Anna Varberg Reisæter

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.

Living donor kidney transplantation : The effects of donor age and gender on short-and long-term outcomes

Background. The influence of donor age and sex on acute rejection episodes and short- and long-term graft survival in living donor (LD) kidney transplantation has not been well characterized. Methods. This prospective cohort study includes 739 first time LD transplantations with median follow-up time of 55.1 months. Death censored graft survival according to donor age and sex was compared with Kaplan–Meier plots. Cox regression was performed to estimate the association between different risk factors and graft survival and acute rejection episodes. Results. Graft survival was not affected by donor age above 50 years as long as these recipients did not experience an early acute rejection episode. Acute rejection episodes increased in recipients of grafts from donors ≥65 years (P=0.009). Donor age ≥65, recipient age less than 50 years, human leukocyte antigen (HLA)-DR matching, and female donor gender were risk factors for early acute rejection episodes. In multivariate analysis donor age ≥65 years was a risk factor for graft loss in all time periods after transplantation. During the first 5 years after transplantation a steroid resistant rejection episode was an additional risk factor. More than 5 years after transplantation male donor gender was the only additional risk factor for graft loss. Conclusion. These results support the continued use of older male and female living donors who meet carefully constructed medical criteria and who are highly motivated to donate. Furthermore, donor age seems to be a more important predictor of graft loss than donor sex.

Pregnancy and Birth After Kidney Donation: The Norwegian Experience

Reports on pregnancies in kidney donors are scarce. The aim was to assess pregnancy outcomes for previous donors nationwide. The Medical Birth Registry of Norway holds records of births since 1967. Linkage with the Norwegian Renal Registry provided data on pregnancies of kidney donors 1967–2002. A random sample from the Medical Birth Registry was control group, as was pregnancies in kidney donors prior to donation. Differences between groups were assessed by two‐sided Fishers exact tests and with generalized linear mixed models (GLMM). We identified 326 donors with 726 pregnancies, 106 after donation. In unadjusted analysis (Fisher) no differences were observed in the occurrence of preeclampsia (p = 0.22). In the adjusted analysis (GLMM) it was more common in pregnancies after donation, 6/106 (5.7%), than in pregnancies before donation 16/620 (2.6%) (p = 0.026). The occurrence of stillbirths after donation was 3/106 (2.8%), before donation 7/620 (1.1%), in controls (1.1%) (p = 0.17). No differences were observed in the occurrence of adverse pregnancy outcome in kidney donors and in the general population in unadjusted analysis. Our finding of more frequent preeclampsia in pregnancies after kidney donation in the secondary analysis must be interpreted with caution, as the number of events was low.

Fasting plasma glucose and glycosylated hemoglobin in the screening for diabetes mellitus after renal transplantation.

Background. Fasting plasma glucose (fPG) is recommended to identify new-onset posttransplant diabetes mellitus (PTDM), but an oral glucose tolerance test (OGTT) has higher diagnostic sensitivity. We aimed to assess the accuracy of fPG and glycosylated hemoglobin (HbA1c) for the selection of patients who should undergo a diagnostic OGTT 10 weeks after renal transplantation. Methods. A total of 1571 renal transplant recipients without prior diabetes underwent an OGTT 10 weeks after transplantation. Receiver operating characteristic analyses were used to identify optimal thresholds to incite further diagnostic tests. A sensitivity level of 80% was chosen for screening purpose. Results. We diagnosed PTDM in 213 (14%) patients of whom 109 (51%) were identified by 2-hr plasma glucose more than or equal to 11.1 mmol/L alone, 35 (17%) by fPG alone, and 69 (32%) by both criteria. Receiver operating characteristic analysis revealed an area under the curve of 0.761 (95% confidence interval 0.714–0.809) for fPG and 0.817 (95% confidence interval 0.758–0.876) for HbA1c. Performing an OGTT on patients with an fPG more than or equal to 5.3 mmol/L or HbA1c more than or equal to 5.8% predicted diabetes with 81% and 83% sensitivity, requiring 49% and 41% of the patients to be tested, respectively. The combined criterion fPG more than or equal to 5.0 mmol/L and HbA1c more than or equal to 5.7%, provided a similar sensitivity (79%) from testing only 29% of the population. Conclusion. We conclude that patients with an fPG between 5.3 and 6.9 mmol/L or HbA1c more than or equal to 5.8%, alternatively an fPG more than or equal to 5.0 mmol/L combined with HbA1c more than or equal to 5.7% in the early posttransplant period should undergo an OGTT for diagnostic verification of PTDM.

Early versus late acute antibody-mediated rejection in renal transplant recipients.

Background Over the last decade, the diagnostic precision for acute antibody-mediated rejection (aABMR) in kidney transplant recipients has improved significantly. The phenotypes of early and late aABMR may differ. We assessed the characteristics and outcomes of early versus late aABMR. Methods Between January 1, 2005 and December 31, 2010, aABMR was diagnosed in 67 grafts in 65 kidney recipients, with a median follow-up of 3.6 years (range, 61 days–7.3 years). Recipients were stratified by early aABMR (<3 months after transplantation; n=40) and late aABMR (>3 months after transplantation; n=27). The main outcome was kidney allograft loss. Outcome of aABMR was compared with recipients with acute early (n=276) or late (n=100) non-ABMR during the same period. Results Recipients with late aABMR had significantly reduced graft survival compared with recipients with early aABMR (P<0.001, log-rank test; 40% vs. 75% at 4 years; hazard ratio, 3.72; 95% confidence interval, 1.65–8.42). Graft survival in late aABMR was also inferior to late non-ABMR acute rejections (P=0.008). At transplantation, more patients were presensitized to human leukocyte antigens (22 [55%] vs. 4 [15%] in the early vs. late aABMR group). The late aABMR group was characterized by younger recipient age (37.9±12.9 vs. 50.9±11.6 years; P<0.001), increased occurrence of de novo donor-specific antibodies (52% vs. 13%; P=0.001), and nonadherence/suboptimal immunosuppression (56% vs. 0%; P<0.001). Conclusion Compared with early aABMR, late aABMR had inferior graft survival and was characterized by young age, frequent nonadherence, or suboptimal immunosuppression and de novo donor-specific antibodies.

Complement activation in early protocol kidney graft biopsies after living-donor transplantation1

Background. To gain insight into complement activation in kidney grafts, we studied the deposition of components from all complement pathways in protocol biopsies from living-donor recipients that were taken 1 week (median 7 days) after transplantation. Methods. Graft protocol biopsies (n=37) were taken consecutively and stained for two-color immunofluorescence, with antibodies to C4d, C3, C1q, factor B, C6, terminal C5b-9 complement complex, mannose-binding lectin (MBL), and MBL-associated serine protease-1, combined with an endothelial marker. Light and electron microscopy were performed in all cases. Clinical acute rejection (AR), graft loss, and long-term kidney function were recorded. Baseline biopsies from 15 of the patients served as controls. Results. Endothelial C4d deposition was demonstrated in peritubular capillaries in 11 of 37 cases (30%), of which 9 of 11 (82%) experienced clinical AR but only 6 of 11 (55%) experienced AR as defined by histopathologic criteria. Biopsies from three patients, two with early graft loss, showed diffuse global C4d in the glomerular endothelium with codeposition of C3 in all patients and MBL-associated serine protease-1 in one patient. Focal peritubular capillary C3 deposition was found in two additional C4d-positive cases with AR. No posttransplant deposition was demonstrated for the other components. Conclusions. Early diffuse C4d deposition in the kidney graft capillaries is closely related to acute humoral rejection, whereas focal staining may occur with mild AR or, rarely, without rejection. Codeposition of C3 indicates early AR with a higher risk of graft loss. In most cases, activation was limited to C4d, indicating efficient in situ regulation of complement activation.

Cardiovascular and noncardiovascular mortality among men and women starting dialysis

BACKGROUND AND OBJECTIVES Although women have a survival advantage in the general population, women on dialysis have similar mortality to men. We hypothesized that this paired mortality risk during dialysis may be explained by a relative excess of cardiovascular-related mortality in women. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We compared 5-year age-stratified cardiovascular and noncardiovascular mortality rates, relative risks, and hazard ratios in a European cohort of incident adult dialysis patients (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry) with the European general population (Eurostat). Cause of death was recorded by ERA-EDTA codes in dialysis patients and by International Statistical Classification of Diseases codes in the general population. RESULTS Overall, sex did not have a predictive effect on outcome in dialysis. Stratification into age categories and causes of death showed greater noncardiovascular mortality in young women (<45 years). In other age categories (45 to 55 and >55 years), women presented lower cardiovascular mortality. This cardiovascular benefit was, however, smaller than in the general population. Stratification by diabetic nephropathy showed that diabetic women in all age categories remained at increased mortality risk compared with men, an effect mainly attributed to the noncardiovascular component. CONCLUSIONS Mortality rates and causes of death in men and women on dialysis vary with age. Increased noncardiovascular mortality may explain the loss of the survival advantage of women on dialysis. Both young and diabetic women starting dialysis are at a higher mortality risk than equal men.

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.

Calcineurin Inhibitor Avoidance with Daclizumab, Mycophenolate Mofetil, and Prednisolone in Dr-matched de Novo Kidney Transplant Recipients

Background. Calcineurin inhibitor (CNI)–free regimens posttransplantation have been claimed to conserve graft function in addition to reduce the risk factors for cardiovascular and malignant disease in renal transplant recipients. Methods. The primary aim of this prospective, open-label, randomized, parallel-group, single-center study was to compare the effect of complete CNI-avoidance posttransplant (daclizumab + mycophenolate mofetil + prednisolone: Dac-group, n=27) with the standard CNI-based immunosuppressive protocol at our transplant unit (cyclosporine A + mycophenolate mofetil + prednisolone: CsA-group, n=27) on renal function (glomerular filtration rate [GFR] determined as plasma clearance of 51Cr-EDTA) in a selected low immunogenic risk population (DR-matched, PRA-negative de novo cadaveric transplant recipients). Results. There were no significant difference in GFR at week 10 (P=0.61), but GFR was significantly (P=0.029) lower in the Dac-group (52±20 ml/min) at month 12 than in the CsA-group (69±29 ml/min). One-year patient and graft survival did not differ between the two groups. Overall acute rejection rate was 70.4% (19/27) in the Dac-group and 29.6% (8/27) in the CsA-group (P=0.006). Conclusions. The strategy to select DR-matched, PRA-negative de novo cadaveric transplant recipients for a CNI-avoidance protocol was not successful. The incidence of acute rejection was unacceptable high even though anti-CD25 antibody induction as well as initial higher mycophenolate mofetil doses (3 g/day) were applied, and renal function was significantly lower in the CNI-avoidance patients at 1 year. Other strategies need to be examined for avoidance of CNIs in the early posttransplant period.

Long-term outcome of pediatric renal transplantation: the Norwegian experience in three eras 1970-2006.

Abstract:  During the years 1970–2006, 251 renal transplantations were performed in 178 children in Norway. The proportion of LD was 84%. Transplantations were performed preemptively in 52%. Pretransplant dialysis time was median three months. Structural abnormalities and hereditary renal disorders constituted 69% of end‐stage renal diseases, 29% were caused by glomerulopathies and other acquired disorders and 2% of unknown cause. Patient survival rates were 94.2, 93.5, and 84.4% at five, 10, and 20 yr, respectively. The most frequent cause of death was infections followed by cardiovascular events. For recipients of living donor grafts (n = 149), survival of first transplant was 82, 68.8, and 45.1% at five, 10, and 20 yr, respectively, and was significantly higher than for recipients of deceased donor organs (n = 29; log rank, p = 0.008). The only significant predictor for better transplant survival when modeled with multiple regression analysis adjusted for pretransplant dialysis, diagnosis, donor age, sex and immunosuppressive era, was the use of LD compared with DD (HR = 2.1, 95% CI [1.1–4.0], p = 0.02). The acute rejection rate declined significantly from 61.5% in 1970–1982 to 14.5% in 2000–2006 (log rank, p = 0.002). It remains to be seen whether the reduction in acute rejection rate and present immunosuppressive therapy will have a positive impact on long‐term graft survival in years to come.