Dag Olav Dahle

Overall and cardiovascular mortality in Norwegian kidney donors compared to the background population

BACKGROUND There are concerns regarding potential long-term risks to the living kidney donor. Cardiovascular mortality has not been evaluated. The aim of this study was to assess overall and cardiovascular mortality in previous kidney donors compared with a general population sample. METHODS All live kidney donors in Norway in the period 1963-2007 were included. Controls matched 3:1 for age, gender and year of birth were provided by Statistics, Norway. Cause of death was retrieved from the death master file. Vital status as of 1 January 2010 was provided for all participants, and cause of death was available until 1 January 2008. Comparative survival analyses were performed by Kaplan-Meier curves and log-rank test. Age-stratified death rates were calculated and compared with a selected group with a health status hypothetically allowing donation. RESULTS There were 2269 living kidney donors in the study period. At donation, mean age was 47.6 + 12.6 years, 41.3% were male. Median observation time was 14.3 years. A total of 324 donors died during the study period. Causes of death were similar for donors and controls. By Kaplan-Meier analysis, overall and cardiovascular mortality was lower for previous kidney donors than for matched controls (P < 0.001 and P = 0.004, respectively). Age-stratified death rates were elevated for the oldest group of donors. CONCLUSIONS Overall and cardiovascular mortality results are partially reassuring. However, the seemingly elevated mortality rate among the oldest donors requires further study.

Inflammation-associated graft loss in renal transplant recipients

BACKGROUND Although short-term graft survival has improved substantially in renal transplant recipients, long-term graft survival has not improved over the last decades. The lack of knowledge of specific causes and risk factors has hampered improvements in long-term allograft survival. There is an uncertainty if inflammation is associated with late graft loss. METHODS We examined, in a large prospective trial, the inflammation markers high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) and their association with chronic graft dysfunction. We collected data from the Assessment of Lescol in Renal Transplant trial, which recruited 2102 maintenance renal transplant recipients. RESULTS Baseline values were hsCRP 3.8 ± 6.7 mg/L and IL-6 2.9 ± 1.9 pg/mL. Adjusted for traditional risk factors, hsCRP and IL-6 were independently associated with death-censored graft loss, the composite end points graft loss or death and doubling of serum creatinine, graft loss or death. CONCLUSION The inflammation markers hsCRP and IL-6 are associated with long-term graft outcomes in renal transplant recipients.

Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism.

Background Hyperparathyroidism is reported in 10% to 66% of renal transplant recipients (RTR). The influence of persisting hyperparathyroidism on long-term clinical outcomes in RTR has not been examined in a large prospective study. Methods We investigated the association between baseline parathyroid hormone (PTH) levels and major cardiovascular events, renal graft loss, and all-cause mortality by Cox Proportional Hazard survival analyses in 1840 stable RTR derived from the Assessment of LEscol in Renal Transplantation trial. Patients were recruited in a mean of 5.1 years after transplantation, and follow-up time was 6 to 7 years. Results Significant associations between PTH and all 3 outcomes were found in univariate analyses. When adjusting for a range of plausible confounders, including measures of renal function and serum mineral levels, PTH remained significantly associated with all-cause mortality (4% increased risk per 10 units; P = 0.004), and with graft loss (6% increased risk per 10 units; P < 0.001), but not with major cardiovascular events. Parathyroid hormone above the upper limit of normal (65 pg/mL) indicated a 46% (P = 0.006) higher risk of death and an 85% higher risk of graft loss (P < 0.001) compared with low/normal values. Conclusions Hyperparathyroidism is an independent, potentially remediable, risk factor for renal graft loss and all-cause mortality in RTR.

Osteoprotegerin as a predictor of renal and cardiovascular outcomes in renal transplant recipients: follow-up data from the ALERT study

BACKGROUND In patients with chronic kidney disease, vascular calcification contributes to increased cardiovascular (CV) morbidity and mortality. CV risk remains high after successful renal transplantation. Osteoprotegerin (OPG) is a glycoprotein, involved in the regulation of the vascular calcification process. Previous studies have shown that elevated OPG is predictive of mortality in high-risk populations. The aim of this study was to investigate the prognostic value of OPG for graft function, CV events and all-cause death, in a large transplant cohort. METHODS OPG was measured at baseline in renal transplant recipients enrolled in the Assessment of Lescol in Renal Transplantation (ALERT) study, a randomized placebo-controlled intervention study comparing fluvastatin and placebo. Patients were followed for 6.7 years with evaluation of pre-specified end points, graft loss, graft function, CV events and death. RESULTS OPG was analysed in 1889 renal transplant recipients, with a mean value of 4.69 ± 1.85 pg/L. The number of renal and CV events increased by quartiles of OPG. In the multivariate analysis, OPG in the fourth as compared to first quartile was an independent predictor of graft failure or doubling of serum creatinine [hazard ratio (HR) 2.20 (1.56-3.11), P < 0.001], major CV events [HR 2.40 (1.58-3.64), P < 0.001], cardiac mortality [HR 2.80 (1.32-5.94), P = 0.007] and all-cause mortality [HR 2.31 (1.53-3.49), P < 0.001]. CONCLUSION In a large cohort of kidney transplant patients with long-term follow-up, OPG was independently associated with renal events, CV events and mortality.

The Association between Marine n-3 Polyunsaturated Fatty Acid Levels and Survival after Renal Transplantation

BACKGROUND AND OBJECTIVES Several studies have reported beneficial cardiovascular effects of marine n-3 polyunsaturated fatty acids. To date, no large studies have investigated the potential benefits of marine n-3 polyunsaturated fatty acids in recipients of renal transplants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this observational cohort study of 1990 Norwegian recipients of renal transplants transplanted between 1999 and 2011, associations between marine n-3 polyunsaturated fatty acid levels and mortality were investigated by stratified analysis and multivariable Cox proportional hazard regression analysis adjusting for traditional and transplant-specific mortality risk factors. Marine n-3 polyunsaturated fatty acid levels in plasma phospholipids were measured by gas chromatography in a stable phase 10 weeks after transplantation. RESULTS There were 406 deaths (20.4%) during a median follow-up period of 6.8 years. Mortality rates were lower in patients with high marine n-3 polyunsaturated fatty acid levels (≥7.95 weight percentage) compared with low levels (<7.95 weight percentage) for all age categories (pooled mortality rate ratio estimate, 0.69; 95% confidence interval, 0.57 to 0.85). When divided into quartiles according to marine n-3 polyunsaturated fatty acid levels, patients in the upper quartile compared with the lower quartile had a 56% lower risk of death (adjusted hazard ratio, 0.44; 95% confidence interval, 0.26 to 0.75) using multivariable Cox proportional hazard regression analysis. There was a lower hazard ratio for death from cardiovascular disease with high levels of marine n-3 polyunsaturated fatty acid and a lower hazard ratio for death from infectious disease with high levels of the marine n-3 polyunsaturated fatty acid eicosapentaenoic acid, whereas there was no association between total or individual marine n-3 polyunsaturated fatty acid levels and cancer mortality. CONCLUSIONS Higher plasma phospholipid marine n-3 polyunsaturated fatty acid levels were independently associated with better patient survival.

Aortic Stiffness in a Mortality Risk Calculator for Kidney Transplant Recipients.

Background The association between aortic stiffness and all-cause mortality in kidney transplant recipients (KTRs) is uncertain, and aortic stiffness has not yet been incorporated into risk prediction tools. Methods During 2007 to 2012, we measured carotid-femoral pulse wave velocity (PWV; SphygmoCor apparatus) 8 weeks after transplantation. The association between PWV and mortality was assessed in a Cox regression analysis adjusting for seven risk factors from a previously validated model. Internal validation was performed by bootstrap resampling, and discrimination and overfitting evaluated by Harrell’s C and the calibration slope. Results Of 1497 KTRs, 1040 (69%) had a valid PWV measurement. During a median follow-up of 4.2 years, 82 patients died. The association between PWV and mortality showed a ceiling effect, and PWV was truncated at 12 m/sec. Each 1 m/sec increase in PWV, up to 12 m/sec, was associated with mortality, hazard ratio (HR) 1.36 (95% CI, 1.14-1.62; P = 0.001). An interquartile range increase (3.8 m/sec) tripled the hazard of mortality, HR, 3.21 (95% CI, 1.63-6.31), similar to the effect of being approximately 20 years older (interquartile range increase (21.6 years); HR, 3.06 [95% CI, 1.87-5.29]). The PWV improved model discrimination with an increase in Harrell’s C from 0.76 to 0.78; C difference, 0.024 (95% CI, 0.005-0.043; P = 0.01). Overfitting was moderate with a calibration slope of 0.89, and the final model was adjusted accordingly. A spreadsheet version is presented to estimate expected 5-year survival. Conclusions The PWV is a strong risk factor for mortality in KTRs.

Serum Calcification Propensity Is a Strong and Independent Determinant of Cardiac and All‐Cause Mortality in Kidney Transplant Recipients

Calcification of the vasculature is associated with cardiovascular disease and death in kidney transplant recipients. A novel functional blood test measures calcification propensity by quantifying the transformation time (T50) from primary to secondary calciprotein particles. Accelerated T50 indicates a diminished ability of serum to resist calcification. We measured T50 in 1435 patients 10 weeks after kidney transplantation during 2000–2003 (first era) and 2009–2012 (second era). Aortic pulse wave velocity (APWV) was measured at week 10 and after 1 year in 589 patients from the second era. Accelerated T50 was associated with diabetes, deceased donor, first transplant, rejection, stronger immunosuppression, first era, higher serum phosphate and lower albumin. T50 was not associated with progression of APWV. During a median follow‐up of 5.1 years, 283 patients died, 70 from myocardial infarction, cardiac failure or sudden death. In Cox regression models, accelerated T50 was strongly and independently associated with both all‐cause and cardiac mortality, low versus high T50 quartile: hazard ratio 1.60 (95% confidence interval [CI] 1.00–2.57), ptrend = 0.03, and 3.60 (95% CI 1.10–11.83), ptrend = 0.02, respectively. In conclusion, calcification propensity (T50) was strongly associated with all‐cause and cardiac mortality of kidney transplant recipients, potentially via a cardiac nonAPWV‐related pathway. Whether therapeutic improvement of T50 improves outcome awaits clarification in a randomized trial.

Limitations of hemoglobin A1c for the diagnosis of posttransplant diabetes mellitus.

Background Posttransplant diabetes mellitus (PTDM) is usually detected 2 to 3 months after transplantation by fasting plasma glucose (fPG) ≥7.0 mmol/L (≥126 mg/dL) and/or 2 hr post-challenge plasma glucose ≥11.1 mmol/L (≥200 mg/dL) during an oral glucose tolerance test (OGTT). Recently, glycosylated hemoglobin (HbA1c) of 6.5% or higher (≥47.5 mmol/mol) has been proposed as an alternative diagnostic criterion (the HbA1c criterion). We aimed to assess the sensitivity of applying the HbA1c criterion alone or in combination with a single measurement of fPG of 7.0 mmol/L or higher (≥126 mg/dL) at 10 weeks after transplantation as screening tests for the diagnosis of PTDM. Methods From 1999 to 2011, measurements of fPG, HbA1c, and OGTT were performed in 1,619 nondiabetic renal transplant recipients. Results The HbA1c criterion detected 38.0% of patients with PTDM diagnosed with the standard diagnostic criteria. The specificity was 86.3%. When the HbA1c threshold value was lowered to 6.2% (44.3 mmol/mol), sensitivity increased to 57.8% with a corresponding reduced specificity of 80.4%. A combination of the HbA1c criterion and fPG of 7.0 mmol/L or higher (126 mg/dL) at 10 weeks after transplantation improved diagnostic precision with a sensitivity of 77.7% and a specificity of 96.1%. Conclusion The proposed diagnostic HbA1c criterion failed to detect most cases of PTDM, and one of four cases of PTDM was detected by OGTT alone. This indicates that the HbA1c threshold value likely needs to be lowered for renal transplant recipients and supports continued use of OGTT as a diagnostic tool for detection of PTDM.

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.

Visceral fat is better related to impaired glucose metabolism than body mass index after kidney transplantation

The role of visceral adipose tissue (VAT) in post‐transplant hyperglycaemia is not known. We evaluated 167 patients without diabetes 8‐10 weeks after kidney transplantation, performing oral glucose tolerance tests and measuring VAT content from dual‐energy X‐ray absorptiometry scans. Median VAT weight in normal glucose tolerance patients was 0.9 kg, impaired fasting glucose patients 1.0 kg, impaired glucose tolerance patients 1.3 kg and patients with post‐transplant diabetes (PTDM) 2.1 kg (P = 0.004, indicating a difference between groups). Percentage VAT of total body fat was associated with fasting (R2 = 0.094, P < 0.001) and 2‐h glucose concentration (R2 = 0.062, P = 0.001), while BMI was only associated with 2‐h glucose concentration (R2 = 0.029, P = 0.028). An association between BMI and 2‐h glucose concentration was lost in adjusted models, as opposed to the associations between VAT as percentage of total body fat and glucose concentrations (R2 = 0.132, P < 0.001 and R2 = 0.097, P = 0.001, respectively for fasting and 2‐h glucose concentration). In conclusion, VAT is more closely related to impaired glucose metabolism than BMI after kidney transplantation. The association with central obesity should encourage additional studies on lifestyle interventions to prevent PTDM.