64.1% experienced graft loss. The graft survival after the onset of NP declined from 75.8% at 12 months to 38% at 5 years, without significant differences between those with and those without NS. Patients who developed NS fewer than 3 months after the onset of NP exhibited a significantly higher risk of death-censored graft loss (HR: 1.711, 95% CI: 1.147-2.553) than those without NS or those with late NS. In conclusion, NP and NS are frequent conditions after a kidney transplant, and they imply extremely poor graft outcomes. The time from the onset of NP to the development of NS is related to graft survival.

Donor-Derived Cell-Free DNA at 1 Month after Kidney Transplantation Relates to HLA Class II Eplet Mismatch Load.

Kidney transplantation is the preferred therapeutic option for end-stage renal disease; however, the alloimmune response is still the leading cause of renal allograft failure. To better identify immunologic disparities in order to evaluate HLA compatibility between the donor and the recipient, the concept of eplet load has arisen. Regular kidney function monitoring is essential for the accurate and timely diagnosis of allograft rejection and the appropriate treatment. Donor-derived cell-free DNA (dd-cfDNA) has been proposed as a potential biomarker of acute rejection and graft failure in kidney transplantation. The proportion of plasma dd-cfDNA was determined in forty-two kidney patients at 1 month after transplantation. A total of eleven (26.2%) patients had a dd-cfDNA proportion of ≥1.0%. The only pretransplant variable related to dd-cfDNA > 1.0% was the HLA class II eplet mismatch load, mainly the HLA-DQB1 eplet mismatch load. Furthermore, dd-cfDNA was able to discriminate the patients with antibody-mediated rejection (AbMR) (AUC 87.3%), acute rejection (AUC 78.2%), and troubled graft (AUC 81.4%). Increased dd-cfDNA levels were associated with kidney allograft deterioration, particularly rejection, as well as a greater HLA class II eplet mismatch load. Consequently, combining dd-cfDNA determination and HLA eplet mismatch load calculation should improve the assessment of the risk of short- and long-term allograft damage.

Management of immunosuppressive therapy in kidney transplant recipients with COVID-19. A multicentre national study derived from the Spanish Society of Nephrology COVID registry.

INTRODUCTION: SARS CoV2 infection has had a major impact on renal transplant patients with a high mortality in the first months of the pandemic. Intentional reduction of immunosuppressive therapy has been postulated as one of the cornerstone in the management of the infection in the absence of targeted antiviral treatment. This has been modified according to the patient`s clinical situation and its effect on renal function or anti-HLA antibodies in the medium term has not been evaluated. OBJECTIVES: Evaluate the management of immunosuppressive therapy made during SARS-CoV2 infection, as well as renal function and anti-HLA antibodies in kidney transplant patients 6 months after COVID19 diagnosis. MATERIAL AND METHODS: Retrospective, national multicentre, retrospective study (30 centres) of kidney transplant recipients with COVID19 from 01/02/20 to 31/12/20. Clinical variables were collected from medical records and included in an anonymised database. SPSS statistical software was used for data analysis. RESULTS: renal transplant recipients with COVID19 were included (62.6% male), with a mean age of 57.5 years. The predominant immunosuppressive treatment prior to COVID19 was triple therapy with prednisone, tacrolimus and mycophenolic acid (54.6%) followed by m-TOR inhibitor regimens (18.6%). After diagnosis of infection, mycophenolic acid was discontinued in 73.8% of patients, m-TOR inhibitor in 41.4%, tacrolimus in 10.5% and cyclosporin A in 10%. In turn, 26.9% received dexamethasone and 50.9% were started on or had their baseline prednisone dose increased. Mean creatinine before diagnosis of COVID19, at diagnosis and at 6 months was: 1.7 ±â€¯0.8, 2.1 ±â€¯1.2 and 1.8 ±â€¯1 mg/dl respectively (p < 0.001). 56.9% of the patients (N = 350) were monitored for anti-HLA antibodies. 94% (N = 329) had no anti-HLA changes, while 6% (N = 21) had positive anti-HLA antibodies. Among the patients with donor-specific antibodies post-COVID19 (N = 9), 7 patients (3.1%) had one immunosuppressant discontinued (5 patients had mycophenolic acid and 2 had tacrolimus), 1 patient had both immunosuppressants discontinued (3.4%) and 1 patient had no change in immunosuppression (1.1%), these differences were not significant. CONCLUSIONS: The management of immunosuppressive therapy after diagnosis of COVID19 was primarily based on discontinuation of mycophenolic acid with very discrete reductions or discontinuations of calcineurin inhibitors. This immunosuppression management did not influence renal function or changes in anti-HLA antibodies 6 months after diagnosis.

Torque Teno Virus Load Predicts Opportunistic Infections after Kidney Transplantation but Is Not Associated with Maintenance Immunosuppression Exposure.

Measuring the non-pathogenic Torque Teno Virus (TTV) load allows assessing the net immunosuppressive state after kidney transplantation (KTx). Currently, it is not known how exposure to maintenance immunosuppression affects TTV load. We hypothesized that TTV load is associated with the exposure to mycophenolic acid (MPA) and tacrolimus. We performed a prospective study including 54 consecutive KTx. Blood TTV load was measured by an in-house PCR at months 1 and 3. Together with doses and trough blood levels of tacrolimus and MPA, we calculated the coefficient of variability (CV), time in therapeutic range (TTR) and concentration/dose ratio (C/D) of tacrolimus, and the MPA-area under the curve (AUC-MPA) at the third month. TTV load at the first and third month discriminated those patients at risk of developing opportunistic infections between months 1 and 3 (AUC-ROC 0.723, 95%CI 0.559-0.905, p = 0.023) and between months 3 and 6 (AUC-ROC 0.778, 95%CI 0.599-0.957, p = 0.028), respectively, but not those at risk of acute rejection. TTV load did not relate to mean tacrolimus blood level, CV, TTR, C/D and AUC-MPA. To conclude, although TTV is a useful marker of net immunosuppressive status after KTx, it is not related to exposure to maintenance immunosuppression.

Recurrence of immune complex and complement-mediated membranoproliferative glomerulonephritis in kidney transplantation.

INTRODUCTION: Membranoproliferative glomerulonephritis (MPGN) represents a histologic pattern of glomerular injury that may be due to several aetiologies. Few studies have comprehensively analysed the recurrence of MPGN according to the current classification system. METHODS: We collected a multicentre, retrospective cohort of 220 kidney graft recipients with biopsy-proven native kidney disease due to MPGN between 1981 and 2021 in 11 hospitals. Demographic, clinical and histologic parameters of prognostic interest were collected. The main outcomes were time to kidney failure, time to recurrence of MPGN and disease remission after recurrence. RESULTS: The study group included 34 complement-mediated and 186 immune complex-mediated MPGN. A total of 81 patients (37%) reached kidney failure in a median follow-up of 79 months. The main predictors of this event were the development of rejection episodes and disease recurrence. In all, 54 patients (25%) had a disease recurrence in a median of 16 months after kidney transplantation. The incidence of recurrence was higher in patients with dysproteinaemia (67%) and complement-mediated MPGN (62%). In the multivariable model, complement-mediated MPGN emerged as a predictor of recurrence. A total of 33 patients reached kidney failure after recurrence. The main determinants of no remission were early time to recurrence (<15 months), estimated glomerular filtration rate <30 mL/min/1.73 m2 and serum albumin <3.5 g/dL at the time of recurrence. CONCLUSIONS: One-fourth of the patients with native kidney disease due to MPGN developed clinical recurrence in the allograft, especially in cases with complement-mediated disease or in those associated with dysproteinaemia. The kidney outcomes of disease recurrence with currently available therapies are heterogeneous and thus more effective and individualized therapies are needed.

Lower Time in Therapeutic Range Relates to a Worse Kidney Graft Outcome.

Tacrolimus has a narrow therapeutic margin. Maintaining tacrolimus blood levels in the appropriate range is difficult because of its intrapatient variability. In fact, greater blood level variability has been related to worse kidney graft outcome, but only measuring variability does not consider the therapeutic range goal. Determining the time in therapeutic range (TTR) using the Rosendaal method allows dose optimization by considering the adverse events associated with both supratherapeutic and subtherapeutic doses. Some previous studies in kidney and lung transplantation have shown that the measurement of TTR has been related to the subsequent graft outcome. We performed a single-center, observational study including 215 consecutive kidney transplants performed in our center. The percentage of time that the patient remained with levels above 6 ng/mL between months 3 and 12 (%TTR3-12) was calculated using the Rosendaal method. A lower %TTR3-12 was associated with a higher risk of acute rejection (area under the receiver operating characteristic curve, 0.614; 95% confidence interval [CI], 0.513-0.714; P = .018) and with a higher risk of having a 1-year glomerular filtration rate < 30 mL/min/1.73 m2 (area under the receiver operating characteristic curve, 0.676; 95% CI, 0.542-0.811; P = .014). The lowest tertile of %TTR3-12 was independently associated with a higher risk of death-censored graft loss (hazard ratio, 10.773; 95% CI, 1.315-88.264; P = .027) after adjusting by 1-year glomerular filtration rate, expanded criteria donation, and acute rejection throughout the first year. To conclude, measuring TTR after kidney transplant is an easy way to estimate the time of exposure to adequate levels of tacrolimus and relates to kidney graft outcome.

[Management of immunosuppressive therapy in kidney transplant recipients with COVID19. A multicentre national study derived form the S.E.N. COVID registry.] / Manejo de la inmunosupresión en pacientes trasplantados de riñón con COVID19. Estudio multicéntrico nacional derivado del registro COVID de la S.E.N.

INTRODUCTION: SARS CoV2 infection has had a major impact on renal transplant patients with a high mortality in the first months of the pandemic. Intentional reduction of immunosuppressive therapy has been postulated as one of the cornerstone in the management of the infection in the absence of targeted antiviral treatment. This has been modified according to the patient`s clinical situation and its effect on renal function or anti-HLA antibodies in the medium term has not been evaluated. OBJECTIVES: Evaluate the management of immunosuppressive therapy made during SARS-CoV2 infection, as well as renal function and anti-HLA antibodies in kidney transplant patients 6 months after COVID19 diagnosis. MATERIAL AND METHODS: Retrospective, national multicentre, retrospective study (30 centres) of kidney transplant recipients with COVID19 from 01/02/20 to 31/12/20. Clinical variables were collected from medical records and included in an anonymised database. SPSS statistical software was used for data analysis. RESULTS: 615 renal transplant recipients with COVID19 were included (62.6% male), with a mean age of 57.5 years.The predominant immunosuppressive treatment prior to COVID19 was triple therapy with prednisone, tacrolimus and mycophenolic acid (54.6%) followed by m-TOR inhibitor regimens (18.6%). After diagnosis of infection, mycophenolic acid was discontinued in 73.8% of patients, m-TOR inhibitor in 41.4%, tacrolimus in 10.5% and cyclosporin A in 10%. In turn, 26.9% received dexamethasone and 50.9% were started on or had their baseline prednisone dose increased.Mean creatinine before diagnosis of COVID19, at diagnosis and at 6 months was: 1.7±0.8, 2.1±1.2 and 1.8±1 mg/dl respectively (p<0.001).56.9% of the patients (N=350) were monitored for anti-HLA antibodies. 94% (N=329) had no anti-HLA changes, while 6% (N=21) had positive anti-HLA antibodies. Among the patients with donor-specific antibodies post-COVID19 (N=9), 7 patients (3.1%) had one immunosuppressant discontinued (5 patients had mycophenolic acid and 2 had tacrolimus), 1 patient had both immunosuppressants discontinued (3.4%) and 1 patient had no change in immunosuppression (1.1%), these differences were not significant. CONCLUSIONS: The management of immunosuppressive therapy after diagnosis of COVID19 was primarily based on discontinuation of mycophenolic acid with very discrete reductions or discontinuations of calcineurin inhibitors. This immunosuppression management did not influence renal function or changes in anti-HLA antibodies 6 months after diagnosis.

Urinary CXCL10 specifically relates to HLA-DQ eplet mismatch load in kidney transplant recipients.

BACKGROUND: Urinary CXCL10 (uCXCL10) is associated with graft inflammation and graft survival, but the factors related to its excretion are not well known. HLA molecular matching at epitope level allow estimating the "dissimilarity" between donor and recipient HLA more precisely, being better related to further transplant outcomes. The relationship between uCXCL10 and HLA molecular mismatch has not been previously explored. METHODS: HLA class I and class II typing of some 65 recipients and their donors was retrospectively performed by high resolution sequence-specific-primer (Life Technologies, Brown Deer, WI). The HLA-Matchmaker 3.1 software was used to assess eplet matching. Urine samples collected on the day of the 1-year surveillance biopsy were available of these 65 patients. uCXCL10 was measured using a commercial enzyme-linked immunoassay kit. RESULTS: 1-year uCXCL10 was independently associated with HLA-DQB1 eplet mismatch load (ß 0.300, 95%CI 0.010-0.058, p = 0.006). Kidney transplant recipients with a HLA-DQB1 eplet mismatch load >3 showed higher values of uCXCL10 at 1-year (p = 0.018) than those with ≤3. Patients with a HLA-DQB1 eplet mismatch load >3 with subclinical AbMR had significantly higher levels of the logarithm of 1-year uCXCL10 (No AbMR 0.88, IQR 0.37; AbMR 1.38, IQR 0.34, p = 0.002) than those without AbMR. CONCLUSIONS: uCXCL10 specifically relates to HLA-DQ eplet mismatch load. This relationship can partly explain the previously reported association between uCXCL10 excretion and graft inflammation. An adequate evaluation of any potential non-invasive biomarker, such as uCXCL10, must take into account the HLA molecular mismatch.

Controlled Donation After Circulatory Death Using Normothermic Regional Perfusion Does Not Increase Graft Fibrosis in the First Year Posttransplant Surveillance Biopsy.

OBJECTIVES: The number of kidney transplants obtained from controlled donations after circulatory death is increasing, with long-term outcomes similar to those obtained with donations after brain death. Extraction using normothermic regional perfusion can improve results with controlled donors after circulatory death; however, information on the histological impact and extraction procedure is scarce. MATERIALS AND METHODS: We retrospectively investigated all kidney transplants performed from October 2014 to December 2019, in which a follow-up kidney biopsy had been performed at 1-year follow-up, comparing controlled procedures with donors after circulatory death and normothermic regional perfusion versus donors after brain death. Interstitial fibrosis/tubular atrophy was assessed by adding the values of interstitial fibrosis and tubular atrophy, according to the Banff classification of renal allograft pathology. RESULTS: When we compared histological data from 66 transplants with donations after brain death versus 24 transplants with donations after circulatory death and normothermic regional perfusion, no differences were found in the degree of fibrosis in the 1-year follow-up biopsy (1.7 ± 1.3 vs 1.7 ± 1.1; P = .971) or in the ratio of patients with increased fibrosis calculated as interstitial fibrosis/tubular atrophy >2 (18% vs 13%; P = .522). In our multivariate analysis, which included acute rejection, expanded criteria donation, and the type of donation, no variable was independently related to an increased risk of interstitial fibrosis/tubular atrophy >2. CONCLUSIONS: The outcomes of kidney grafts procured in our center using controlled procedures with donors after circulatory death and normothermic regional perfusion were indistinguishable from those obtained from donors after brain death, showing the same degree of fibrosis in the 1-year posttransplant surveillance biopsy. Our data support the conclusion that normothermic regional perfusion should be the method of choice for extraction in donors after circulatory death.

Paternal safety of the use of mycophenolic acid in kidney transplant recipients. Results of the EMVARON study.

BACKGROUND: The use of mycophenolic acid (MPA) in women during pregnancy causes an increase in miscarriages and birth defects with a typical embryopathy profile. Although epidemiological data does not suggest a greater risk among the offspring of male kidney transplant recipients, the European Medicines Agency and The Spanish Agency of Medicines and Medical Devices introduced the recommendation of using contraceptive methods. METHODS: We conducted a national retrospective study in 15 Spanish Kidney Transplant Centers to evaluate the frequency of miscarriages and birth defects between the offspring from male kidney transplants recipients. We included 151 males who had fathered 239 offspring, 225 under MPA and 14 without MPA. RESULTS: The results of our study showed an incidence of miscarriages in the MPA group of 9.8%, and of birth defects of 4%. CONCLUSIONS: We observed an incidence of miscarriages between the offspring fathered by kidney transplant males under MPA lower than the general population. The incidence of birth defects was similar to the incidence described in other studies and the fact that we did not find the typical embryopathy profile makes it difficult to associate them to the use of MPA. Because of that, we urge the European and Spanish Agencies to reconsider their recommendations for males.

Strict selection criteria in uncontrolled donation after circulatory death provide excellent long-term kidney graft survival.

BACKGROUND: We aimed to report our experience in uncontrolled donation after circulatory death (uDCD) kidney transplantation applying a strict donor selection and preservation criteria. METHODS: All kidney recipients received a graft from a local uDCD. As controls, we included all renal transplants from local standard criteria donation after brain death (SDBD) donors. Normothermic regional perfusion was the preservation method in all cases. RESULTS: A total of 19 kidneys from uDCD donors were included and 67 controls. Delayed graft function (DGF) was higher in the uDCD group (42.1% vs 17.9%; P = .033), whereas no differences were observed in primary nonfunction (0% cases vs 3% controls; P = .605). The estimated glomerular filtration rate was identical in both groups. No differences were observed in graft survival censored for death between the uDCD and the SDBD groups at 1-year (100% vs 95%) or 5-year follow-up (92% vs 91%). uDCD kidney recipients did not have higher risk of graft loss in the multivariate analysis adjusted by recipient age, cold ischemic time, presence of DGF, and second kidney transplant (HR: 0.4; 95% CI 0.02-6; P = .509). CONCLUSIONS: Obtaining renal grafts from uDCD is feasible in a small city and provides similar outcomes compared to standard DBD donors.

Myeloid-Derived Suppressor Cells in Kidney Transplant Recipients and the Effect of Maintenance Immunotherapy.

Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of myeloid regulatory cells that were originally described in cancer. Several studies in animal models point to MDSC as important players in the induction of allograft tolerance due to their immune modulatory function. Most of the published studies have been performed in animal models, and the data addressing MDSCs in human organ transplantation are scarce. We evaluated the phenotype and function of different MDSCs subsets in 38 kidney transplant recipients (KTRs) at different time points. Our data indicate that monocytic MDSCs (Mo-MDSC) increase in KTR at 6 and 12 months posttransplantation. On the contrary, the percentages of polymorphonuclear MDSC (PMN-MDSC) and early-stage MDSC (e-MDSC) are not significantly increased. We evaluated the immunosuppressive activity of Mo-MDSC in KTR and confirmed their ability to increase regulatory T cells (Treg) in vitro. Interestingly, when we compared the ability of Mo-MDSC to suppress T cell proliferation, we observed that tacrolimus, but not rapamycin-treated KTR, was able to inhibit CD4+ T cell proliferation in vitro. This indicates that, although mTOR inhibitors are widely regarded as supportive of regulatory responses, rapamycin may impair Mo-MDSC function, and suggests that the choice of immunosuppressive therapy may determine the tolerogenic pathway and participating immune cells that promote organ transplant acceptance in KTR.

High Pretransplant BAFF Levels and B-cell Subset Polarized towards a Memory Phenotype as Predictive Biomarkers for Antibody-Mediated Rejection.

Antibody-mediated rejection (AbMR) is one of the leading causes of graft loss in kidney transplantation and B cells play an important role in the development of it. A B-cell activating factor (BAFF) is a cytokine involved in B cell ontogeny. Here, we analyzed whether B cell maturation and the effect of B cell soluble factors, such as BAFF could be involved in AbMR. Serum BAFF levels and B and T cell subpopulations were analyzed 109 kidney transplant patients before transplantation and at 6 and 12 months after kidney transplantation. Pretransplant serum BAFF levels as well as memory B cell subpopulations were significantly higher in those patients who suffered clinical AbMR during the first 12 months after kidney transplantation. Similar results were observed in the prospective analysis of patients with subclinical antibody-mediated rejection detected in the surveillance biopsy performed at 12 months after kidney transplantation. A multivariate analysis confirmed the independent role of BAFF in the development of AbMR, irrespective of other classical variables. Pretransplant serum BAFF levels could be an important non-invasive biomarker for the prediction of the development of AbMR and posttransplant increased serum BAFF levels contribute to AbMR.

Early outcomes of kidney transplantation from elderly donors after circulatory death (GEODAS study).

BACKGROUND: Spain has dramatically increased the number of controlled circulatory death donors (cDCD). The initial selection criteria for considering cDCD for kidney transplantation (KT) have been expanded progressively, with practically no limits in donor age during the last years. We aimed to analyze the early clinical outcomes using expanded (> 65 years) cDCD in comparison with standard ones. METHODS: Observational multicenter study including 19 transplant centers in Spain. We performed a systematic inclusion in a central database of every KT from expanded cDCD at each participant unit from January-2012 to January-2017. Surgical procedures and immunosuppressive protocols were based on local practices. Data was analyzed in the central office using logistic and Cox regression or competitive-risk models for multivariate analysis. Median time of follow-up was 18.1 months. RESULTS: 561 KT were performed with kidneys from cDCD, 135 from donors older than 65 years. As expected, recipients from older cDCD were also older (65.8 (SD 8.8) vs 53.7 (SD 11.4) years; p < 0.001) and with higher comorbidity. At 1 year, no differences were found amongst older and younger cDCD KT recipients in terms of serum creatinine (1.6 (SD 0.7) vs 1.5 (SD 0.8) mg/dl; p = 0.29). Non-death censored graft survival was inferior, but death-censored graft survival was not different (95.5 vs 98.2% respectively; p = 0.481). They also presented a trend towards higher delayed graft function (55.4 vs 46.7%; p = 0.09) but a similar rate of primary non-function (3.7 vs 3.1%; p = 0.71), and acute rejection (3.0 vs 6.3%; p = 0.135). In the multivariate analysis, in short follow-up, donor age was not related with worse survival or poor kidney function (eGFR < 30 ml/min). CONCLUSIONS: The use of kidneys from expanded cDCD is increasing for older and comorbid patients. Short-term graft outcomes are similar for expanded and standard cDCD, so they constitute a good-enough source of kidneys to improve the options of KT wait-listed patients.

The Polymorphism -308G/A of Tumor Necrosis Factor-α Gene Modulates the Effect of Immunosuppressive Treatment in First Kidney Transplant Subjects Who Suffer an Acute Rejection.

The -308G/A SNP of tumor necrosis factor-alpha (TNF-α) gene affects TNF-α production. As its impact on transplant outcome remains open to debate, we decided to genotype it in a cohort of transplant subjects. A retrospective analysis of 439 first kidney recipients randomly divided into two subgroups (discovery and validation cohorts) was performed to identify the best predictors of acute rejection (AR). The effect on transplant outcome was analyzed by an adjusted logistic regression model. Carriers of the A allele, associated with elevated TNF-α production, presented a higher risk of AR (OR = 2.78; 95% CI = 1.40-5.51). Logistic regression analyses for AR showed an interaction between the polymorphism and treatment with thymoglobulin (p-interaction = 0.03). In recipients who did not receive thymoglobulin, carriers of A allele had higher risk of AR (OR = 4.05; 95% CI = 1.76-9.28). Moreover, carriers of A allele not treated with thymoglobulin presented higher risk of AR than those who received thymoglobulin (OR = 13.74; 95% CI = 1.59-118.7). The AUC of the model in the discovery cohort was 0.70 and in the validation cohort was 0.69. Our findings indicate that the -308G/A TNF-α polymorphism is associated with AR risk and it modulates the effectiveness of thymoglobulin treatment. This pharmacogenetic effect lets us propose this SNP as a useful predictor biomarker to tailor immunosuppressive regimens.

Serum level of fibroblast growth factor 23 in maintenance renal transplant patients.

BACKGROUND: The discovery of fibroblast growth factor 23 (FGF23) provides a new conceptual framework that improves our understanding of the pathogenesis of post-transplant bone disease. Excess FGF23 is produced in the early post-transplant period; levels return to normal in the months following transplant. However, few manuscripts discuss FGF23 levels in stable long-term renal transplant recipients. METHODS: We performed a cross-sectional observational study of 279 maintenance kidney recipients with chronic kidney disease (CKD) Stages 1-4 and stable allograft function who had received their transplant at least 12 months previously. We calculated the estimated GFR (eGFR) using the MDRD4 equation. RESULTS: FGF23, parathyroid hormone (PTH) and phosphorus values were higher in more advanced stages, while the serum calcitriol levels and the phosphate reabsorption rate were lower. A significant inverse correlation was found between eGFR and FGF23 (r = -0.487; P < 0.001), PTH (r = -0.444; P < 0.001), serum phosphate levels (r = -0.315; P < 0.001) and fractional excretion of magnesium (r = -0.503; P < 0.001). Multivariable analysis showed that increased time on corticosteroids (P < 0.001), PTH (P < 0.001), serum phosphate (P = 0.003), decreased serum calcitriol (P = 0.049) and estimated glomerular filtration (P = 0.003) rate were associated with high FGF23 levels. In contrast with pre-transplant patients and first year post-transplant patients, higher FGF23 values were not correlated with increased phosphate excretion. An elevated phosphate reabsorption rate was associated with decreased PTH (P < 0.001) and calciuria (P = 0.028) and increased serum calcitriol (P = 0.009), plasma bicarbonate (P = 0.024) and estimated glomerular filtration (P = 0.003). CONCLUSIONS: Serum FGF23 concentrations remain increased in long-term kidney graft recipients, even in the early stages of CKD. It remains to be seen whether measures aimed at reducing serum levels of PTH and phosphate and/or corticosteroid doses might help to lower serum FGF23 and whether this will improve kidney recipient outcomes.

Limited-sampling strategy for mycophenolic acid in renal transplant recipients reciving enteric-coated mycophenolate sodium and tacrolimus.

BACKGROUND: Substantial research has been conducted to develop limited-sampling strategies (LSS) to estimate the area under the curve (AUC(0-12h)) in patients treated with mycophenolate mofetil. However, no LSS has been validated for enteric-coated mycophenolate sodium (EC-MPS). Our aim was to develop an LSS to measure the AUC(0-12h) of mycophenolic acid in kidney recipients treated with tacrolimus and EC-MPS. STUDY DESIGN: Thirteen serial blood samples were collected over 12 hours from 71 patients treated with tacrolimus and EC-MPS. Mycophenolic acid was measured in plasma using the enzyme-multiplied immunoassay. LSSs were developed and validated by multiple regression analysis using a 2-group method (test, n = 47; validation, n = 24). RESULTS: The best LSS obtained in the test group were for 3 and 4 time points AUC(0-12h) (mg·h(-1)·L(-1)) = 15.99 + 0.87C1 h + 0.68C2 h + 7.85C4 h and AUC(0-12h) (mg·h(-1)·L(-1)) =11.15 + 0.68C1 h + 0.45C1.5 h + 0.57C2 h + 8.16C4 h, respectively. When these LSS were tested in the validation group, the results were acceptable (adjusted r(2) = 0.71, bias =-0.214 [95% confidence interval (CI): -7.91 to 7.48], precision = 7.48 (95% CI: 3.69-19.39) for 3 time points and adjusted r(2) = 0.76, bias = -1.48 (95% CI: -8.23 to 5.27), precision = 7.68 (95% CI: 4.23-13.50) for 4 time points). CONCLUSIONS: : An LSS using time points at C(1h)-C(2h)-C(4h) or C(1h)-C(1.5h)-C(2h)-C(4h) provides the most reliable and accurate estimation of the AUC(0-12h) of mycophenolic acid in stable renal transplant recipients treated with EC-MPS and tacrolimus.

Intracellular ATP concentrations of CD4 cells in kidney transplant patients with and without infection.

In the field of organ transplantation, overimmunosuppression is associated with severe side effects, such as infection, drug toxicity, and cancer, whereas underimmunosuppression is associated with acute rejection. Intracellular adenosine triphosphate (iATP) concentration following CD4 cell activation provides an assessment of cellular immune function to help monitor the immune status of immunosuppressed patients. This assay has shown to be the first post-transplant test related not only to the risk of acute rejection but also with the appearance of infection. The aim of our study was to compare the iATP concentrations of CD4 cells between healthy adults and kidney transplant recipients from a European population, analyzing the differences according to transplant clinical status. Samples from 81 kidney transplant patients who were admitted to our hospital over a nine-month period were drawn. T-cell activation was measured by determining the increase of iATP from CD4 cells. Results were compared with patient clinical status (rejection, infection, and stability). Three patients suffered an acute rejection episode and they were not included in the analysis (mean iATP concentration 247 +/- 87 ng/mL). iATP concentrations differed significantly between stable and infected patients (313 +/- 193 vs. 197 +/- 114 ng/mL; p = 0.008). iATP concentration values were not related to the length of admission, age, peak and current panel reactive antibodies, mismatches, leukocytes, weight, creatinine, days after transplantation and blood levels of cyclosporin, tacrolimus, and sirolimus. This assay measures global immune responses of CD4 T cells from a whole-blood sample, allowing for the assessment of the impact of immuno- suppressive drugs and of the patient's underlying clinical conditions. This assay identifies transplant patients at risk for infection or rejection, providing information which can guide immunosuppressive therapy.

New-onset diabetes after kidney transplantation: risk factors.

New-onset diabetes after transplantation (NODAT) contributes to the risk for cardiovascular disease and infection, reducing graft and patient survival. For improvement of the outcome of kidney transplant recipients, it is of great interest to know precisely the risk factors that contribute to NODAT development. Nonmodifiable risk factors for development of NODAT are age, race, genetic background, family history of diabetes, and previous glucose intolerance. Modifiable risk factors are obesity and overweight, hepatitis C virus and cytomegalovirus infections, and immunosuppressive drugs. Both steroids and calcineurin inhibitors influence the appearance of NODAT, whereas the role of sirolimus in glucose metabolism currently is controversial.