Papers by Anders Hartmann
Antiviral Therapy
Background The rate of cytomegalovirus (CMV) mutations conferring ganciclovir resistance was asse... more Background The rate of cytomegalovirus (CMV) mutations conferring ganciclovir resistance was assessed in a trial comparing intravenous ganciclovir and oral valganciclovir for treatment of CMV disease in solid organ transplant (SOT) recipients. Methods Viral genes ( UL97 and UL54) conferring ganciclovir resistance were amplified and sequenced from blood samples collected at days 0 (before therapy), 21 (end of induction) and 49 (end of maintenance). Results The overall risk of developing a confirmed or probable ganciclovir resistance mutation during treatment was similar for patients treated with ganciclovir (2.3%) and valganciclovir (3.6%; P=0.51). A persistent viral load at day 21 was associated with a significant risk of ganciclovir resistance by day 49 (odds ratio 11.83; P=0.022). In multivariate analyses, presence of a confirmed ganciclovir resistance mutation was independently associated with virological failure (viral load ≥600 copies/ml) at days 21 and 49. One-third (3/9) of p...
Nutrients, 2021
Kidney transplant recipients are at high risk of progressive bone loss and low-energy fractures i... more Kidney transplant recipients are at high risk of progressive bone loss and low-energy fractures in the years following transplantation. Marine n-3 polyunsaturated fatty acids (n-3 PUFA) supplementation may have beneficial effects on bone strength. The Omega-3 fatty acids in Renal Transplantation (ORENTRA) trial was an investigator initiated, randomized, placebo-controlled trial investigating the effects of marine n-3 PUFA supplementation after kidney transplantation. Effects of supplementation on bone mineral density (BMD) and calcium metabolism were pre-defined secondary endpoints. Adult kidney transplant recipients (n = 132) were randomized to 2.6 g marine n-3 PUFA supplement or olive oil (control) from 8 to 52 weeks post-transplant. Dual energy X-ray absorptiometry was performed to assess changes in bone mineral density of hip, spine, and forearm, as well as trabecular bone score (TBS) of the lumbar spine. Student’s t test was used to assess between-group differences. There were ...
Nephrology Dialysis Transplantation, May 1, 2018
concentration defect in 71% of patients, increase of urinary volume in 55.6% and increase in the ... more concentration defect in 71% of patients, increase of urinary volume in 55.6% and increase in the excretion of tubular proteins. The percentage of patients with a high urinary elimination of b2m was 70%, high urinary elimination of CC16 61%, and NAG 20%. We found hyperphosphaturia (TRP<75%) in 35% of patients and hypercalciuria in 27%. We found a high percentage of patients with urinary concentration defect, and 44% of these patients also showed high excretion of tubular proteins. When we compared patients with urine concentration defect and high excretion of tubular proteins (n¼ 28, 44% of patients), with those with a normal tubular function study (n¼ 8), we only found significant differences in phosphate plasmatic levels (3.24 6 0.54 vs 3.6 6 0.34 mg/dl, p¼0.02), TP/GFR (2.5 6 0.44 vs. 2.97 6 0.41 mg/dl, p¼ 0.02) and the mean plasmatic levels of tacrolimus of the postrasplant follow-up (9.03 6 1.38 vs 7.87 6 0.48 ng/ml). We observed that the tacrolimus plasmatic level of the postrasplant follow-up that predicts the development of this tubulopathy was 8.05 ng/ml (RR¼9; CI 95%: 1.25-64.89; p¼ 0.006). We found tubular defects in KT patients that resemble those found in a proximal tubulopathy called "Dent disease". We could hypothesize that this defect at the proximal tubular transport may be due to a defect in the endocytosis of proximal tubular cells, as well as Dent disease, and in KT patients this could be related with the exposure to calcineurin inhibitors drugs, but further studies are needed. CONCLUSIONS: We found a high percentage of tubular defects in KT patients, that resemble those found in a proximal tubulopathy called "Dent disease". This could be explained by a defect in the endocytosis of proximal tubular cells, as well as Dent disease, and in KT patients may be related with the exposure to calcineurin inhibitors drugs.
Nephrology Dialysis Transplantation, May 1, 2018
INTRODUCTION AND AIMS: Tacrolimus (Tac) is the cornerstone of solid organ transplant immunosuppre... more INTRODUCTION AND AIMS: Tacrolimus (Tac) is the cornerstone of solid organ transplant immunosuppression & is also used as second or third line therapy of various immunological diseases. Fatty acids (FAs) may influence Tac absorption & metabolism. To date, no study has investigated effects of marine n-3 FA intake on Tac pharmacokinetics. METHODS: In this single center prospective study, we included 15 renal transplant recipients who received standard maintenance triple immunosuppression with oncedaily tacrolimus (AdvagrafV R ), mycophenolate & prednisolone at one year post-transplant. We performed two 8-hours pharmacokinetic investigations before & after 4 weeks of high-dose marine n-3 FA administration (2.6 g/day). Tac doses were kept unchanged during the treatment period. Standard non-compartmental methods were used to determine pharmacokinetic parameters & we used the European Medicines Agency guidelines for performance of bioequivalence studies to assess pharmacokinetic interaction. RESULTS: Twelve patients, median age 59 years (range 28 -75 years) provided two evaluable pharmacokinetic Tac profiles. Concomitant administration of marine FA supplements induced a 25% 6 30% increase in Tac AUC 0-8 (p < 0.01). Mean Tac AUC 0-8 ratio (before vs after marine n-3 FA supplementation) was 1.22 (90% CI: 1.08-1.37) & corresponding C max ratio was 1.20 (90% CI: 1.11-1.30), which infers that the bioequivalence criteria was not fulfilled. Concordantly, there was a trend towards increased Tac trough concentrations after marine n-3 FA supplementation (before: 5.5 6 1.2 lg/L vs after: 6.3 6 1.8 lg/L, p¼0.19). CONCLUSIONS: In renal transplant recipients, high-dose marine n-3 FA supplementation significantly increased the exposure of once-daily Tac. It is therefore necessary to closely monitor Tac concentrations following initiation & discontinuation of marine n-3 FA supplements.
Background Cardiovascular disease is common in kidney transplant recipients. They are considered ... more Background Cardiovascular disease is common in kidney transplant recipients. They are considered high risk surgery candidates due to comorbidity and immunosuppression. We assessed short-term results of open-heart surgery in kidney transplant recipients and matched controls between 1989 – 2016 at our center. Methods Ninety-five patients underwent open heart surgery (48 coronary artery bypass grafting, 27 valve replacements or repairs and 29 combined procedures) after kidney transplantation. Controls (n=95) were matched for age, sex, type and year of surgery. Mean follow-up was 5.6 (4.9) years. Independent two-sample t-test and chi-square test were used to compare continuous variables and frequencies, respectively. Logistic regression was used to identify preoperative risk factors for 30-day mortality. Results Included were 76 men and 19 women; mean age 60.3 (11.1) years, 7.1 (5.6) years after transplantation. Kidney transplants had lower renal function, more hypertension, but less pu...
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, Jan 24, 2018
The major n-6 polyunsaturated fatty acids linoleic acid (LA) and arachidonic acid (AA) play a rol... more The major n-6 polyunsaturated fatty acids linoleic acid (LA) and arachidonic acid (AA) play a role in inflammation and glucose metabolism, which could affect patient and renal transplant survival. In this single center cohort study of 1988 Norwegian renal transplant recipients, we assessed associations between plasma levels of LA and AA at baseline, measured by gas chromatography, and patient and graft survival, as well as inflammation and cardiovascular risk markers. During follow-up (median of 9.6 years), 595 patients died and 805 renal transplants were lost, either due to recipient death or graft failure. In multivariable survival analysis, we found no associations with mortality for plasma levels of LA (hazard ratios: 0.99, 95% confidence intervals: 0.96-1.01) or AA (hazard ratios: 1.01, 95% confidence intervals: 0.96-1.06). No associations were found for cardiovascular mortality, overall graft loss, or death-censored graft loss. Plasma glucose, proglycemic marker chemerin, and ...
Transplantation direct, 2018
We aimed to evaluate changes in health-related quality of life (HRQoL) in patients 65 years or ol... more We aimed to evaluate changes in health-related quality of life (HRQoL) in patients 65 years or older from time of kidney transplantation (KTx) until 1 year postengraftment. A single-center prospective study was conducted. HRQoL was measured pre-KTx and at 2, 6, and 12 months postengraftment using self-reported Kidney Disease and Quality of Life short-form version 1.3. Intraindividual scores before and after KTx were evaluated. Liu Comorbidity Index was registered at enlisting. short-form-36 scores were additionally compared with scores from an age-matched population. From January 1, 2013, until November 30, 2016, a total of 289 waitlisted patients were included. By September 1, 2017, 134 had reached 1 year postengraftment, and valid questionnaires were available in 120 (90%) patients. Mean age at KTx was 71.6 years (±4.3 years), 71% were male. Living donor was used in 21%, and preemptive KTx was performed in 30% of the recipients. Median waiting time for KTx from deceased donor was ...
Nephrology Dialysis Transplantation, 1999
Nephrology Dialysis Transplantation, 2015
Nephrology Dialysis Transplantation, 2015
American Journal of Transplantation, 2016
Kidney transplanted patients still have significantly higher mortality compared with the general ... more Kidney transplanted patients still have significantly higher mortality compared with the general population. The innate immune system may play an important role during periods, with suppression of the adaptive immune system. In the present study, two soluble pattern recognition molecules of the innate immune system were investigated, collectin liver 1 (CL-L1) and collectin kidney 1 (CL-K1). Potential associations of their pretransplant levels and long-term graft and recipient survival were examined. The levels of CL-L1 and CL-K1 were measured at the time of transplantation in 382 patients (≥17 years) transplanted in 2000-2001. The cohort was subsequently followed until December 31, 2014. Data on patient and graft survival were obtained from the Norwegian Renal Registry. Both high CL-L1 (≥376 ng/mL) and high CL-K1 (≥304 ng/mL) levels were significantly associated with overall mortality in multivariate Cox analyses with hazard ration (HR) 1.50, 95% confidence interval (CI) 1.09-2.07, p = 0.013 and HR 1.43, 95% CI 1.02-1.99, p = 0.038, respectively. Moreover, high CL-K1 levels were significantly associated with cardiovascular mortality. No association between measured biomarkers and death-censored graft loss was found. Finally, there was a significant correlation between these two collectins, r = 0.83 (95% CI 0.80-0.86). In conclusion, CL-L1 and CL-K1 were significantly associated with mortality in kidney transplant recipients.
Transplantation direct, 2016
Calcific uremic arteriolopathy (CUA), also referred to as calciphylaxis, is a rare and serious co... more Calcific uremic arteriolopathy (CUA), also referred to as calciphylaxis, is a rare and serious complication of kidney failure with limited treatment options. Kidney transplantation (KTX) restores kidney function and is hence a potential treatment option for CUA. We present 3 patients who had their CUA lesions successfully healed after urgent KTX. Data were retrospectively retrieved from hospital records at our national transplant center. All 3 patients had previously been kidney transplanted and had experienced graft loss and were in stage 5 kidney failure when CUA developed. One patient was on warfarin treatment for pulmonary embolism. Skin lesions developed in the lower limbs in all 3 patients. Multidisciplinary care including intensified hemodialysis did not induce any clinically relevant improvement of the lesions. The recipients were enlisted on a clinically urgent waitlist for KTX and received a deceased donor kidney after 2 to 4 weeks. All recipients experienced good graft fu...
Clinical Infectious Diseases, 2016
The VICTOR study showed comparable efficacy of treatment with intravenous ganciclovir and oral va... more The VICTOR study showed comparable efficacy of treatment with intravenous ganciclovir and oral valganciclovir for cytomegalovirus (CMV) disease in solid organ transplant recipients. Oral therapy is now recommended treatment in clinical practice and guidelines. The VICTOR biobank was used in a series of post hoc analyses that yielded unique and clinically valuable insights into CMV treatment and pathogenesis. For example, the importance of tailoring therapy to initial viral load, the effect of immunosuppression on outcomes, and the need to continue therapy until undetectable viral load to prevent recurrence and emergence of resistant strains. Data were also used to validate the use of international units (IU) in quantitative measurements of CMV DNAemia, which may help future studies to define relevant cutoffs for treatment guidance. The analyses also showed the importance of inflammation on viral outcomes and identified potential targets for future studies. Here we summarize the valuable lessons learned from analysis of the VICTOR data set and sample repository.
Transplant International, 2013
Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjust... more Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C 0 concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three-compartment model with first-order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat-free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3-4 tacrolimus concentrations were known. After this, a model without CYP3A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation.
Lancet, 2003
Background Renal transplant recipients are at increased risk of premature cardiovascular disease.... more Background Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population. Methods We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4•0-9•0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, nonfatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat. Findings After a mean follow-up of 5•1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0•83 [95% CI 0•64-1•06], p=0•139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0•65 [0•48-0•88] p=0•005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups. Interpretation Although cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.
Nephrology Dialysis Transplantation, 2008
Nephrology Dialysis Transplantation, 2003
Background. It is well known that both insulin resistance and insulin deficiency are involved in ... more Background. It is well known that both insulin resistance and insulin deficiency are involved in the pathogenesis of post-transplant diabetes mellitus (PTDM), but the relative importance of the two different mechanisms is still under debate. The present prospective longitudinal study was performed over 6 years to investigate the impact of impaired insulin secretion (ISec) and insulin sensitivity (IS) in the development of PTDM in renal transplant recipients. Methods. A total of 95 non-diabetic patients underwent a 75 g oral glucose tolerance test (OGTT) 10 weeks post-transplant. Six years later, 63 of these recipients were re-examined, the majority (n ¼ 58) with an OGTT. Fasting, 1-and 2-h insulin and glucose levels were measured and used to estimate the insulin secretory response and IS both at baseline and at follow-up. Results. The proportion of recipients with normal glucose tolerance (NGT) rose from 46% (baseline) to 65% (follow-up) (P ¼ 0.008), and median fasting and 2-h serum glucose were reduced by 0.7 mmol/l (P < 0.001) and 1.3 mmol/l (P ¼ 0.039), respectively. The recipients with PTDM at follow-up had a significant decline in the estimated median first and second phase ISec (-58 and -47%, respectively, P ¼ 0.005 for both). The patients who normalized their glucose tolerance from PTDM or IGT at baseline to NGT at follow-up increased their IS significantly (68%, P ¼ 0.002) without significant alterations in ISec. Conclusions. Impaired ISec seems to be the dominant mechanism in the development of PTDM after renal transplantation. In contrast, normalization of glucose intolerance is associated with improved IS.
Nephrology Dialysis Transplantation, 2014
Background. New-onset diabetes after transplantation (NODAT) is a common complication after renal... more Background. New-onset diabetes after transplantation (NODAT) is a common complication after renal transplantation. There are limited available oral drugs to treat hyperglycaemia in this population owing to reduced renal function, potential interactions with immunosuppressive drugs and adverse effects such as hypoglycaemic events that may increase the cardiovascular risk. This study was initiated to investigate efficacy and safety of sitagliptin treatment that may represent a novel alternative in renal transplant recipients. Methods. Nineteen long-term stable renal transplant recipients with NODAT were included in a controlled, cross-over
Nephrology Dialysis Transplantation, 2009
Background. Renal insufficiency predisposes to insulin resistance, hyperparathyroidism and derang... more Background. Renal insufficiency predisposes to insulin resistance, hyperparathyroidism and derangements in calcium phosphate and nitrogenous compound balance, leading to pre-transplant hyperglycaemia. These metabolic risk factors are not fully corrected after renal transplantation. The present study aimed to assess the role of pre-transplant glycaemia and the named metabolic risk factors in posttransplant hyperglycaemia [PHYG; impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes mellitus (DM)]. Methods. This is a retrospective cohort study involving 301 patients without pre-transplant DM. Measurements included a pre-and post-transplant oral glucose tolerance test (OGTT) as well as glomerular filtration rate (GFR), parathyroid hormone (PTH), phosphate, calcium and urea measured 10 weeks post-transplant. The risk of PHYG at 10 weeks post-transplant was analysed using multiple logistic regression. Results. Ninety-three patients (31%) had PHYG (two IFG, 52 IGT, 39 DM). Variables associated with PHYG included pre-transplant 2-h glycaemia [OR 1.26, 95% CI (1.09, 1.46)] and post-transplant urea levels [OR 1.14, 95% CI (1.02, 1.27)]. Older age, non-Caucasian ethnicity, previous transplants, ≥3 HLA class 1 mismatches and high prednisolone doses were likewise associated with an increased PHYG risk (all P < 0.05). Conclusions. Pre-transplant glycaemia and high posttransplant levels of urea were associated with a greater risk of PHYG. This seemed to be independent of GFR, PTH, phosphate, calcium and traditional risk factors such as age and glucocorticoid load.
Uploads
Papers by Anders Hartmann