Karsten Midtvedt

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.

Insulin Resistance after Renal Transplantation: The Effect of Steroid Dose Reduction and Withdrawal

Cardiovascular disease is a prevalent and serious complication after solid organ transplantation. Treatment with glucocorticoids is associated with increased risk for diabetes mellitus, insulin resistance, weight gain, hypercholesterolemia, and hypertension, all shown to be independent risk factors for cardiovascular disease. We sought to test the hypothesis that tapering of prednisolone (TAP) the first year after renal transplantation improves insulin sensitivity (IS), and to assess the effect of complete steroid withdrawal (SW) on IS in patients on a cyclosporine-based immunosuppressive regimen. All patients (n = 57) completed two consecutive hyperinsulinemic euglycemic glucose clamp procedures, a TAP group (n = 34) and a control group (n = 12) at 3 and 12 mo after transplantation, and a SW group (n = 11) before and 5 mo after SW. The IS index (ISI) was calculated as the glucose disposal rate divided by mean serum insulin the last 60 min of the clamp. In the TAP group, the mean (range) daily prednisolone was reduced from 16 (10 to 30) to 9 (5 to 12.5) mg accompanied by an average increased ISI of 24% (P = 0.008). In contrast, no significant change in ISI was observed in the control group (0%, P = 0.988). In the SW group, withdrawal of 5 mg prednisolone did not influence mean ISI significantly (-8%, P = 0.206). Lowering daily prednisolone toward 5 mg/d has beneficial effects on insulin action after renal transplantation, but withdrawal of 5 mg prednisolone may not influence IS significantly.

Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients treated with nifedipine as compared to lisinopril

BACKGROUND Treatment of posttransplant hypertension is still a matter of debate. Calcium antagonists may ameliorate renal side effects of cyclosporin. Angiotensin converting enzyme- (ACE) inhibitors may be more effective in sustaining renal function in native chronic renal disease. We prospectively compared the effect of controlled release nifedipine and lisinopril on long-term renal function in hypertensive kidney transplant patients treated with cyclosporin. METHODS A total of 154 renal transplant patients presenting with hypertension (diastolic blood pressure >or=95 mmHg) during the first 3 weeks after transplantation were randomised to receive double-blind nifedipine 30 mg or lisinopril 10 mg once daily. A total of 123 patients completed 1 year of treatment (69 nifedipine, 54 lisinopril) and 64 patients completed 2 years of double-blind treatment (39 nifedipine, 25 lisinopril). Baseline glomerular filtration rate was measured as 99 mTc-diethylene-triaminepentaacetate clearance in a stable phase 2 to 5 weeks after inclusion and repeated at 1 and 2 years. RESULTS Baseline glomerular filtration rates were similar (46+/-16 ml/min with nifedipine, 43+/-14 ml/min with lisinopril). The changes in glomerular filtration rates from baseline were statistically significant between the groups after 1 year (9.6 ml/min mean treatment difference (95% confidence interval [CI]s 5.5-13.7 ml/min, P=0.0001) and remained statistically significant also after 2 years (10.3 ml/min mean difference (95% CIs 4.0-16.6], P=0.0017). After 1 year glomerular filtration rates averaged 56+/-19 ml/min in the nifedipine group and 44+/-14 ml/min in the lisinopril group. CONCLUSIONS Both nifedipine and lisinopril were safe and effective in treatment of hypertension in renal transplant patients treated with cyclosporin. Patients receiving nifedipine but not lisinopril improved kidney transplant function over a period of 2 years.

Conversion of Long-Term Kidney Transplant Recipients From Calcineurin Inhibitor Therapy to Everolimus: A Randomized, Multicenter, 24-Month Study

Background. Benefits of conversion from calcineurin inhibitor (CNI) to mammalian target of rapamycin inhibitor-based immunosuppression in long-term kidney transplant patients remain uncertain. Methods. ASCERTAIN was a 24-month, open-label, multicenter study. Kidney transplant patients more than 6 months posttransplant receiving CNI (baseline glomerular filtration rate [GFR] 30–70 mL/min/1.73 m2) were randomized to everolimus with CNI elimination (n=127) or CNI minimization (n=144), or continued CNI unchanged (controls, n=123) to assess the effect on measured GFR at month 24 after randomization. Results. Renal function was stable in all groups to month 24. Mean measured GFR at month 24, the primary endpoint, was 48.0±22.0 mL/min/1.73 m2, 46.6±21.1 mL/min/1.73 m2, and 46.0±20.4 mL/min/1.73 m2 in the CNI elimination, CNI minimization, and control groups, respectively. Differences between CNI elimination (1.12 mL/min/1.73 m2, 95% confidence interval [CI] −3.51 to 5.76, P=0.63) and CNI minimization (0.59 mL/min/1.73 m2, 95% CI −3.88 to 5.07, P=0.79) versus controls at month 24 were nonsignificant that is, the primary endpoint was not met. No efficacy endpoint differed significantly between groups. Post hoc analyses showed that patients with baseline creatinine clearance (CrCl) more than 50 mL/min had a significantly greater increase in measured GFR after CNI elimination versus controls (difference 11.4 mL/min/1.73 m2, 95% CI 2.1 to 20.8 mL/min/1.73 m2, P=0.017). Adverse events resulted in discontinuation in 36 (28.3%) CNI elimination patients, 24 (16.7%) CNI minimization patients, and 5 (4.1%) controls (P<0.001 vs. CNI elimination; P=0.020 vs. CNI minimization). Conclusion. Conversion to everolimus with CNI elimination or minimization a mean of 5.6 years after kidney transplantation had no overall renal benefit and was associated with more frequent adverse events and discontinuations. Patients with CrCl more than 50 mL/min may benefit from a change in therapy more than 6 months after renal transplantation.

Recommendations for the implementation of neoral C2 monitoring in clinical practice

University of Toronto, Toronto General Hospital, 621 University Ave., Toronto, Ontario, M5G 2C4, Canada; Medical Department of Nephrology, Rikshospitalet, Oslo N-0027, Norway; Barts and The London, Queen Mary’s School of Medicine and Dentistry, Charterhouse Square, London EC1 M 6BQ, UK; Renal Unit, Guy’s Hospital, London SE1 9RT, UK; University of Toronto, Toronto General Hospital, 621 University Ave., Toronto, Ontario, M5G 2C4, Canada

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.

Benefit of kidney transplantation beyond 70 years of age

Background. Kidney transplantation generally improves long-term survival in patients with end-stage renal disease. However, in patients older than 70 years of age, only limited data are available that directly compare the potential survival benefit of transplantation versus dialysis. Methods. All patients aged above 70 years who started dialysis between 1990 and 2005 and were waitlisted for kidney transplantation were included in the study. They were categorized according to time periods of inclusion (1990–99 vs 2000–05). Survival rates of altogether 286 dialysis patients were analyzed with a Kaplan–Meier model, as well as with a time-dependent Cox model. Comparisons were made between those who received a transplant and those who did not, and further between the two time periods. Results. Median age at inclusion was 73.6 years (interquartile range 72.3–75.6). Two hundred and thirty-three patients (81%) received a kidney transplant during follow-up. Transplant recipients experienced an increased mortality in the first year after transplantation when compared to waitlisted patients. Patients starting dialysis between 1990 and 1999 had no significant long-term benefit of transplantation; HR for death 1.01 (0.58–1.75). In contrast, there was a substantial long-term benefit of transplantation among those starting dialysis after 2000; HR for death 0.40 (0.19–0.83), P = 0.014. Conclusions. Survival after kidney transplantation in patients over 70 years has improved during the last decade and offers a survival advantage over dialysis treatment. Our experience supports the use of kidney transplantation in this age group if an increased early post-operative risk is accepted. This transplant policy may be challenged for priority reasons.

Assessment of renal allograft fibrosis by acoustic radiation force impulse quantification--a pilot study.

Chronic allograft nephropathy characterized by interstitial fibrosis and tubular atrophy is a major cause of renal transplant failure. Acoustic radiation force impulse (ARFI) quantification is a promising noninvasive method for assessing tissue stiffness. We evaluated if the method could reveal renal transplant fibrosis. In a prospective study, 30 adult renal transplant recipients were included. ARFI quantification, given as shear wave velocity (SWV), of the renal cortex was performed by two observers. SWV was compared to grade of fibrosis (0–3) in biopsies. The median SWV was 2.8 m/s (range: 1.6–3.6), 2.6 m/s (range: 1.8–3.5) and 2.5 m/s (range: 1.6–3) for grade 0 (n = 12), 1 (n = 10) and grades 2/3 (n = 8) fibrosis respectively. SWV did not differ significantly in transplants without and with fibrosis (grade 0 vs. grade 1, P = 0.53 and grade 0 vs. grades 2/3, P = 0.11). The mean intraobserver coefficient of variation was 22% for observer 1 and 24% for observer 2. Interobserver agreement, expressed as intraclass correlation coefficient was 0.31 (95% CI: −0.03 to 0.60). This study does not support the use of ARFI quantification to assess low‐grade fibrosis in renal transplants. ARFI quantification in its present stage of development has also high intra‐ and interobserver variation in renal transplants.

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.

Reduction of left ventricular mass by lisinopril and nifedipine in hypertensive renal transplant recipients: a prospective randomized double-blind study.

Background. Cardiovascular disease is the dominant cause of death in renal transplant recipients. Left ventricular hypertrophy (LVH) is a known risk factor. After renal transplantation, persistent hypertension is an important determinant for the further evolution of LVH. The aim of the present study was to compare the effect of an angiotensin converting enzyme (ACE) inhibitor (lisinopril) with a calcium channel blocker (CCB) (controlled release nifedipine) in treatment of posttransplant hypertension focusing on changes in LVH. Methods. One hundred fifty-four renal transplant recipients presenting with hypertension (diastolic BP≥95 mmHg) during the first 3 weeks after transplantation were randomized to receive double-blind 30 mg nifedipine or 10 mg lisinopril once daily. Results. One hundred twenty-three patients completed 1 year of treatment. Good quality echocardiographic data were available in 116 recipients (62 nifedipine/54 lisinopril) 2 and 12 months posttransplant. Blood pressure was equally well controlled in the two groups throughout the study (mean systolic/diastolic±SD after 1 year: 140±16/87±8 mmHg with nifedipine and 136±17/85±8 mmHg with lisinopril). Left ventricular mass index was reduced by 15% (P <0.001) in both groups (from 153±43 to 131±38 g/m2 with nifedipine and from 142±35 to 121±34 g/m2 with lisinopril). There were no statistically significant differences between the two treatment groups at baseline or at follow-up. Conclusions. In hypertensive renal transplant recipients with well-controlled blood pressure, there is a regression of left ventricular mass after renal transplantation. The regression of left ventricular mass index is observed to a similar extent in patients treated with lisinopril or nifedipine.