Geir Mjøen

Long-term risks for kidney donors

Previous studies have suggested that living kidney donors maintain long-term renal function and experience no increase in cardiovascular or all-cause mortality. However, most analyses have included control groups less healthy than the living donor population and have had relatively short follow-up periods. Here we compared long-term renal function and cardiovascular and all-cause mortality in living kidney donors compared with a control group of individuals who would have been eligible for donation. All-cause mortality, cardiovascular mortality, and end-stage renal disease (ESRD) was identified in 1901 individuals who donated a kidney during 1963 through 2007 with a median follow-up of 15.1 years. A control group of 32,621 potentially eligible kidney donors was selected, with a median follow-up of 24.9 years. Hazard ratio for all-cause death was significantly increased to 1.30 (95% confidence interval 1.11-1.52) for donors compared with controls. There was a significant corresponding increase in cardiovascular death to 1.40 (1.03-1.91), while the risk of ESRD was greatly and significantly increased to 11.38 (4.37-29.6). The overall incidence of ESRD among donors was 302 cases per million and might have been influenced by hereditary factors. Immunological renal disease was the cause of ESRD in the donors. Thus, kidney donors are at increased long-term risk for ESRD, cardiovascular, and all-cause mortality compared with a control group of non-donors who would have been eligible for donation.

Morbidity and Mortality in 1022 Consecutive Living Donor Nephrectomies: Benefits of a Living Donor Registry

Background. We assessed postoperative complication rates in living donor nephrectomies (LDN) during the last decade (1997–2008). Methods. Postoperative complications were classified by the Clavien grading system. We defined Clavien grade more than or equal to 3 as major complications. A total of 1022 LDNs performed during the period 1997–2008 were included. Results. Median age at donation was 47.7 years (range 18.4–78.9), and mean body mass index was 25.4 (SD 3.2). There was no peri- or postoperative mortality. Laparoscopic nephrectomy was performed in 244 (23.9%) donors. Three of these needed surgical conversion. A total of 30 major (2.9%) and 184 (18%) minor complications were registered. There was a higher frequency of major complications in the laparoscopic group (4.1% vs. 2.6%), but the difference was not statistically significant. Twenty-three donors underwent early re-operations. Wound infection developed in 3.7% of donors. Increased risk was associated with body mass index more than 25 (OR 4.03; 95% CI 1.80, 9.04) and smoking (OR 4.38; 95% CI 2.30, 9.96). Significant perioperative bleeding occurred in 1.6%. There were seven cases of renal artery laceration. Increased risk for a combined endpoint of intraoperative incidents, major complications and significant bleeding were seen in relation to laparoscopic surgery (OR 2.63; 95% CI 1.33, 5.19). Conclusion. The risk of major complications related to LDN is low, but do represent a potential hazard to the donor. The special nature of LDN and the constantly evolving operative technique requires vigilant surveillance, by the use of national or supranational registries/databases.

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.

Quality of life in kidney donors.

Reports on quality of life of kidney donors include small populations with variable response rates. The aim was to evaluate quality of life in kidney donors in a large cross‐sectional study. Through the Norwegian Renal Registry we contacted all 1984 kidney donors in the period 1963–2007 with a response rate of 76%. All received the Short‐Form‐36 (SF ‐ 36) survey form and a questionnaire specifically designed for kidney donors. SF ‐ 36 scores for a subgroup (n = 1414) of kidney donors were not inferior to a general population sample, adjusted for age, gender and education. When asked to reconsider, a majority stated that they still would have consented to donate. Risk factors for having doubts were graft loss in the recipient (OR 3.1, p < 0.001), medical problems after donation (OR 3.7, p < 0.001), unrelated donor (OR 2.2, p = 0.01) and less than 12 years since donation (OR 1.8, p = 0.04). Older age at donation was associated with lower risk (OR 0.98, p = 0.03). Compared with other donors, those expressing doubts had inferior SF ‐ 36 scores. Norwegian kidney donors are mostly first‐degree relatives. They are fully reimbursed and offered life‐long follow‐up. All inhabitants are provided universal healthcare. This should be considered when extrapolating these results to other countries.

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.

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.

One- and five-year follow-ups on blood pressure and renal function in kidney donors.

It is considered safe to donate a kidney if internationally accepted medical criteria are fulfilled. However, some donors have encountered hypertension, proteinuria and impaired renal function after donation. The study was based on retrospective data on 908 donors, donating in the period 1997–2007. Preoperative and follow‐up data were collected from patient files and the Norwegian Living Donor Registry. Follow‐up data were available for 665 donors at 1 year after donation, and 256 donors at 5 years after donation. We calculated the estimated glomerular filtration rate (eGFR) using the four variable Modification of Diet in Renal Disease equation. At 1 and 5 years after donation, the prevalence of hypertension was 11.7% and 27.1% respectively compared to 2.6% before donation. Proteinuria was present in 3.3% and 1.6% at 1 and 5 years. Mean eGFR was 56.1 ± 10.8 ml/min/1.73 m² at 1 year and 61.0 ± 11.8 ml/min/1.73 m² at 5 years. Mean blood pressure was 122.5 ± 10.6/76.2 ± 7.5 mmHg at donation (n = 908), 124.3 ± 14.2/77.9 ± 8.2 mmHg at 1‐year (n = 649) and 127.2 ± 15.4/78.8 ± 8.3 mmHg at 5‐year follow‐ups (n = 247). We found no evidence of further decline in renal function beyond the initial decrement following nephrectomy.

High ficolin-3 level at the time of transplantation is an independent risk factor for graft loss in kidney transplant recipients.

Background Recent studies have shown that activation of the complement system may be associated with long-term graft function. The aim of this retrospective study was to assess the impact of the pattern recognition molecules of the lectin pathway on long-term graft survival after kidney transplantation. Methods Patients transplanted in 2000 to 2001 were included. Mannose-binding lectin, Ficolin-1, and Ficolin-3 were measured in serum at the time of transplantation. Data on death-censored graft loss were obtained from the Norwegian Renal Registry. Competing risks regression was used to investigate the association between time to graft loss and the explanatory variables. The variables were: high Ficolin-3 (upper quartile, ≥33.3 &mgr;g/mL) versus low Ficolin-3 (<33.3 &mgr;g/mL), acute rejection (time-dependent), age, basiliximab induction, sex, donor age, human leukocyte antigen mismatches, human leukocyte antigen antibodies, cold ischemia time, living donor, and preemptive transplantation. Results A total of 382 patients with a median follow-up of 9.8 years were included. Sixty-six patients (17%) had death-censored graft loss, and 116 (30%) patients died. In a final competing risks model, high Ficolin-3 (subhazard ratio [SHR] = 1.95, P = 0.009), acute rejection (one vs. none) (SHR = 1.93, P = 0.033), acute rejection (two vs. none) (SHR = 5.45, P < 0.001), and age (SHR = 0.98, P = 0.006) were associated with death-censored graft loss. Basiliximab induction was associated with improved graft survival (SHR = 0.50, P = 0.016). No associations between mannose-binding lectin or Ficolin-1 and graft loss were found. Conclusion High Ficolin-3 level at the time of transplantation was an independent significant risk factor for shorter graft survival, even when adjusted for other covariates.