Time trends in preemptive kidney transplantation in Europe: an era registry study.

BACKGROUND: Preemptive kidney transplantation has better outcomes when compared to transplantation after dialysis. We aimed to examine trends in preemptive kidney transplantation between 2000 and 2019 in Europe and to provide an overview of associated policies, barriers and initiatives. METHODS: Adult patients from 12 European countries who received a preemptive kidney transplant were included. The representatives of the registries providing these data were questioned on the policies, barriers and initiatives around preemptive kidney transplantation. RESULTS: Between 2000 and 2019, 20 251 adults underwent preemptive kidney transplantation (11 169 from living donors, 8937 from deceased donors). The proportion of first kidney transplantations that were preemptive more than doubled from 7% in 2000 to 18% in 2019, reflecting a similar relative increase for living donor kidney recipients (from 21% to 43%) and deceased donor kidney recipients (from 4% to 11%). Large international differences were found. The increase in preemptive kidney transplantation was observed across all age, sex and primary renal disease groups. Countries had similar criteria for preemptive waitlisting. Barriers mentioned included donor shortage, late referral to the transplant center and long donor or recipient work-up. Suggested initiatives included raising awareness on the possibility of preemptive kidney transplantation, earlier start and shorter work-up time for recipient and living donor. CONCLUSIONS: Over the last two decades the proportion of patients receiving a first kidney transplant preemptively has more than doubled, reflecting a similar relative increase for living and deceased donor kidney recipients.

Increased risk of ischaemic heart disease after kidney donation.

BACKGROUND: Previous reports suggest increased risk of hypertension and cardiovascular mortality after kidney donation. In this study we investigate the occurrence of ischaemic heart disease and cerebrovascular disease, diabetes and cancer in live kidney donors compared with healthy controls eligible for donation. METHODS: Different diagnoses were assessed in 1029 kidney donors and 16 084 controls. The diagnoses at follow-up were self-reported for the controls and registered by a physician for the donors. Stratified logistic regression was used to estimate associations with various disease outcomes, adjusted for gender, age at follow-up, smoking at baseline, body mass index at baseline, systolic blood pressure at baseline and time since the donation. RESULTS: The mean observation time was 11.3 years [standard deviation (SD) 8.1] for donors versus 16.4 years (SD 5.7) for controls. The age at follow-up was 56.1 years (SD 12.4) in donors versus 53.5 years (SD 11.1) in controls and 44% of donors were males versus 39.3% in the controls. At follow-up, 35 (3.5%) of the donors had been diagnosed with ischaemic heart disease versus 267 (1.7%) of the controls. The adjusted odds ratio for ischaemic heart disease was 1.64 (confidence interval 1.10-2.43; P = 0.01) in donors compared with controls. There were no significant differences for the risks of cerebrovascular disease, diabetes or cancer. CONCLUSIONS: During long-term follow-up of kidney donors, we found an increased risk of ischaemic heart disease compared with healthy controls. This information may be important in the follow-up and selection process of living kidney donors.

Vitamin D as a risk factor for patient survival after kidney transplantation: A prospective observational cohort study.

BACKGROUND: Short-term survival after kidney transplantation is excellent, but long-term survival remains low and is equivalent to non-end-stage renal disease patients with many invasive malignancies. The aim of the study was to explore vitamin D status in the early phase after transplantation as a prognostic marker for long-term graft and patient survival. METHODS: All first-time kidney transplant recipients between October 2007 and October 2012 in Norway were included. Vitamin D was measured 10 weeks post-transplant. Information on graft failure and death was obtained from the Norwegian Renal Registry. RESULTS: Seven hundred and sixty-two first-time kidney transplant recipients were included, with a median age of 57 years and a median follow-up of 82 months. In the follow-up period, there were 172 graft failures (23%) and 118 deaths (15%). Eighty-six percent of the transplant recipients with sufficient vitamin D levels were alive with a well-functioning graft after 5 years using Kaplan-Meier survival estimates, compared with 79% and 76% of the patients with vitamin D deficiency and insufficiency, respectively (P = 0.006). CONCLUSION: In a nation-wide cohort of 762 first-time kidney transplant recipients, long-term graft and patient survival were better in recipients with vitamin D sufficiency 10 weeks post-transplant compared with those with vitamin D deficiency and insufficiency.

Complement-Activating Anti-HLA Antibodies in Kidney Transplantation: Allograft Gene Expression Profiling and Response to Treatment.

Complement-activating anti-HLA donor-specific antibodies (DSAs) are associated with impaired kidney transplant outcome; however, whether these antibodies induce a specific rejection phenotype and influence response to therapy remains undetermined. We prospectively screened 931 kidney recipients for complement-activating DSAs and used histopathology, immunostaining, and allograft gene expression to assess rejection phenotypes. Effector cells were evaluated using in vitro human cell cultures. Additionally, we assessed the effect of complement inhibition on kidney allograft rejection phenotype and the clinical response to complement inhibition in 116 independent kidney recipients with DSAs at transplant receiving rejection prophylaxis with eculizumab or standard of care (plasma exchange and intravenous Ig) at ten international centers. The histomolecular rejection phenotype associated with complement-activating DSA was characterized by complement deposition and accumulation of natural killer cells and monocytes/macrophages in capillaries and increased expression of five biologically relevant genes (CXCL11, CCL4, MS4A7, MS4A6A, and FCGR3A) indicative of endothelial activation, IFNγ response, CD16-mediated natural killer cell activation, and monocyte/macrophage activation. Compared with standard of care, eculizumab specifically abrogated this histomolecular rejection phenotype and associated with a decreased 3-month rejection incidence rate in patients with complement-activating DSAs (56%; 95% confidence interval [95% CI], 38% to 74% versus 19%; 95% CI, 8% to 35%; P=0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%; P=0.65). In conclusion, circulating complement-activating anti-HLA DSAs are associated with a specific histomolecular kidney allograft rejection phenotype that can be abrogated by complement inhibition.

Changes in co-morbidity pattern in patients starting renal replacement therapy in Europe-data from the ERA-EDTA Registry.

Background: Patients starting renal replacement therapy (RRT) for end-stage renal disease often present with one or more co-morbidities. This study explored the prevalence of co-morbidities in patients who started RRT in Europe during the period from 2005 to 2014. Methods: Using data from patients aged 20 years or older from all 11 national or regional registries providing co-morbidity data to the European Renal Association - European Dialysis and Transplant Association Registry, we examined the prevalence of the following co-morbidities: diabetes mellitus (DM) (primary renal disease and/or co-morbidity), ischaemic heart disease (IHD), congestive heart failure (CHF), peripheral vascular disease (PVD), cerebrovascular disease (CVD) and malignancy. Results: Overall, 70% of 7578 patients who initiated RRT in 2014 presented with at least one co-morbidity: 39.0% presented with DM, 25.0% with IHD, 22.3% with CHF, 17.7% with PVD, 16.4% with malignancy and 15.5% with CVD. These percentages differed substantially between countries. Co-morbidities were more common in men than in women, in older patients than in younger patients, and in patients on haemodialysis at Day 91 when compared with patients on peritoneal dialysis. Between 2005 and 2014 the prevalence of DM and malignancy increased over time, whereas the prevalence of IHD and PVD declined. Conclusions: More than two-thirds of patients initiating RRT in Europe have at least one co-morbidity. With the rising age at the start of RRT over the last decade, there have been changes in the co-morbidity pattern: the prevalence of cardiovascular co-morbidities decreased, while the prevalence of DM and malignancy increased.

Kidney allograft subclinical rejection modulates systemic inflammation measured by C-reactive protein at 1 year after transplantation.

Kidney allograft inflammation is associated with proinflammatory modifications of peripheral blood mononuclear cells, suggesting that renal inflammation contributes to systemic inflammation. Thus, the aim of this study was to evaluate the relationship between subclinical inflammation in surveillance biopsies performed at 1 year and systemic inflammation assessed by C-reactive protein (CRP) levels at the time of biopsy. We analyzed 544 surveillance biopsies performed at 1 year that were classified as normal (n = 368), borderline (n = 148), or subclinical rejection (SCR) (n = 28). CRP levels were divided into quartiles. Patients in 1st, 2nd, and 3rd quartile were classified as low CRP (n = 408) and patients in the 4th quartile as high CRP (n = 136). Univariate analysis showed that the proportion of patients with SCR was higher in the high CRP group (10.3% vs 3.4%, P = 0.0067). Multivariate analysis showed that independent predictors of high CRP were body mass index (odds ratio [OR] 1.072 and 95% confidence interval [CI] 1.027-1.119), a positive urine culture at the day of the biopsy (OR 2.760 and 95% CI 1.205-6.323), and the presence of SCR at 1-year surveillance biopsy (OR 7.260 and 95% CI 3.530-14.935). In summary, we describe that subclinical acute rejection constitutes an independent predictor of systemic inflammation as measured by CRP.

Inflammatory and related biomarkers are associated with post-transplant diabetes mellitus in kidney recipients: a retrospective study.

In this study, we investigate the association between selected inflammatory-related biomarkers and post-transplant hyperglycemia in kidney transplant recipients. This retrospective analysis comprises 852 patients receiving a kidney transplant at the Norwegian national transplant center between 2007 and 2012, all having a normal oral glucose tolerance test (OGTT) before transplantation. A diagnostic OGTT was performed 10 weeks post-transplant to examine the association between inflammation-related biomarkers and two-hour plasma glucose (2HPG) by multivariable linear regression models adjusting for BMI, age, graft function, fasting insulin levels, dosage of prednisolone, and concentration of calcineurin inhibitors. Six of 20 biomarkers were significantly associated with 2HPG in multivariate analyses showing strong associations with soluble tumor necrosis factor type 1 (P = 0.027), Pentraxin 3 (P = 0.019), macrophage migration inhibitory factor (P = 0.024), and endothelial protein C receptor (P = 0.001). These associated markers reflect several distinct but also overlapping pathways including activation of tumor necrosis factor, macrophages, and endothelial cells. The multinomial logistic regression model showed a clear association between the inflammatory biomarkers and post-transplant diabetes mellitus (PTDM). The association between a range of inflammation markers and PTDM suggests that these markers may be target for future studies on pathogenesis and perhaps also treatment of PTDM.

Changes in health-related quality of life in older candidates waiting for kidney transplantation.

AIM: There is limited available knowledge regarding health-related quality of life (HRQoL) in older patients with chronic kidney disease. We aimed to describe HRQoL in renal transplant candidates 65 years or older at transplant acceptance, and during the first year on the waiting list. METHODS: A nationwide prospective observational study in Norway was conducted. HRQoL was evaluated at baseline (wait listing) and after 6 and 12 months using the patient self-reported Kidney Disease and Quality of Life Short form version 1.3. Intra-individual scores at different times were evaluated. Generic HRQoL was compared with scores from an age-matched Norwegian population. RESULTS: From January 2013 to November 2016, 261 patients ≥65 years accepted for deceased donor kidney transplantation were included. Mean age at inclusion was 71.1 years, 67% male and 69% were on dialysis. HRQoL sum scores significantly decreased during the first year on the waiting list. Physical, mental and kidney disease component summary score reduced from 39.6 to 38.1 (P = 0.045), 48.8 to 44.7 (P < 0.001) and 72.1 to 70.2 (P = 0.03), respectively. When evaluating each domain separately, only the decrease in social function was clinically significant. Age and being on dialysis were the most important predictors for low HRQoL. Compared to the age-matched general population, males had significant lower HRQoL scores. Females were comparable to the general female population at baseline except in general health and vitality. CONCLUSIONS: HRQoL in older patients waiting for kidney transplantation decreases during the first year on the waiting list, but only the change in social function is clinically significant.

Development of Kidney Transplant Fibrosis Is Inversely Associated With Plasma Marine Fatty Acid Level.

OBJECTIVE(S): We assessed associations between plasma levels of polyunsaturated fatty acids (PUFAs) and degree of inflammation and interstitial fibrosis in transplanted kidneys. DESIGN: The design of the study was single center cohort study. SUBJECTS: A study population of 156 patients who received a kidney transplant at Oslo University Hospital during 2010. MAIN OUTCOME MEASURE: Kidney transplant biopsies were obtained at 2 months and 1 year after transplantation. Degree of inflammation and interstitial fibrosis in the cortex of transplanted kidneys were estimated semi-quantitatively. Plasma phospholipid fatty acids levels were measured in a stable phase 2 months posttransplant. We used multivariate linear regression to assess associations between plasma levels of PUFAs and degree of inflammation and interstitial fibrosis at 2 months and 1 year postoperatively and change in degree of interstitial fibrosis during the first year after transplantation, adjusting for inflammation and fibrosis risk factors. RESULTS: Higher plasma marine n-3 PUFA levels were associated with less development of interstitial fibrosis in the kidney transplant (unstandardized ß-coefficient -1.12, standardized ß-coefficient -0.18, P = .03) during the first year after transplantation. Plasma levels of alpha linoleic acid, linoleic acid, and arachidonic acid were not associated with development of interstitial fibrosis. No associations were found between plasma levels of PUFAs and inflammation inside fibrotic areas or outside fibrotic areas in the kidney transplant at neither 2 months nor 1 year postoperatively. Linolenic acid levels in plasma were positively associated with change in renal function during the first year after transplantation. CONCLUSION: The inverse association between plasma marine n-3 PUFA levels and development of interstitial fibrosis during the first year after kidney transplantation suggests that marine fatty acid consumption might halt progression of fibrosis.

Tacrolimus and mycophenolate regimen and subclinical tubulo-interstitial inflammation in low immunological risk renal transplants.

The aim was to evaluate the relationship between maintenance immunosuppression, subclinical tubulo-interstitial inflammation and interstitial fibrosis/tubular atrophy (IF/TA) in surveillance biopsies performed in low immunological risk renal transplants at two transplant centers. The Barcelona cohort consisted of 109 early and 66 late biopsies in patients receiving high tacrolimus (TAC-C0 target at 1-year 6-10 ng/ml) and reduced MMF dose (500 mg bid at 1-year). The Oslo cohort consisted of 262 early and 237 late biopsies performed in patients treated with low TAC-C0 (target 3-7 ng/ml) and standard MMF dose (750 mg bid). Subclinical inflammation, adjusted for confounders, was associated with low TAC-C0 in the early (OR: 0.75, 95% CI: 0.61-0.92; P = 0.006) and late biopsies (OR: 0.69, 95% CI: 0.50-0.95; P = 0.023) from Barcelona. In the Oslo cohort, it was associated with low MMF in early biopsies (OR: 0.90, 95% CI: 0.83-0.98; P = 0.0101) and with low TAC-C0 in late biopsies (OR: 0.77, 95% CI: 0.61-0.97; P = 0.0286). MMF dose was significantly reduced in Oslo between early and late biopsies. IF/TA was not associated with TAC-C0 or MMF dose in the multivariate analysis. Our data suggest that in TAC- and MMF-based regimens, TAC-C0 levels are associated with subclinical inflammation in patients receiving reduced MMF dose.

Should patients older than 65 years be offered a second kidney transplant?

BACKGROUND: Age and number of recipients in need of kidney re-transplantation are increasing. Re-transplantation practices and outcomes in elderly recipients are not previously explored. We aimed to retrospectively evaluate the outcomes of recipients 65 years and older receiving their second deceased donor allograft. METHODS: The study was designed as a retrospective registry based study. All recipients 65 years or older who received a deceased donor kidney transplant at Oslo University Hospital between 2000 and 2014 were included in the study. Survival outcomes were compared between recipients of first (TX1) and second (TX2) allograft. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazard models with patient survival, uncensored graft survival and death-censored graft survival as outcomes in the analyses. RESULTS: Seven hundred and thirty-tree recipients > 65 years received a first (n = 687) or second (n = 46) deceased donor kidney transplant. Five years uncensored graft survival rates were 64% in TX 2 and 67% in TX 1 (P= 0.789). Estimated five years graft survival rates censored for death with functioning graft were 88% in TX2 and 90% in TX1 (P=0.475). Adjusted hazard ratio for uncensored graft loss (TX2 vs. TX1) was 1.24 (95% CI 0.77 - 2.00). Adjusted hazard ratio for graft loss censored for death with functioning graft (TX2 vs. TX1) was 1.70 (0.72-4.02). CONCLUSIONS: Older recipients of second transplants have outcomes that are comparable to the outcomes of age-matched first transplant recipients, and far better than previously documented for older transplant candidates remaining on dialysis treatment. Advanced age by itself should not be a contraindication for re-transplantation. Best results are achieved with short time on dialysis before re-transplantation.

Plasma levels of marine n-3 polyunsaturated fatty acids and renal allograft survival.

BACKGROUND: Marine n-3 polyunsaturated fatty acids (PUFAs) may exert beneficial effects on inflammation, fibrosis, endothelial function, lipid profile and blood pressure that may prevent graft loss. METHODS: In this observational cohort study in Norwegian renal transplant recipients (n = 1990), transplanted between 1999 and 2011, associations between plasma marine n-3 PUFA levels and graft loss were assessed by multivariable Cox proportional hazard regression analysis. Plasma phospholipid fatty acid composition was determined by gas chromatography and individual fatty acids recorded as weight percentage (wt%) of total fatty acids in a stable phase 10 weeks after transplantation. RESULTS: During a median follow-up time of 6.8 years, 569 (28.6%) renal allografts were lost, either due to patient death (n = 340, 59.8% of graft loss) or graft loss in surviving patients (n = 229, 40.2%). Plasma marine n-3 PUFA levels ranged from 1.35 to 23.87 wt%, with a median level of 7.95 wt% (interquartile range 6.20-10.03 wt%). When adjusting for established graft loss risk factors, there was a 11% reduced risk of graft loss for every 1.0 wt% increase in marine n-3 PUFA level [adjusted hazard ratio (HR) 0.89; 95% confidence interval (CI) 0.84-0.93], and a 10% reduced risk of graft loss in surviving patients (adjusted HR 0.90; 95% CI 0.84-0.97). CONCLUSION: High levels of plasma marine n-3 PUFAs were associated with better renal allograft survival.

Pregnancy outcomes following maternal kidney transplantation: a national cohort study.

INTRODUCTION: Internal design flaws in previous reports of pregnancies following kidney transplantation have been outlined, and the need for a validation has been stated. The aim of this study was to collect information about obstetrical and neonatal outcomes in all Norwegian pregnancies following maternal kidney transplantation, and to compare these data with the general Norwegian population. MATERIAL AND METHODS: A retrospective cohort study based on 1 272 000 deliveries in Norway between 1969 and 2013. All data were collected from medical records. From the source population, we compared 119 first deliveries in kidney transplanted women with 238 first deliveries in nontransplanted women. An explanatory strategy was used in the analysis. RESULTS: The risk of preeclampsia was significantly increased in kidney-transplanted women compared with nontransplanted women (adjusted incidence rate ratio: 6.06, 95% confidence interval 3.18-11.55). Additionally, preeclampsia in kidney-transplanted women was early onset (diagnosed <34 gestational weeks) in half of the cases. There were also persistent risks of cesarean delivery (adjusted incidence rate ratio 4.14, 95% confidence interval 2.56-6.66), preterm delivery (adjusted incidence rate ratio 4.45, 95% confidence interval 2.13-9.30) and a birthweight below the 10th centile (22.7% vs. 9.7%) in the kidney-transplanted group. A high proportion (63%) of the kidney-transplanted women with chronic hypertension developed preeclampsia. CONCLUSIONS: Using consistent diagnostic criteria, this study shows high rates of maternal and neonatal complications in pregnancies following kidney transplantation. In particular, we reveal a high rate of early-onset preeclampsia requiring operative preterm delivery, conferring long-term risks on both the mother and child.

Low-target tacrolimus in de novo standard risk renal transplant recipients: A single-centre experience.

AIM: Optimal tacrolimus exposure in transplant recipients is not well established. The results from the Symphony study indicated that low-target tacrolimus (trough concentrations 3-7 µg/L) in de novo standard risk renal transplant recipients should be appropriate. The aim of this study was to evaluate real-life outcomes when applying a similar strategy in a clinical setting. METHODS: A single-centre analysis was conducted in standard risk renal transplant recipients receiving low-target tacrolimus, mycophenolate mofetil, glucocorticoids and basiliximab induction. One-year estimated glomerular filtration rate (eGFR, Cockcroft-Gault), one-year biopsy-proven acute rejection rate and graft- and patient survival up to 3 years post-transplant were compared with the outcomes in the Symphony study. RESULTS: From 1 January 2009 to 31 March 2013, we included 406 patients. One year after transplantation, the mean ± SD eGFR was 76.8 ± 28.3 mL/min (Symphony: 65.4 ± 27.0 mL/min, P < 0.001). Biopsy-proven acute rejections were seen in 14.5% of the patients (Symphony: 12.3%, P = 0.35). Kaplan-Meier estimates [95% confidence interval] of three-year death-censored graft- and patient survival were 96.6% [94.2-99.0%] (Symphony: 93%) and 95.0% [92.6-97.3%] (Symphony: 95%), respectively. CONCLUSION: Low-target tacrolimus-based immunosuppression is safe and effective also in a standard clinical setting in de novo standard risk renal transplant recipients.

Impact of initial dialysis modality on mortality: a propensity-matched study.

BACKGROUND: Whether the choice of dialysis modality in patients with end stage renal disease may impact mortality is undecided. No randomized controlled trial has properly addressed this issue. Propensity-matched observational studies could give important insight into the independent effect of peritoneal (PD) opposed to haemodialysis (HD) on all-cause and cardiovascular mortality. METHODS: To correct for case-mix differences between patients treated with PD and HD, propensity-matched analyses were utilized in all patients who initiated dialysis as first renal replacement therapy in Norway in the period 2005-2012. PD patients were matched in a 1:1 fashion with HD patients, creating 692 pairs of patients with comparable baseline variables. As-treated and intention-to treat analyses were undertaken to assess cardiovascular and all-cause mortality. Interaction analyses were used to assess differences in the relationship between initial dialysis modality and mortality, between strata of age, gender and prevalent diabetes mellitus. RESULTS: In the as-treated analyses, initial dialysis modality did not impact 2-year (PD vs. HD: HR 0.87, 95 % CI 0.67-1.12) or 5-year all-cause mortality (HR 0.95, 95 % CI 0.77-1.17). In patients younger than 65 years, PD was superior compared to HD with regard to both 2-year (HR 0.39, 95 % CI 0.19-0.81), and 5-year all-cause mortality (HR 0.49, 95 % CI 0.27-0.89). Cardiovascular mortality was also lower in the younger patients treated with PD (5-year HR 0.38, 95 % CI 0.15-0.96). PD was not associated with impaired prognosis in any of the prespecified subgroups compared to HD. The results were similar in the as-treated and intention-to-treat analyses. CONCLUSION: Survival in PD was not inferior to HD in any subgroup of patients even after five years of follow-up. In patients below 65 years, PD yielded superior survival rates compared to HD. Increased use of PD as initial dialysis modality in ESRD patients could be encouraged.

The impact of early cytomegalovirus infection after kidney transplantation on long-term graft and patient survival.

This prospective observational cohort study is an extension of a previous study reporting effects of cytomegalovirus (CMV) on graft and patient survival in 471 patients who underwent kidney transplantation between 1994 and 1997. CMV pp65 antigen was measured every 7-14 d during the first three months after transplantation, given as number of CMV pp65-positive cells per 10(5) leukocytes. A positive test was defined as CMV infection. None of the patients received CMV prophylaxis or preemptive treatment. During a median of 13.7 (7.1-14.9) yr, the number of death-censored graft losses was 118 (25%) and of patient deaths 224 (48%). CMV infection was an independent significant risk factor for mortality in multivariate analysis (HR = 1.453, 95% CI 1.033-2.045, p = 0.032), adjusting for patient and donor age, preemptive transplantation, HLA-DR and -AB mismatches, living donor, acute rejection during the first three months, donor-recipient CMV IgG antibody status and diabetic nephropathy. In univariate analysis, CMV infection was significantly associated with death-censored graft loss but the association was not significant in multivariate model. CMV infection early after kidney transplantation is a predictor of overall mortality but not of death-censored graft loss after a median observation period of 13.7 yr.

Uric acid has a J-shaped association with cardiovascular and all-cause mortality in kidney transplant recipients.

The association between serum uric acid and kidney graft and recipient survival is uncertain. During 2000-2011, we measured serum uric acid at week 10 after transplantation. Of 2748 transplanted patients, 2200 (80.1%) attended this visit. After a median follow-up of 7.4 yr, 378 patients had died, 143 from a cardiovascular cause, and 185 patients lost their graft. The third quintile of uric acid levels (357-405 µM) had the lowest mortality risk and was used as reference group. In Cox proportional hazard models adjusting for graft and patient characteristics, the fifth quintile of uric acid levels (>474 µM) was independently associated with cardiovascular mortality (hazard ratio [HR] = 2.87 [1.55-5.32], p = 0.001) and all-cause mortality (HR = 1.57 [1.09-2.25], p = 0.02). Also, the lowest quintile of uric acid levels (<309 µM) showed a trend toward increased risk of cardiovascular mortality (HR = 1.79 [0.90-3.58], p = 0.10) and all-cause mortality (HR = 1.31 [0.89-1.93], p = 0.18). The increased risk at low uric acid levels was confined to diabetic recipients. Uric acid was not associated with death-censored graft loss. In conclusion, uric acid has a J-shaped association with cardiovascular and all-cause mortality in kidney transplant recipients.

Trabecular Bone Score Improves Early After Successful Kidney Transplantation Irrespective of Antiresorptive Therapy and Changes in Bone Mineral Density.

Background: Trabecular bone score (TBS) is a new tool to assess trabecular bone microarchitecture based on standard dual-energy x-ray absorptiometry (DXA) of lumbar spine images. TBS may be important to assess bone quality and fracture susceptibility in kidney transplant recipients (KTRs). This study aimed to investigate the effect of different bone therapies on TBS in KTRs. Methods: We reanalyzed DXA scans to assess TBS in 121 de novo KTRs at baseline, 10 wk, and 1 y. This cohort, between 2007 and 2009, participated in a randomized, placebo-controlled trial evaluating the effect of ibandronate versus placebo in addition to vitamin D and calcium. Results: Although bone mineral density (BMD) Z scores showed a subtle decrease in the first weeks, TBS Z scores increased from baseline to 10 wk for both treatment groups, followed by a slight decline at 12 mo. When comparing treatment groups and adjusting for baseline TBS, there were no differences found in TBS at 12 mo (P = 0.419). Correlation between TBS and BMD at baseline was weak (Spearman's ρ = 0.234, P = 0.010), and change in TBS was not correlated with changes in lumbar spine BMD in either of the groups (ρ = 0.003, P = 0.973). Conclusions: Treatment with ibandronate or vitamin D and calcium did not affect bone quality as measured by TBS in de novo KTRs, but TBS increased early, irrespective of intervention. Changes in TBS and BMD during the study period were not correlated, indicating that these measurements reflect different aspects of bone integrity. TBS may complement BMD assessment in identifying KTRs with a high fracture risk.

Long-term outcomes after cyclosporine or mycophenolate withdrawal in kidney transplantation - results from an aborted trial.

Long-term triple immunosuppressive therapy with cyclosporine (CsA), mycophenolate mofetil (MMF) and prednisolone may be excessively powerful for many transplant recipients. We compared withdrawal of either MMF or CsA in stable kidney transplants on triple immunosuppression. The study was a prospective, randomized, controlled 12-months trial in stable kidney transplants. The patients who withdrew CsA were given MMF 2 g/d, and CsA troughs were between 75 and 125 ng/mL in MMF withdrawal. Planned inclusion was 298 patients. The study was prematurely aborted after inclusion of 39 patients. Acute rejection rates were 6/20 (30%) in the MMF group compared with 0/19 (0%) in the CsA group (p = 0.02). Time to acute rejections was 4.0-28.7 months after withdrawal. Trough concentrations of mycophenolic acid (MPA) and CsA showed therapeutic levels. The subjects have been observed for eight yr, and of the 28 patients remaining on randomized therapy, the MMF patients preserved graft function better than CsA patients. Death-censored graft survival was 75% and 95% (p = 0.18) and patient survival was 70% and 68% (p = 0.99) in the MMF and CsA groups, respectively, at the end of long-term follow-up. CsA withdrawal was associated with a high rate of acute rejections. Initially, the treatment of acute rejections was successful. However, five of six lost their grafts in the long term.

Humoral vaccine response and breakthrough infections in kidney transplant recipients during the COVID-19 pandemic: a nationwide cohort study.

Background: Kidney transplant recipients (KTRs) experienced reduced SARS-CoV-2 vaccine response and were at increased risk of severe COVID-19. It is unknown if level of vaccine induced anti-receptor binding domain IgG (anti-RBD IgG) correlates with protection from and survival following COVID-19. We aimed to evaluate the effect of vaccine response on risk of breakthrough infections (BTI) and COVID-19 death in KTRs. Methods: We performed a nationwide study, examining the competing risk of SARS-CoV-2 infection, COVID-19 related/unrelated death, and vaccine efficacy as assessed by level of anti-RBD IgG response 4-10 weeks after each vaccination. The study included all KTR in Norway alive and with a functioning graft on February 20th, 2020, and events after November 11th, 2022 were right-censored. A pre-pandemic reference-cohort from January 1st 2019 to January 1st 2020 was included to evaluate excess mortality. The study was conducted at Oslo University Hospital, Rikshospitalet, Norway. Findings: The study included 3607 KTRs (59 [48-70] years) with a functioning graft at February 20th, 2020, who received (median [IQR]) 4 [3-4] vaccines (range 2-6, 99% mRNA). Anti-RBD IgG was measured in 12 701 serum samples provided by 3213 KTRs. Vaccine response was assessed 41 [31-57] days after vaccination. A total of 1090 KTRs were infected with SARS-CoV-2, 1005 (92%) were BTI, and vaccine response did not protect against BTI. The hazard ratio for COVID-19 related death 40 days post-infection was 1.71 (95% CI: 1.14, 2.56) comparing vaccine response levels (≥5 vs. ≥5000 BAU/mL). No excess non-COVID-19 mortality was registered in KTRs surviving SARS-CoV-2 infection compared to a 2019 pre-pandemic reference. Interpretation: Our findings suggested that SARS-CoV-2 mRNA vaccine response did not predict protection against infection, but prevention of fatal disease progression in KTRs and greater vaccine response further reduced the risk of COVID-19 death. No excess non-COVID-19 mortality was seen during the pandemic. Funding: CEPI and internal funds.