Scandiatransplant Exchange Program (STEP): Development and Results From an International Kidney Exchange Program.

Background: Kidney transplant candidates may be incompatible with their intended living donors because of the presence of antibodies against HLA and/or ABO. To increase the possibility of finding an acceptable kidney donor for these patients, the Scandiatransplant Exchange Program (STEP) program within Scandiatransplant was launched in 2019. Methods: This is a retrospective review of our experiences from the first 4 y of the STEP program, including details about the match runs, performed transplantations, and recipient outcomes within the program. Results: During 2019-2022, 11 match runs and 4 reruns were performed. In total, 114 pairs and 6 anonymous donors participated in these match runs. Fifty-one pairs (45%) participated in 1 match run, 31 pairs (27%) participated in 2 match runs, and 32 pairs (29%) participated in ≥3 match runs. Seventy-two individuals (63%) participated because of HLA incompatibility, 19 (17%) because of ABO incompatibility, and 7 (6%) because of both HLA and ABO incompatibility.Forty percent of the patients enrolled in the program underwent transplantation. In total, 49 transplantations have so far been performed within the program, and 46 (94%) of the recipients had a functioning kidney graft at follow-up in February 2023. Conclusions: The STEP program offers sensitized patients an enlarged pool of living donors and a chance of a compatible international living donor, resulting in an increased number of total transplantations. Currently, STEP is one of the largest transnational kidney exchange programs and has improved the situation for patients waiting for kidney transplantation in Scandiatransplant.

Kidney transplant in Denmark.

Since the first kidney transplant was conducted in Denmark in 1964, almost 10,000 transplants have been performed. Graft survival has improved over the past two decades despite the increase in age and comorbidities in both donors and recipients, but organ shortage remains a challenge. The focus of this review is to describe the challenges in kidney transplant and highlight the progress achieved in solving these challenges.

Cardiovascular Risk Following Conversion to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: A Randomized Clinical Trial.

Rationale & Objective: In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. Our objective was to compare the calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs. Study Design: Prospective, randomized, open-label, parallel-group, investigator-initiated, international multicenter trial. Setting & Participants: KTRs aged 18-80 years with a stable graft function (estimated glomerular filtration rate > 20 mL/min/1.73 m2), 3-60 months after transplantation, treated with tacrolimus or cyclosporine A, were eligible for inclusion. Intervention: Continuation with a CNI-based regimen or switch to belatacept for 12 months. Outcomes: Comparison of the change in the estimated 7-year risk of major adverse CV events and all-cause mortality, changes in traditional markers of CV health, as well as measures of arterial stiffness. Results: Among the 105 KTRs randomized, we found no differences between the treatment groups in the predicted risk for major adverse CV events or mortality. Diastolic blood pressure, measured both centrally by using a SphygmoCor device and peripherally, was lower after the belatacept treatment than after the CNI treatment. The mean changes in traditional cardiovascular (CV) risk factors, including kidney transplant function, were otherwise similar in both the treatment groups. The belatacept group had 4 acute rejection episodes; 2 were severe rejections, of which 1 led to graft loss. Limitations: The heterogeneous baseline estimated glomerular filtration rate and time from transplantation to trial enrollment in the participants. A limited study duration of 1 year. Conclusions: We found no effects on the calculated CV risk by switching to the belatacept treatment. Participants in the belatacept group had not only lower central and peripheral diastolic blood pressure but also a higher rejection rate. Funding: The trial has received a financial grant from Bristol-Myers Squibb. Trial Registration: EudraCT no. 2013-001178-20.

Prediction of Renal Function in Living Kidney Donors and Recipients of Living Donor Kidneys Using Quantitative Histology.

BACKGROUND: Living kidney donors (LKDs) are at increased risk of chronic kidney disease, whereas transplant recipients experience progressive reduction of graft function. We examined the predictive value of quantitative stereology on renal function in LKDs and recipients of living donor kidneys, based on perioperative biopsies from the donated kidney. METHODS: Cortex volume of both donor kidneys was determined by contrast-enhanced computed tomography and single-kidney glomerular filtration rate (GFR) by 51 chrome-EDTA clearance together with renography. Glomerular density was used to estimate total glomeruli number in addition to glomerular volume, glomerular sclerosis, kidney fibrosis, and arteriole dimensions. GFR measurements were repeated 1 y after transplantation in both LKDs and recipients. Associations between GFR at follow-up and cortex volume and histomorphometric parameters after adjustment of age, gender, body mass index, smoking status, 24-h blood pressure, and single-kidney GFR were examined. RESULTS: We included 49 LKDs (age, 51 ± 12 y) and 51 recipients (age, 44 ± 13 y). At follow-up, GFR was 71 ± 16 mL/min in LKDs and 61 ± 18 mL/min in recipients with hyperfiltration being more prominent in LKDs (30.4%) as compared to recipients (16.4%; P < 0.05). One-year GFR in donors correlated to cortex volume ( P < 0.001) but not to any histological parameters, whereas GFR in recipients correlated to the amount of interstitial fibrosis ( P < 0.01) but not to other histological parameters or cortex volume. CONCLUSIONS: Kidney cortex volume, but not renal histology parameters, predicts 1-y renal outcome in LKDs. In contrast, the amount of interstitial fibrosis, but not cortex volume, predicts 1-y graft function in recipients.

Short-term Outcome of Danish Kidney Donors: Postoperative Complications and Labor Affiliation.

BACKGROUND: Living kidney donation is safe and effective, but disincentives to donation include risk of short- and long-term complications, which need to be addressed in order to ensure care of live kidney donors. METHODS: From January 1, 2016 to December 31, 2019, 123 living kidney donors (LKDs) underwent LKD nephrectomy at Aarhus University Hospital, Aarhus, Denmark. Data from The Scandiatransplant registry and patient records were reviewed in order to identify short-term postoperative complications within 90 days after donation, as well as affiliation to the labor market and health data at follow-up. The Clavien-Dindo classification of surgical complications with modifications by Kocak et al was used to categorize minor and major complications. RESULTS: There were available data for 119 of 123 LKDs. Of these, 25 (21%) developed minor complications and 4 (3%) developed major complications. Ninety LKDs (76%) had an uneventful course without any complications. The most common complications were pain and nausea that required additional medical treatment. Seventy-two of the 82 LKDs working before donation had returned to work within 3 months after donor nephrectomy. No one retired or became disabled as a result of being a live kidney donor. CONCLUSIONS: Short-term follow up of the LKDs showed that most donors experienced an uneventful course and that the frequency of major complications was low. Donation did not seem to impact the ability to resume work. At the 90-day follow-up the majority of donors with both minor and major complications resumed work and reported full convalescence at the same level as donors without any complications. Nine of the LKDs (8%), all women, were out of work for >3 months with the main reason being fatigue.

A Randomized Controlled Trial on Safety of Steroid Avoidance in Immunologically Low-Risk Kidney Transplant Recipients.

INTRODUCTION: Steroid-based immunosuppression after transplantation increases the risk of post-transplant diabetes mellitus (PTDM), with adverse effects on patient and graft survival. In the SAILOR study, we investigated the safety and efficacy of complete steroid avoidance in immunologically low-risk kidney recipients without diabetes on the current standard-of-care maintenance regimen with tacrolimus/mycophenolate mofetil (MMF). METHODS: In this 2-year, multicenter, open-label trial, a total of 222 patients were randomized to receive either steroid avoidance protocol (tacrolimus/MMF/antithymocyte globulin [ATG] induction [n = 113]) or steroid maintenance protocol (tacrolimus/MMF/prednisolone/basiliximab-induction [n = 109]). RESULTS: At 1 year, no significant differences were found between steroid avoidance and steroid maintenance arms in the incidence of PTDM, the primary end point (12.4% vs. 18.3%, respectively, P = 0.30, CI: 16.3-4.4), or in overall biopsy-proven rejections (15% vs. 13.8%, respectively, P = 0.85). At 2 years, the composite end point of freedom from acute rejection, graft loss, and death (81% vs. 85%, respectively, P = 0.4), kidney function, or adverse events was comparable between the 2 arms. Moreover, 63.9% of the patients in the steroid avoidance arm remained free from steroids at 2 years. CONCLUSION: The SAILOR study provides further evidence for the feasibility, safety, and efficacy of early steroid-free treatment at 2 years in immunologically low-risk kidney recipients with tacrolimus/MMF maintenance regimen.

Effects of Corticosteroid Treatment on Mycophenolic Acid Exposure in Renal Transplant Patients-Results From the SAILOR Study.

Background: Mycophenolic acid (MPA) is a potent immunosuppressive agent used in solid organ transplantation. MPA exhibits large interindividual variation in dose-normalized plasma concentrations but is nevertheless usually prescribed as a fixed dose without use of therapeutic drug monitoring (TDM). Data on the effect of corticosteroid (CS) treatment on MPA concentrations during concomitant tacrolimus treatment remains sparse. Methods: Data is based on TDM of MPA area under the concentration curve (AUC) in 210 renal transplant recipients participating in the prospective, randomized, controlled, multi-center trial (SAILOR) where a steroid-free immunosuppressive regimen with mycophenolate mofetil (MMF) and low-dose tacrolimus was compared with a conventional prednisolone-based treatment regimen. Multilevel mixed-effects linear regression post-hoc analyses of MPA AUC was performed. Results: Median MPA AUC at baseline (within the first 2 weeks post-transplant) in patients taking 2 g MMF daily was 53 mg*h/L (interquartile range: 43-69 mg*h/L, min: 24-max: 117 mg*h/L). Between-patient variation in MPA AUC was up to 5-fold on the same MMF dose. Patients in the steroid-free group had 12.5% lower (95% CI; 3.2-20.9%, p = 0.01) MPA AUC levels at baseline compared to the steroid treated group. During follow-up (14 days-2 years post-transplant) there were no significant differences in MPA AUC between the groups with MPA AUC being 4.2% lower (95% CI: -4.8%-12,5%, p = 0.35) in the steroid-free vs standard treatment group in restricted analysis after multivariate adjustment for tacrolimus trough level, body weight, time after transplantation and MMF dose. MMF dose was positively correlated with MPA AUC (p < 0.001) whereas body weight was negatively correlated with MPA AUC (p < 0.001). MPA AUC was 0.4% (95% CI: 0.2-0.6%, p < 0.001) lower per 1 kg increase in weight. Tacrolimus trough levels had no significant effect on MPA AUC. Conclusion: Immunosuppression with CS during concomitant tacrolimus treatment was shortly after transplantation associated with a significantly higher MPA exposure but the effect was small and not maintained during follow-up. Low body weight was associated with higher MPA exposure, which suggests a potential for weight adjusted MMF dosing.

Unattended automated office blood pressure in living donor kidney transplant recipients.

PURPOSE: Hypertension is common in kidney transplant recipients (KTRs). For the evaluation of blood pressure (BP), 24-h ambulatory BP measurements (ABPM) are considered superior to usual office measurements but are also resource demanding and troublesome to many patients. We therefore evaluated the use of unattended automated office BP (AOBP) during the first year following living donor kidney transplantation and compared AOBP with ABPM as obtained 12 months after transplantation. MATERIALS AND METHODS: Data were retrieved from a cohort of 57 KTRs (mean age 45 ± 14 years, 75% males) who all received kidneys from living donors and had a good graft function (estimated glomerular filtration rate (eGFR) 52 ± 16 ml/min/1.73 m2 at 12 months). Unattended AOBP was measured at each visit to the outpatient clinic using the BpTru® device, while ABPM was obtained by Spacelabs® equipment before and 12 months after transplantation. RESULTS: AOBP remained stable from month 2 (130.2 ± 10.8/82.2 ± 7.8 mmHg) to month 12 (129.0 ± 12.8/83.1 ± 9.6 mmHg) post-transplantation. At 12 months follow-up, ambulatory daytime systolic BP was slightly higher than AOBP (132.7 ± 10.7 vs. 129.4 ± 12.2 mmHg, p = 0.04), while diastolic BP was similar (82.7 ± 7.7 vs. 82.0 ± 10.2 mmHg). Using Bland-Altman plots, 95% limits of agreements were -17.9 to 24.5 mmHg for systolic and -16.5 to 15.1 mmHg for diastolic BP. When considering a target BP of ≤130/<80 mmHg, 62% had sustained hypertension, 9% white coat hypertension and 11% masked hypertension. Using multiple linear regression analysis, only urine albumin-creatinine ratio tended to predict a higher systolic AOBP (p = 0.07). CONCLUSION: In a cohort of stable living donor KTRs, mean values of unattended AOBP using BpTru® are comparable to daytime ABPM with a misclassification rate of approximately 20%.

[The Nordic kidneyexchangeprogramme].

This review describes the ScandiaTransplant Kidney Exchange Programme and the background of renal exchange programmes gaining popularity worldwide, possibilities and limitations of the programmes, the ethical aspects and perspectives. The first kidney exchanges between Danish and Swedish countries were performed in 2019, and until now 23 exchanges and transplantations have been performed. All surgical procedures have been performed simultaneously and/or coordinated at different hospitals in Scandinavia, and the kidney grafts were transported between the participating units.

Uneventful case of COVID-19 in a kidney transplant recipient.

Kidney transplant recipients have been reported at a particularly high risk of severe COVID-19 illness due to chronic immunosuppression and coexisting conditions. Yet, here we describe a remarkably mild case of COVID-19 in a 62-year-old female who had a kidney transplantation 10 years earlier due to autosomal dominant polycystic kidney disease. The patient was admitted for 1 day; immunosuppressive therapy with tacrolimus and low-dose prednisolone was continued; and the patient recovered successfully without the use of antiviral agents or oxygen therapy. The case demonstrates that kidney transplant recipients are not necessarily severely affected by COVID-19. Withdrawal of immunosuppressive therapy could be associated with poorer outcomes and should not be implemented thoughtlessly.

[The first kidney exchanges between two Scandinavian countries have been performed]. / De första njurbytena mellan två skandinaviska länder är gjorda.

This article describes the Scandinavian expansion of the previously described kidney exchange program STEP, and the first two exchanges that were performed between two Scandinavian countries late in 2019. All surgical procedures were performed simultaneously and/or coordinated at different hospitals in Scandinavia and the kidney grafts were transported between the participating units. Four weeks after surgery, all recipients had a good and stable kidney function and all donors had recovered.

Kidney structural characteristics based on a kidney biopsy and contrast-enhanced computed tomography in healthy living kidney donors.

The demands for kidney transplantations are increasing, and so is the number of live kidney donors (LKDs). Recent studies show that LKDs have an increased risk of developing end-stage renal disease compared with healthy non-donors. However, the knowledge about factors predicting renal disease in kidney donors is sparse. Some evidence points to increased glomerular sclerosis and kidney fibrosis, as well as a low number of glomeruli as associated with a worse renal outcome. This methodological study investigated that which estimates are obtainable with a standard kidney biopsy taken from the donated kidney during the transplantation, and a standard contrast-enhanced computed tomography (CT) in kidney donors. CT-scans were used to obtain total volume of the kidney and kidney cortex using the Cavalieri estimator and 2D-nucleator. Glomerular number density in the biopsies was estimated by a model-based method, and was multiplied by total cortex volume in order to estimate the total number of glomeruli in the kidney. Glomerular volume was estimated by the 2D-nucleator and a model-based stereological technique. Kidney fibrosis (point-counting), glomerular sclerosis (evaluation of glomerular profiles), and arteriole dimensions (2D-nucleator) were also estimated in the biopsy sections from the donated kidney. Various studies have attempted to identify predictors of renal outcome in LKDs. There is no consensus yet, and further studies are needed to elucidate if and how the estimates described in this study are associated with renal outcome in LKDs.

Influence of Renal Transplantation and Living Kidney Donation on Large Artery Stiffness and Peripheral Vascular Resistance.

BACKGROUND: Vascular status following renal transplantation (RT) may improve while living kidney donation (LKD) is possibly associated with an increased cardiovascular risk. METHODS: We prospectively assessed glomerular filtration rate (mGFR, 51Chrome EDTA clearance) and intermediate vascular risk factors in terms of blood pressure (BP), pulse wave velocity (PWV), central augmentation index (AIx), excess pressure (Pexcess), and forearm vascular resistance in donors (n = 58, 45 ± 13 years) and recipients (n = 51, 50 ± 12 years) before and one year following LKD or RT. RESULTS: After kidney donation, mGFR decreased by 33% to 65 ± 11 ml/min/1.73m2, while recipients obtained a mGFR of 55 ± 9 ml/min/1.73m.2 Ambulatory 24-hour mean arterial BP (MAP) remained unchanged in donors but decreased by 5 mm Hg in recipients (P < 0.05). Carotid-femoral PWV increased by 0.3 m/s in donors (P < 0.05) but remained unchanged in recipients. AIx was unaltered after LKD but decreased following RT (P < 0.01), and Pexcess did not change in either group. Resting forearm resistance (Rrest), measured by venous occlusion plethysmography, increased after LKD (P < 0.05) but was unaffected by RT, while no changes were seen in minimum resistance (Rmin). ΔPWV showed a positive linear association to Δ24-hour MAP in both groups. Multiple linear regression analysis (adjusting for age, gender, and the baseline value of the studied parameter) did not detect independent effects of graft function on 24-hour MAP, PWV, AIx, vascular resistance, or Pexcess, whereas low post-donation GFR was related to higher AIx and Rrest. CONCLUSIONS: RT reduced BP and AIx without affecting PWV, whereas LKD resulted in increased PWV and Rrest, despite unchanged BP.

Arterial stiffness and peripheral vascular resistance in offspring of hypertensive parents: influence of sex and other confounders.

AIM: Established essential hypertension is associated with increased arterial stiffness and peripheral resistance, but the extent of vascular changes in persons genetically predisposed for essential hypertension is uncertain. METHODS: Participants from the Danish Hypertension Prevention Project (DHyPP) (both parents hypertensive) (n = 95, 41 ±â€Š1 years, 53% men) were compared with available spouses (n = 45, 41 ±â€Š1 years) using measurements of ambulatory blood pressure (BP), left ventricular mass index (LVMI), pulse wave velocity, central BP and augmentation index (AIx) in addition to forearm resting and minimal resistance [forearm resting vascular resistance (Rrest) and forearm minimal vascular resistance (Rmin)]. RESULTS: DHyPP patients with participating spouses had higher 24-h mean BP (94 ±â€Š1 vs. 88 ±â€Š1 mmHg, P < 0.01), LVMI (94 ±â€Š3 vs. 80 ±â€Š2 g/m, P < 0.01), central SBP (121 ±â€Š2 vs. 111 ±â€Š2 mmHg, P < 0.01) and AIx (16.0 ±â€Š1.2 vs. 10.5 ±â€Š1.7%, P < 0.01), but similar carotid-femoral pulse wave velocity (7.5 ±â€Š0.2 vs. 7.1 ±â€Š0.2 m/s), Rrest (53 ±â€Š3 vs. 51 ±â€Š3 mmHg/ml/min/100 ml) and log Rmin (0.58 ±â€Š0.02 vs. 0.55 ±â€Š0.02 mmHg/ml/min/100 ml) when compared with spouses. Using multiple linear regression analysis (adjusting for sex, age, BMI, creatinine clearance and 24-h BP, heart rate and sodium excretion) AIx and LVMI remained elevated in DHyPP patients [4.2% (0.7; 7.7), P = 0.02 and 6.3 g/m (0.7; 11.9), P = 0.03]. For the entire DHyPP cohort AIx, Rrest and Rmin were higher in women than men (P < 0.01), and the same was true for AIx and Rmin among spouses (P < 0.05). Furthermore, AIx was linearly associated with Rrest and Rmin. CONCLUSION: Young to middle-aged individuals genetically predisposed for essential hypertension display increased AIx and LVMI, although vascular stiffness and peripheral resistance are still normal.

Cervical HPV prevalence and genotype distribution in immunosuppressed Danish women.

INTRODUCTION: Women receiving immunosuppressive treatment due to organ transplantation are at increased risk of Human papilloma virus (HPV)-related diseases, including cervical neoplasia. This pilot study aimed to describe the cervical HPV prevalence and genotype distribution in immunosuppressed Danish women. MATERIAL AND METHODS: We included women who underwent renal (RTR) or bone marrow transplantation (BMTR) in 2009-2012 or 2014 at Aarhus University Hospital, Denmark. Women undergoing transplantation in 2009-2012 had one cervical cytology performed, whereas women undergoing transplantation in 2014 had three, one before and two after transplantation. The samples were examined for cytological abnormalities and tested for HPV using Cobas® HPV Test and CLART® HPV2 Test. RESULTS: Of 94 eligible cases we included 60 RTR and BMTR. The overall prevalence of high-risk HPV was 15.0 [95% confidence interval (CI) 7.1-26.6] and the prevalence was higher among BMTR (29.4; 95% CI 10.3-56.0) than RTR (9.3%, 95% CI 2.6-22.1), although this was not statistically significant (p = 0.10). The distribution of high-risk HPV was broad, with HPV 45 as the most common genotype (3.3%). The prevalences of high-risk HPV types included in the bivalent/quadrivalent and the nonavalent vaccines were 1.7 and 8.3%, respectively. The prevalence of low-grade and high-grade cytological abnormalities was 6.7 and 5.0%, respectively. CONCLUSIONS: Immunosuppressed women were infected with a broad range of high-risk HPV genotypes and the prevalence of cytological abnormalities was higher than found in previous studies of the general population. The nonavalent HPV vaccine will offer immunosuppressed individuals a greater protection against HPV-related diseases compared with the bivalent/quadrivalent HPV vaccines.

Renal resistance and long-term blood pressure in individuals genetically predisposed for essential hypertension: 10-year follow-up of the Danish Hypertension Prevention Project.

AIM: Young individuals genetically predisposed for essential hypertension have increased renal vascular resistance. We evaluated whether 1 year of angiotensin II receptor blockade decreases afferent arteriolar resistance (RA) and induces a sustained blood pressure (BP) reduction during a 10-year follow-up period in offspring of parents both diagnosed with essential hypertension. METHODS: Based on renal plasma flow (p-aminohippurate clearance) and glomerular filtration rate (Cr-EDTA clearance) RA was calculated according to the model originally established by Gomez. Following baseline measurements, the participants (n = 110, mean age 30 years) were randomly allocated to 12 months of treatment with either candesartan or placebo followed by repetition of measurements and withdrawal of medication. Four-hour ambulatory BP (ABP) was recorded at baseline, by end of active treatment and after 6 months, 1, 2, 3, 5, and 10 years. ABP was analyzed according to RA achieved at the end of active treatment. RESULTS: Candesartan reduced RA by 14% (P < 0.01). Ten years posttreatment systolic ABP increased by 2.1 mmHg (P = 0.04) and diastolic by 4.2 mmHg (P < 0.01) compared with baseline, without any difference between treatment arms. A high posttreatment RA was associated with higher BP levels during follow-up, but long-term alterations in 24-h BP were similar in participants with low and high RA and not different between treatment arms. CONCLUSION: RA is associated with 24-h BP levels, but temporary lowering of BP and RA by candesartan does not prevent BP from increasing further. Prevention of hypertension appears not feasible by short-term inhibition of the rennin-angiotensin system in young adults.

An in-progress, open-label, multi-centre study (SAILOR) evaluating whether a steroid-free immunosuppressive protocol, based on ATG induction and a low tacrolimus dose, reduces the incidence of new onset diabetes after transplantation.

BACKGROUND: Corticosteroids and calcineurin inhibitors (CNIs) are included in renal transplantation immunosuppressive protocols around the world. Well-known side effects are associated with the use of these drugs, including new onset of diabetes after transplantation (NODAT). Long-term patient survival rates are lower among patients with NODAT. The optimal immunosuppressive protocol would therefore include not using corticosteroids and minimization of CNI use. METHODS/DESIGN: This is a prospective, multi-centre, controlled, randomized, parallel group, open-label study involving kidney transplant patients. The study compares a steroid-free immunosuppressive protocol (study arm A), which is based on low-dose tacrolimus and mycophenolate mofetil (MMF) maintenance therapy together with antithymocyte globulin (ATG) induction, with the conventional immunosuppressive protocol (study arm B), being based on low-dose tacrolimus, MMF and steroids together with interleukin-2 receptor (IL2-R) induction. The study is designed to include most normal-risk patients. It will exclude patients seen as at a high risk of rejection. The primary objective of the study is to assess the cumulative incidence of NODAT in the two study arms 12 months after transplantation using the American Diabetes Association type 2 diabetes diagnostic criteria. The composite measure of freedom from acute rejection, graft survival and patient survival will be evaluated. Renal function and chronic changes in the transplanted kidney will be assessed. DISCUSSION: If this study confirms conceptual expectations, namely decreased incidence of NODAT, the steroid-free study protocol could be used with all patients. The regimen could be especially beneficial for patients at a high risk of diabetes mellitus. TRIAL REGISTRATION: EudraCT 2012-000451-13.

Treatment of young subjects at high familial risk of future hypertension with an angiotensin-receptor blocker.

UNLABELLED: Offspring of hypertensive parents are at high risk of future hypertension and subsequent cardiovascular diseases. We investigated whether early treatment with an angiotensin-receptor blocker in young normotensive offspring of hypertensive parents persistently lowered blood pressure after treatment withdrawal, a possibility supported by animal studies. The study is an investigator-initiated, double-blind study of 110 healthy normotensive subjects aged 18 to 36 years where both parents have essential hypertension randomly assigned to 1 of 2 treatment groups: candesartan (Atacand, Astra Zeneca), 16 mg o.d. or placebo. The intervention period was 12 months, with 24 months of follow-up. PRIMARY OUTCOME was mean 24-hour ambulatory blood pressure recordings (mean AMBP) after 12 and 24 months follow-up and was based on intention to treat (n=110). SECONDARY OUTCOMES were changes during treatment in mean AMBP, left ventricular mass, renal hemodynamics, and adverse events during intervention and were based on those completing the intervention period (n=105). PRIMARY OUTCOME: At 12 and 24 months follow-up, mean AMBP was not different to placebo. SECONDARY OUTCOMES: After 12 months of intervention, mean AMBP was reduced: -3.9/-3.4 mm Hg for candesartan versus 0.3/0.6 mm Hg for placebo, P<0.0001. Renal vascular resistance and left ventricular mass were also reduced (P=0.0007, P=0.019, respectively). There were no significant differences in adverse advents between the 2 groups. In conclusion, temporary treatment of subjects at high familial risk of future hypertension with an angiotensin receptor blocker is feasible, but the treatment had no persistent effect on blood pressure when treatment was withdrawn.

Renal haemodynamics are not related to genotypes in offspring of parents with essential hypertension.

UNLABELLED: INTRODUCTION. The pathogenesis of essential hypertension (EH) has a major genetic component and is associated with renal abnormalities. Normotensive offspring of hypertensive parents are likely to develop EH and are a suitable population for identifying possible relations between genetic and renal abnormalities. METHODS: We investigated if renin-angiotensinaldosterone system associated genotypes (angiotensinogen [M235T] and ACE [I/D]) are related to blood pressure (BP), renal haemodynamics and sodium excretion in sex and age-matched (1835 years) healthy Caucasian offspring of either two parents with EH (n=101, EH-offspring) or two normotensive parents (n=50, controls). The alpha-adducin polymorphism (G460W) was also investigated. RESULTS: Compared to controls, BP, heart rate, renal vascular resistance (RVR) and urinary sodium excretion were, respectively, 5%, 7%, 15% and 20% higher in EHoffspring. In controls, the TT-genotype of the M235T angiotensinogen polymorphism was associated with higher BP and higher plasma angiotensinogen. By contrast, in EHoffspring the TT-genotype was associated with lower BP and unchanged plasma angiotensinogen. Plasma angiotensinogen correlated positively with BP in EH-offspring, with a similar tendency (p=0.08) in controls. The distributions of the three candidate polymorphisms were similar in EH-offspring and controls. There were no associations between any of the polymorphisms and any of the renal parameters measured. CONCLUSION: The markedly greater RVR, proportionally larger than the greater BP, supports a role for RVR in the pathogenesis of EH. The lack of association between the candidate polymorphisms and the investigated parameters, even in this homogenous and for hypertension strongly predisposed group, suggests that the polymorphisms investigated do not play important roles in the pathogenesis of hypertension.

Can hypertension be prevented? The Danish Hypertension Prevention Project and the Trial of Prevention of Hypertension studies.

Essential hypertension, a major health problem worldwide, is a disease generally considered to require life-long treatment. However, evidence suggests that hypertension is caused by specific phenotypic changes caused by the combination of genetic and environmental factors. Thus, in principle, hypertension could be prevented by prevention of these phenotypic changes. Animal data indicate that early treatment that blocks the renin-angiotensin system have long-term effects after treatment withdrawal. Here we report on two human trials that are testing whether early treatment (with the AT1-antagonist, candesartan) is able to have a persistent effect after stopping treatment: the Danish Hypertension Prevention Project and Trial of Prevention of Hypertension.