Inflammation in the early phase after kidney transplantation is associated with increased long-term all-cause mortality.

In the general population, low-grade inflammation has been established as a risk factor for all-cause mortality. We hypothesized that an inflammatory milieu beyond the time of recovery from the surgical trauma could be associated with increased long-term mortality in kidney transplant recipients (KTRs). This cohort study included 1044 KTRs. Median follow-up time post-engraftment was 10.3 years. Inflammation was assessed 10 weeks after transplantation by different composite inflammation scores based on 21 biomarkers. We constructed an overall inflammation score and five pathway-specific inflammation scores (fibrogenesis, vascular inflammation, metabolic inflammation, growth/angiogenesis, leukocyte activation). Mortality was assessed with Cox regression models adjusted for traditional risk factors. A total of 312 (29.9%) patients died during the follow-up period. The hazard ratio (HR) for death was 4.71 (95% CI: 2.85-7.81, p < .001) for patients in the highest quartile of the overall inflammation score and HRs 2.35-2.54 (95% CI: 1.40-3.96, 1.52-4.22, p = .001) for patients in the intermediate groups. The results were persistent when the score was analyzed as a continuous variable (HR 1.046, 95% CI: 1.033-1.056, p < .001). All pathway-specific analyses showed the same pattern with HRs ranging from 1.19 to 2.70. In conclusion, we found a strong and consistent association between low-grade systemic inflammation 10 weeks after kidney transplantation and long-term mortality.

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.

High Plasma Oxalate Levels Early After Kidney Transplantation Are Associated With Impaired Long-Term Outcomes.

Background: Elevated levels of oxalate are common in renal failure patients and non-hyperoxaluria disease, and may cause damage after transplantation. We examined outcomes after 15 years for 167 kidney transplant recipients who had plasma oxalate measured early after transplantation. Analyses included plasma oxalate, recipient age, donor age, live donor, HLA-DR mismatch, mGFR, and smoking. Results: Median age was 52 years (range 18-81), 63% were male and 38% had live donors. Median plasma oxalate concentration 10 weeks after transplantation was 9.0 µmol/L (range 2.7-53.0), one third above the upper reference limit (11.0 µmol/L). Multivariable analysis revealed upper quartile plasma oxalate (>13.0 µmol/L, p = 0.008), recipient age (p < 0.001), deceased donor (p = 0.003), and current smoking (p < 0.001) as significant factors associated with patient survival. Upper quartile plasma oxalate (p = 0.021), recipient age (p = 0.001), deceased donor kidney (p = 0.001), HLA-DR mismatch (p = 0.015), and current smoking (p = 0.014) were also associated with graft loss. Factors associated with death censored graft losses were donor age (p = 0.012), deceased donor (p = 0.032), and HLA-DR mis-matched kidneys (p = 0.005) but plasma oxalate was not (p = 0.188). Conclusions: Plasma oxalate in the upper quartile early after transplantation was significantly associated with impaired long-term patient survival and graft losses, but not when censored for death.

Estimated glomerular filtration rate as a measurement of kidney function. / Estimert glomerulær filtrasjonshastighet som mål på nyrefunksjon.

Estimated glomerular filtration rate is an established, routine clinical measurement for kidney function, but the estimate has limitations and cannot be used in all clinical situations. Estimated glomerular filtration rate has a high coefficient of variation, and deviations in the patient's height, weight or muscle mass may result in an imprecise estimate. If an accurate measurement of kidney function is essential, glomerular filtration rate can be measured using an exogenous substance.

Endothelial function after pancreas transplantation-A single-center observational study.

BACKGROUND: Patients with diabetes mellitus treated with successful pancreas transplantation (PTX) normalize hyperglycemia, but are exposed to immunosuppressive drugs that may impair endothelial function. This study aimed to evaluate endothelial function in single PTX recipients. METHODS: Flow-mediated dilatation (FMD) in the brachial artery was measured by ultrasound 8 weeks after transplantation in single PTX (n = 27) and compared with healthy controls (n = 58), simultaneous pancreas and kidney recipients (n = 9), and kidney transplant recipients with (n = 41) and without (n = 95) diabetes mellitus. Adjustments for age, gender, blood pressure, and body mass index were included in a linear regression model. Changes in FMD from before to 1 year after transplantation were assessed in a subgroup of PTX recipients (n = 9). RESULTS: Flow-mediated dilatation% in PTX recipients was not inferior to healthy controls (8.7 ± 3.6 vs 7.7 ± 3.3, P = .06) and simultaneous pancreas and kidney recipients (6.7 ± 4.5, P = .24) in an adjusted model, and superior to kidney recipients with and without diabetes (3.0 ± 3.0 and 4.8 ± 3.3, respectively, both P < .005). FMD% improved significantly from eight weeks to one year after PTX, mean 7.9 ± 4.2% vs 11.8 ± 4.8% (N = 9; P = .03). CONCLUSION: Flow-mediated dilatation is well preserved in patients undergoing pancreas transplantation and is not impaired when immunosuppressive drugs are introduced.

Increased long-term risk for hypertension in kidney donors - a retrospective cohort study.

Kidney donors may be at increased risk of end-stage renal disease and premature mortality. Elevated blood pressure after donation may contribute to the increased risks. In this cohort study, we have assessed long-term risk for the development of hypertension in kidney donors compared to a control group potentially eligible as donors. Follow-up data were obtained from previous living kidney donors. A healthy control group with baseline assessment from similar time periods as the donor nephrectomies was selected. Hypertension was defined as blood pressure >140/90, use of blood pressure medication, or established diagnosis of hypertension. Stratified logistic regression was used to estimate risk of hypertension at follow-up, adjusted for systolic blood pressure at baseline, age at follow-up, time since donation/baseline, gender, smoking at baseline, and BMI at baseline. A total of 368 donors (36%) had hypertension at follow-up, and 241 of these (23%) were using blood pressure medication. In adjusted stratified logistic regression analyses, odds ratio for hypertension was significantly increased (1.25, 95% confidence interval 1.12-1.39, P < 0.001) in donors compared with controls. Kidney donors appear to be at increased long-term risk for hypertension compared with healthy controls. This finding supports regular follow-up of blood pressure in kidney donors.

Effects of marine n-3 fatty acid supplementation in renal transplantation: A randomized controlled trial.

Marine n-3 fatty acids (FAs) may exert beneficial effects on inflammation, fibrosis, and endothelial function, which could preserve renal graft function. In this randomized controlled trial, 132 Norwegian renal transplant recipients received either 2.6 g of marine n-3 FAs or olive oil (control) daily for 44 weeks, in addition to standard care. Thirty patients did not complete the trial. The primary endpoint was change (Δ) in measured glomerular filtration rate (mGFR) during follow-up. We found no significant difference in Δ mGFR between the marine n-3 FA group and controls (6.7 vs 3.8 mL/min per 1.73 m2 , P = .15). Significant beneficial effects from marine n-3 FA supplementation were, however, seen in secondary endpoints plasma triglycerides, plasma high-sensitivity C-reactive protein, and brachial artery flow-mediated dilation. In the per-protocol population, the renal graft indices percent interstitial fibrosis and Chronic Allograft Damage Index also were significantly lower in the marine n-3 FA group. The cumulative incidence of adverse events did not differ between the marine n-3 FA group (n = 218) and controls (n = 240). In conclusion, marine FA supplementation did not improve renal function compared with controls, but was safe, lowered plasma triglyceride and high-sensitivity C-reactive protein levels, and improved endothelial function (Clinical.Trials.gov identifier NCT01744067).

Correction: Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection.

[This corrects the article DOI: 10.1371/journal.ppat.1006299.].

Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection.

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues.

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.

High tacrolimus clearance - a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single-center cohort study.

Patients with high tacrolimus clearance are more likely to experience transient under-immunosuppression in case of a missed or delayed dose. We wanted to investigate the association between estimated tacrolimus clearance and development of graft interstitial fibrosis and tubular atrophy (IFTA) in kidney transplant recipients. Associations between estimated tacrolimus clearance [daily tacrolimus dose (mg)/trough concentration (µg/l)] and changes in IFTA biopsy scores from week 7 to 1-year post-transplantation were investigated. Data from 504 patients transplanted between 2009 and 2013 with paired protocol biopsies (7 weeks + 1-year post-transplant) were included. There were no differences in baseline biopsy scores (7 weeks) in patients with different estimated tacrolimus clearance. Increasing tacrolimus clearance was significantly associated with increased ci + ct score of ≥2 at 1 year, odds ratio of 1.67 (95% CI; 1.11-2.51). In patients without fibrosis (ci + ct ≤ 1) at 7 weeks (n = 233), increasing tacrolimus clearance was associated with development of de novo IFTA (i + t ≤ 1 and ci + ct ≥ 2) at 1 year, odds ratio of 2.01 (95% CI; 1.18-3.50) after adjusting for confounders. High tacrolimus clearance was significantly associated with development of IFTA the first year following renal transplantation.

Long-term risk for kidney donors with hypertension at donation - a retrospective cohort study.

In the general population, small increases in blood pressure are associated with increased mortality. In kidney donors this association is less certain. We therefore assessed long-term overall and cardiovascular mortality in donors who were hypertensive at the time of donation compared with normotensive donors. Hypertension was defined as blood pressure >140/90 mmHg or use of antihypertensive drugs. Adequate records available in 2131 donors revealed that 140 were hypertensive and 1991 were normotensive. Multivariable regression analyses were performed for overall and cardiovascular mortality. Hypertensive donors were significantly older (mean 57.7 vs. 46.9 years), more were males (44.3% vs. 41.5%), had higher body mass index (26.4 vs. 24.7) and lower estimated glomerular filtration rate (91.8 vs. 101.2 ml/min/1.73 m2 ). After a median observation time of 20.8 years (interquartile range 11) 71 hypertensive donors had died and 26 of the deaths were cardiovascular. Multivariable analysis did not suggest a generalizable association between hypertension and long-term overall mortality [hazard ratio (HR) 1.1, 95% confidence interval (CI) 0.9-1.5, P = 0.34] or cardiovascular mortality (HR 1.1, 95% CI 0.7-1.8, P = 0.55). These data may support the use of older healthy kidney donors with hypertension at donation.

Evaluation of tools for annual capture of adherence to immunosuppressive medications after renal transplantation - a single-centre open prospective trial.

Annual assessment of adherence would strengthen long-term outcome assessments from registry data. The objective of this study was to evaluate tools suitable for annual routine capture of adherence data in renal transplant recipients. A single-centre open prospective trial included 295 renal transplant recipients on tacrolimus. Two-thirds of the patients were included 4 weeks post-transplant, randomized 1:1 to intensive or single-point adherence assessment in the early phase and 1-year post-transplant. One-third were included 1-year post-transplant during a cross-sectional investigation. Adherence was assessed using multiple methods: The "Basel Assessment of Adherence to Immunosuppressive Medication Scale" (BAASIS© ) questionnaire was used to assess self-reported adherence. The treating clinician scored patient's adherence and tacrolimus trough-concentration variability was calculated. In the analyses, the data from the different tools were dichotomized (adherent/nonadherent). The BAASIS© overall response rate was over 80%. Intensive BAASIS© assessment early after transplantation increased the chance of capturing a nonadherence event, but did not influence the 1-year adherence prevalence. The adherence tools generally captured different populations. Combining the tools, the nonadherence prevalence at 1 year was 38%. The different tools identified to a large degree different patients as nonadherent. Combining these tools is feasible for annual capture of adherence status.

Validation of diagnostic utility of fasting plasma glucose and HbA1c in stable renal transplant recipients one year after transplantation.

BACKGROUND: The use of HbA1c ≥6.5% for diagnosis of diabetes has been challenged for post-transplantation diabetes mellitus (PTDM) also known as new onset diabetes after transplantation (NODAT) due to a low sensitivity early after renal transplantation. PTDM diagnosed with an oral glucose tolerance test (OGTT) is highly predictable for long-term patient mortality. HbA1c was introduced for diagnosis based on the risk of developing diabetic retinopathy. The utility of HbA1c measures versus glucose criteria has not been widely assessed in stable transplant patients but still HbA1c is widely used in this population. The aim of the present analyses was to validate the utility of fasting plasma glucose (FPG) together with HbA1c in diagnosing PTDM in stable renal transplant recipients (RTRs). METHODS: OGTT's were performed one year after transplantation in 494 consecutive RTRs without diabetes. FPG and HbA1c were obtained the same day, before starting the OGTT. Validation was performed using C-statistics and logistic regression analyses. RESULTS: PTDM was diagnosed in 51 patients (10.3%) by glucose criteria, 38 (74%) patients were diagnosed by FPG ≥7.0 mmol/L [126.1 mg/dl], and 13 (26%) only by 2-h plasma glucose. Six of the latter had HbA1c ≥6.5%. Only seven patients out of the 51 (13.7%) PTDM patients remained undiagnosed when HbA1c ≥6.5% was used together with FPG, and five of these regressed to normal after a median follow-up of 14 months. ROC curves including FPG and HbA1c versus OGTT derived criteria revealed an AUC of 0.858. CONCLUSIONS: Combining standard diagnostic FPG and HbA1c criteria captured almost all patients with persistent PTDM in stable RTRs. The combined use of the criteria appears to be an applicable diagnostic strategy for PTDM without the need of an OGTT one year post-transplant. TRIAL REGISTRATION: Retrospectively registered.

Trans-fatty Acids and Survival in Renal Transplantation.

OBJECTIVE: High consumption of trans-fatty acids (TFAs) is associated with increased mortality. DESIGN AND METHODS: Observational cohort study of 1.988 Norwegian renal transplant recipients with a median follow-up time of 9.6 years. We assessed multivariable adjusted associations between plasma levels of industrial and ruminant TFAs with patient and graft survival. Plasma phospholipid fatty acid levels were determined by gas chromatography at 10 weeks after transplantation. RESULTS: During follow-up, there were 595 deaths, and 805 grafts were lost. Plasma industrial TFA levels dropped from 0.3 wt% in years 1999-2004 to reach a plateau of 0.2 wt% from year 2005 and beyond, whereas plasma levels of ruminant TFAs remained stable throughout the study period. In the former era (years 1999 to 2004, n = 902), we found multivariable adjusted associations between plasma industrial TFA levels and mortality (hazard ratio 4.44, P = .02) and graft loss (hazard ratio 4.22, P = .01). In the latter era (years 2005 to 2011, n = 1,086), there were no associations between plasma industrial TFA levels and patient or graft survival. Plasma ruminant TFAs were not associated with mortality or graft loss in either eras. CONCLUSION: In this Norwegian transplant cohort, plasma industrial TFA levels dropped from around 0.3 wt% in the former era to 0.2 wt% in the latter era. While plasma industrial TFA was significantly associated with survival in the former era, no associations were found with survival in the latter era. This finding suggests that lowering industrial TFA consumption from modest to low levels could possibly influence health beneficially after renal transplantation.

Long-term renal allograft survival: a quiet revolution.

Short-term renal allograft survival has improved more quickly than long-term outcomes. Analysis of more than 100,000 deceased donor renal transplants in Europe from 1986 to 2015 identified a declining rate of improvement in 1-year, death-censored graft survival but a continued improvement in longer-term survival, with a year-on-year 3% reduction in the risk of graft failure. These reassuring observations likely reflect improved overall transplant management rather than specific advances.

Arterial stiffness is associated with visceral fat mass in kidney transplanted patients-A nationwide cohort study.

Arterial stiffness, visceral fat, and hyperglycemia are acknowledged risk factors for adverse outcomes after transplantation, but whether arterial stiffness is associated with visceral adipose tissue and hyperglycemia is unknown. We studied 162 non-diabetic kidney transplant recipients 8-10 weeks after transplantation. Arterial stiffness was measured as pulse wave velocity (PWV) by SphygmoCor and visceral fat using a validated software applied on DXA scans. Also a standard oral glucose tolerance test was performed. Median PWV was 8.6 m/s (IQR 7.3-10.4 m/s). Patients in the upper quartile of PWV had 31%-106% higher visceral fat percentage (P < 0.001), they were older (P < 0.001) and had a fasting plasma glucose of 5.8 mmol/L that was higher than in the other quartiles (P = 0.006). In univariate analysis, visceral fat percentage and age were the parameters strongest associated with PWV (P < 0.001), but cholesterol and glucose were also significant (P < 0.05). In multivariate analysis, visceral fat was the only significant predictor of PWV along with age (P < 0.001). In conclusion, arterial stiffness is significantly associated with visceral fat but not hyperglycemia in non-diabetic kidney transplant patients. We identified age and VAT as risk variables for arterial stiffness. A potential reversibility of arterial wall stiffness with reduction in VAT needs further study.

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.

Estimated glomerular filtration rate in stable older kidney transplant recipients-are present algorithms valid? A national cross-sectional cohort study.

Several equations have been developed for estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD), but none were developed based on data from elderly kidney transplant recipients (KTR). The primary aim of this study was to evaluate different creatinine-based equations in stable elderly KTR. A national cross-sectional study was performed using data from 263 consecutive kidney transplant recipients 60 years or older who performed a routine GFR measurement one year after engraftment. GFR was measured by iohexol clearance calculation based on two samples. eGFR was calculated from a range of different creatinine-based equations using information obtained at the time of GFR measurement. Bias, precision, and accuracy were evaluated for each equation. All equations apart from Nankivell had accuracy (P30) > 80%. The BIS1, FAS, LMRCR , and Cockcroft & Gault equations in recipients older than 70 years and the FAS, LMRCR , and MDRD in recipients 60-69 years old had nonsignificant bias. The CKD-EPI had significant bias in both groups. If one should choose a single equation for follow-up of individual CKD progression in all recipients ≥ 60 years, the FAS or LMRCR equations are probably the best alternatives.

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.