Effect of Spironolactone on Kidney Function in Kidney Transplant Recipients: A Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Long-term kidney allograft survival is hampered by progressive interstitial fibrosis and tubular atrophy. The SPIREN trial tested the hypothesis that the mineralocorticoid receptor antagonist spironolactone stabilizes kidney function and attenuates glomerular barrier injury in kidney transplant patients treated with calcineurin inhibitors. METHODS: Randomized, placebo-controlled, double blind clinical trial including 188 prevalent kidney transplant patients. Patients were randomized to spironolactone or placebo for three years. Glomerular filtration rate was measured along with proteinuria and kidney fibrosis. The primary endpoint was change in measured glomerular filtration rate. Secondary outcomes were 24h proteinuria, kidney allograft fibrosis and cardiovascular events. Measured glomerular filtration rates, 24h proteinuria and blood pressure were determined yearly. Kidney biopsies were collected at baseline and after two years (n=48). Fibrosis was evaluated by quantitative stereology and classified according to Banff. RESULTS: The groups were comparable at baseline except for slightly older allografts in the spironolactone group. Spironolactone reduced measured glomerular filtration rates (up to -7.6 (95% CI -10.9;-4.3) ml/min compared to placebo) independently of time since transplantation and blood pressure with no impact on the kidney function curve over time and reduced 24h proteinuria after one year. There was no significant effect of spironolactone on the development of interstitial fibrosis. CONCLUSION: Spironolactone added to standard therapy for three years in kidney transplant patients did not improve kidney function, long-term proteinuria or interstitial fibrosis.

Protocol for a randomised controlled trial comparing warfarin with no oral anticoagulation in patients with atrial fibrillation on chronic dialysis: the Danish Warfarin-Dialysis (DANWARD) trial.

INTRODUCTION: Atrial fibrillation is highly prevalent in patients on chronic dialysis. It is unclear whether anticoagulant therapy for stroke prevention is beneficial in these patients. Vitamin K-antagonists (VKA) remain the predominant anticoagulant choice. Importantly, anticoagulation remains inconsistently used and a possible benefit remains untested in randomised clinical trials comparing oral anticoagulation with no treatment in patients on chronic dialysis. The Danish Warfarin-Dialysis (DANWARD) trial aims to investigate the safety and efficacy of VKAs in patients with atrial fibrillation on chronic dialysis. The hypothesis is that VKA treatment compared with no treatment is associated with stroke risk reduction and overall benefit. METHODS AND ANALYSIS: The DANWARD trial is an investigator-initiated trial at 13 Danish dialysis centres. In an open-label randomised clinical trial study design, a total of 718 patients with atrial fibrillation on chronic dialysis will be randomised in a 1:1 ratio to receive either standard dose VKA targeting an international normalised ratio of 2.0-3.0 or no oral anticoagulation. Principal analyses will compare the risk of a primary efficacy endpoint, stroke or transient ischaemic attack and a primary safety endpoint, major bleeding, in patients allocated to VKA treatment and no treatment, respectively. The first patient was randomised in October 2019. Patients will be followed until 1 year after the inclusion of the last patient. ETHICS AND DISSEMINATION: The study protocol was approved by the Regional Research Ethics Committee (journal number H-18050839) and the Danish Medicines Agency (case number 2018101877). The trial is conducted in accordance with the Helsinki declaration and standards of Good Clinical Practice. Study results will be disseminated to participating sites, at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT03862859, EUDRA-CT 2018-000484-86 and CTIS ID 2022-502500-75-00.

Plasma concentration of orally administered amoxicillin and clindamycin in patients receiving haemodialysis.

OBJECTIVES: In the randomized controlled trial PANTHEM, the prophylactic effect of oral amoxicillin or clindamycin is investigated in patients receiving chronic haemodialysis (HD). However, data on plasma concentrations of these antibiotics during HD are sparse. This study aims to determine if the plasma concentration of amoxicillin and clindamycin is sufficient during HD after oral administration of amoxicillin and clindamycin at three different time intervals prior to the HD procedure. METHODS: Adult patients receiving chronic HD were investigated twice with an interval of at least 7 days starting with either a tablet of 500/125 mg amoxicillin/clavulanic acid or a tablet of 600 mg clindamycin. Patients were randomized to take the antibiotics either 30, 60 or 120 min prior to the HD procedure. Plasma antibiotic concentrations were measured at start, midway and at the end of HD. A lower threshold was set at 2.0 mg/L for amoxicillin and at 1.0 mg/L for clindamycin. In addition, a population pharmacokinetic (PK) analysis was performed, assessing PTA. RESULTS: In the amoxicillin cohort (n = 37), 84% of patients and 95% of all plasma amoxicillin concentrations were above or at the threshold throughout the dialysis procedure. In the clindamycin cohort (n = 33), all concentrations were above the threshold throughout the dialysis procedure. Further, in all patients, the mean plasma concentration of both amoxicillin and clindamycin across the HD period was well above the threshold. Finally, the PK model predicted a high PTA in the majority of patients. DISCUSSION: In patients on chronic HD, oral administration of amoxicillin/clavulanic acid (500/125 mg) or clindamycin (600 mg) within 30-120 min prior to HD leads to a sufficient prophylactic plasma concentration across the HD period.

Comparison of 24-hour urinary creatinine clearance and estimated glomerular filtration rate based on a panel of filtration markers in patients with chronic kidney disease.

Diagnosis and management of chronic kidney disease (CKD) requires accurate assessment of glomerular filtration rate (GFR). In practice, GFR is typically estimated by equations based on creatinine concentration in blood, but creatinine is affected by non-GFR factors such as age and sex. Alternative filtration markers such as cystatin C, beta-trace protein (BTP), and beta-2 microglobulin (B2M) may be less dependent on age and sex, but equations combining these markers have not been investigated in patients with chronic kidney disease (CKD). In this cross-sectional study of 50 patients with CKD stage 3-4, we compared kidney function estimates based on creatinine, cystatin C, BTP, B2M, or a combination of markers. Compared to the creatinine/cystatin C combination equation, the panel equation yielded a mean difference of only 2.8 ml/min/1.73 m2 , indicating that switching to the panel equation would be unlikely to affect management.

Durability of Antibody Response after Primary Pneumococcal Double-Dose Prime-Boost Vaccination in Adult Kidney Transplant Recipients and Candidates: 18-Month Follow-Up in a Non-Blinded, Randomised Clinical Trial.

BACKGROUND: Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients and candidates. The long-term durability of the antibody (AB) response is unknown. The same applies to a dose-dependent immune response. METHODS: We studied the durability of the vaccine response after 18 months in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs). Both groups received either a normal dose (ND) or a double dose (DD) of the 13-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal polysaccharide vaccine. The average pneumococcal AB geometric mean concentration (GMC) was evaluated. A level ≥ 1 mg/L was considered protective against invasive pneumococcal disease (IPD). RESULTS: Sixty WLPs and 70 KTRs were included. The proportion of participants protected declined from 52% to 33% in WLPs and from 29% to 16% in KTRs, with the previously significant dose-effect in WLPs no longer present (40% DD vs. 27% ND; p = 0.273). Average pneumococcal AB GMCs remained significantly above baseline levels (all groups p ≤ 0.001). Drug-induced immunosuppression diminished the vaccine dose-effect. CONCLUSIONS: At follow-up, the pneumococcal prime-boost vaccination still provided significantly elevated average pneumococcal AB GMCs in both populations. Though the proportion of participants protected against IPD in WLP-DD and WLP-ND were statistically comparable, a DD may still be recommended for WLPs (EudraCT: 2016-004123-23).

Immunogenicity and safety of double dosage of pneumococcal vaccines in adult kidney transplant recipients and waiting list patients: A non-blinded, randomized clinical trial.

BACKGROUND: Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients, but is not thoroughly tested in this population. Furthermore, a pneumococcal vaccine dose effect has never been investigated, though observed in healthy adults. To assess whether a double dose of 13-valent pneumococcal conjugate vaccine (PCV13) and of 23-valent pneumococcal polysaccharide vaccine (PPV23) increases the immunogenicity of prime-boost vaccination in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs), a phase 3, randomized, non-blinded trial was conducted. METHODS: KTRs and WLPs were in parallel groups assigned either normal or double dosage of both vaccines 12 weeks apart. A 'protective response' was an average geometric mean concentration ≥ 1 mg/L based on 12 vaccine shared serotype-specific IgG antibodies. Furthermore, number of antibodies with ≥ 2-fold rises and individual serotype-specific antibody concentrations were evaluated. Follow-up was 48 weeks. RESULTS: Seventy-four KTRs and 65 WLPs were enrolled. In WLPs, double dosage resulted in a significantly higher proportion of participants with a 'protective response' (66.7%), 5 weeks after PPV23, compared to normal dosage (35.5%), p = 0.015. KTRs exhibited no dose effect. After PPV23, all four groups had increased their number of serotypes with ≥ 2-fold rises (p ≤ 0.05 for both WLPs groups; p ≤ 0.01 for both KTRs groups). Vaccines were safe, well tolerated and still immunogenic at week 48. CONCLUSIONS: Data suggests that double dosage of pneumococcal vaccines used according to the prime-boost strategy might be recommendable for WLPs. Furthermore, our data supports PPV23́s additive effect to PCV13 in KTRs and WLPs. (EudraCT: 2016-004123-23).

The coverage of influenza and pneumococcal vaccination among kidney transplant recipients and waiting list patients: A cross-sectional survey in Denmark.

BACKGROUND: To characterize level and predictors of influenza and pneumococcal vaccine uptake among Danish kidney transplant recipients (KTR) and kidney transplant waiting list patients (WLP). METHODS: A cross-sectional survey based on self-reported vaccine uptake including WLP and KTR ≤ 1½ years post transplantation. Descriptive statistics and logistic regression analyses identifying factors associated with influenza vaccine uptake in the latest season were performed. RESULTS: A total of 220 participants were included in the study, 54% KTR and 46% WLP. Self-reported influenza vaccine uptake in the latest season was overall 41.8%. Uptake of influenza vaccine on any prior season apart from the latest season was 53.2% and significantly higher among WLP than KTR (P = .007). Pneumococcal vaccine uptake was only 4% overall. The only factor positively associated with influenza vaccine uptake in the latest season was any prior influenza vaccine uptake (OR 5.79, CI95 2.44-13.76) (P < .001). Recommendations given by other persons (non-physician) were negatively associated with receiving the influenza vaccination in the latest season (OR 0.34, CI95 0.13-0.92) (P = .03). Reasons for not being vaccinated were primarily lack of information, perception of own good health, and fear of adverse reactions. CONCLUSIONS: Influenza and pneumococcal vaccine uptakes were suboptimal among Danish WLP and KTR. Increased awareness about guidelines and physicians´ education are warranted.

Collagen turnover profiles in chronic kidney disease.

Renal fibrosis is a hallmark of chronic kidney disease (CKD) caused by an imbalance between formation and degradation of extracellular matrix proteins. We investigated the collagen turnover profile of 81 non-dialysis CKD stage 2-5 patients by measuring peptides reflecting formation and degradation of collagen type (COL) I, III, IV, and VI. Based on the collagen turnover profile, we identified four clusters of patients. Cluster 1 contained one patient with prostate cancer, who had a distinct collagen turnover. The other clusters generally had severe (Cluster 2), moderate (Cluster 4), or mild CKD (Cluster 3). Cluster 4 patients were characterized by higher levels of COL III, COL IV, and COL VI (all p < 0.001) degradation fragments in plasma, while patients in Clusters 2 and 4 had higher levels of COL VI formation (p < 0.05). COL IV fragments in plasma were lower in Cluster 2 (p < 0.01). Urinary COL III fragments decreased from Cluster 3 to 4, and from Cluster 4 to 2 (both p < 0.001). We show that patients with similar kidney function have a different collagen remodeling profile, suggesting that different phenotypes exist with different disease activity and potentially disease progression. Biomarkers of collagen remodeling could provide additional information to traditional markers of renal function.

[Successful treatment of severe dabigatran intoxication with idarucizumab in a patient with acute kidney injury].

In the course of an uncomplicated sigmoidostomy a 63-year-old male who had severe comorbidity developed a critical bleeding due to dabigatran intoxication induced by acute kidney injury. Massive blood transfusions, tranexamic acid, Octaplex and haemodialysis were not effective. Administration of idarucizumab induced immediate clinical and paraclinical improvement. Dabigatran should be carefully administrated in patients who have any degree of renal insufficiency. Idarucizumab may be effective in severe bleeding caused by dabigatran.

Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemia is a concern with the use of mineralocorticoid receptor antagonists. We aimed to determine whether the renal protective benefits of mineralocorticoid antagonists outweigh the risk of hyperkalaemia associated with this treatment in patients with chronic kidney disease. METHODS: We conducted a meta-analysis investigating renoprotective effects and risk of hyperkalaemia in trials of mineralocorticoid receptor antagonists in chronic kidney disease. Trials were identified from MEDLINE (1966-2014), EMBASE (1947-2014) and the Cochrane Clinical Trials Database. Unpublished summary data were obtained from investigators. We included randomised controlled trials, and the first period of randomised cross over trials lasting ≥4 weeks in adults. RESULTS: Nineteen trials (21 study groups, 1 646 patients) were included. In random effects meta-analysis, addition of mineralocorticoid receptor antagonists to renin angiotensin system inhibition resulted in a reduction from baseline in systolic blood pressure (-5.7 [-9.0, -2.3] mmHg), diastolic blood pressure (-1.7 [-3.4, -0.1] mmHg) and glomerular filtration rate (-3.2 [-5.4, -1.0] mL/min/1.73 m(2)). Mineralocorticoid receptor antagonism reduced weighted mean protein/albumin excretion by 38.7 % but with a threefold higher relative risk of withdrawing from the trial due to hyperkalaemia (3.21, [1.19, 8.71]). Death, cardiovascular events and hard renal end points were not reported in sufficient numbers to analyse. CONCLUSIONS: Mineralocorticoid receptor antagonism reduces blood pressure and urinary protein/albumin excretion with a quantifiable risk of hyperkalaemia above predefined study upper limit.

Eplerenone attenuates pulse wave reflection in chronic kidney disease stage 3-4--a randomized controlled study.

BACKGROUND: Patients with chronic kidney disease (CKD) have high cardiovascular mortality and morbidity associated with increased arterial stiffness. Plasma aldosterone levels are increased in CKD, and aldosterone has been found to increase vascular inflammation and fibrosis. It was hypothesized that aldosterone receptor inhibition with eplerenone could reduce arterial stiffness in CKD stage 3-4. STUDY DESIGN: The design was randomized, open, parallel group. Measurements of arterial stiffness markers were undertaken at weeks 1 and 24. INTERVENTION: 24 weeks of add-on treatment with 25-50 mg eplerenone or standard medication. OUTCOMES: Primary outcome parameter was carotid-femoral pulse wave velocity (cfPWV). Secondary outcomes were augmentation index (AIx), ambulatory arterial stiffness index (AASI) and urinary albumin excretion. RESULTS: Fifty-four CKD patients (mean eGFR 36 mL/min/1.73 m(2), SD 11) were randomized. Forty-six patients completed the trial. The mean difference in cfPWV changes between groups was 0.1 m/s (95%CI: -1.0, 1.3), P = 0.8. The mean difference in AIx changes between groups was 4.4% (0.1, 8.6), P = 0.04. AASI was unchanged in both groups. The ratio of change in urinary albumin excretion in the eplerenone group compared to the control was 0.61 (0.37, 1.01), P = 0.05. Four patients were withdrawn from the eplerenone group including three because of possible side effects; one was withdrawn from the control group. Mild hyperkalemia was seen on three occasions and was easily managed. LIMITATIONS: The full planned number of patients was not attained. The duration of the trial may have been too short to obtain full effect of eplerenone on the arteries. CONCLUSIONS: Add-on treatment with eplerenone in CKD stage 3-4 did not significantly reduce cfPWV. There may be beneficial vascular effects leading to attenuated pulse wave reflection. Treatment was well-tolerated. TRIAL REGISTRATION: ClinicalTrials.govNCT01100203.

[Participation in dinner at a medical conference reduces vascular age and is recommended]. / Deltagelse i konferencemiddag reducerer den vaskulære alder og anbefales af helbredsmæssige grunde

A total of 60 attendees at a medical conference had their peripheral and central blood pressure measured before and after the conference dinner. While heart rate increased, all measurements of peripheral and central blood pressure showed lower values after dinner. Furthermore, attendees' central vascular age was reduced by 13 years after dinner when augmentation index was evaluated in relation to age. Although 13% experienced postprandial hypotension, the present study motivates attendance at medical conference dinners due to the health implications of lowered blood pressure.

Ambulatory arterial stiffness index in chronic kidney disease stage 2-5. Reproducibility and relationship with pulse wave parameters and kidney function.

BACKGROUND: Arterial stiffness contributes to the increased cardiovascular risk in patients with chronic kidney disease (CKD). Reproducible and easily obtainable indices of arterial stiffness are needed in order to monitor therapeutic strategies. The ambulatory arterial stiffness index (AASI) has been proposed as such a marker. The present study investigated the day-to-day reproducibility of AASI in CKD stage 2-5 and its relationship with other markers of arterial stiffness as well as with kidney function. METHODS: Eighty-three patients (29% female, median age 62 years) were studied by 24 h ambulatory blood pressure monitoring (ABPM), aortic pulse wave velocity (aPWV), augmentation index (AIx) and estimated glomerular filtration rate (eGFR) at a median interval of 7 days. Individual AASIs were calculated from 24 h ABPMs as 1 minus the regression slope of diastolic blood pressure over systolic blood pressure. RESULTS: Mean AASI, aPWV, AIx and 24 h pulse pressure (PP) were similar on repeated measurements. The intraclass correlation coefficients were between 72% and 78% for AASI calculated by three different methods, 87% for aPWV, 88% for AIx, and 96% for 24 h PP. The correlation coefficients between AASI and aPWV were from 0.48 to 0.53; with AIx it was between 0.19 and 0.34. After adjustment for covariates none of the arterial stiffness indices were significantly correlated to eGFR. CONCLUSIONS: In patients with CKD stage 2-5 AASI had a moderate, but acceptable reproducibility. The correlation between AASI and aPWV was good whilst the correlation between AASI and AIx was considerably lower. There was no significant correlation between AASI and eGFR.

Moderate antiproteinuric effect of add-on aldosterone blockade with eplerenone in non-diabetic chronic kidney disease. A randomized cross-over study.

BACKGROUND: Reduction of proteinuria and blood pressure (BP) with blockers of the renin-angiotensin system (RAS) impairs the progression of chronic kidney disease (CKD). The aldosterone antagonist spironolactone has an antiproteinuric effect, but its use is limited by side effects. The present study evaluated the short-term antiproteinuric effect and safety of the selective aldosterone antagonist eplerenone in non-diabetic CKD. STUDY DESIGN: Open randomized cross-over trial. SETTING AND PARTICIPANTS: Forty patients with non-diabetic CKD and urinary albumin excretion greater than 300 mg/24 hours. INTERVENTION: Eight weeks of once-daily administration of add-on 25-50 mg eplerenone to stable standard antihypertensive treatment including RAS-blockade. OUTCOMES & MEASUREMENTS: 24 hour urinary albumin excretion, BP, p-potassium, and creatinine clearance. RESULTS: The mean urinary albumin excretion was 22% [CI: 14,28], P < 0.001, lower during treatment with eplerenone. Mean systolic BP was 4 mmHg [CI: 2,6], P = 0.002, diastolic BP was 2 mmHg [CI: 0,4], P = 0.02, creatinine clearance was 5% [CI: 2,8], P = 0.005, lower during eplerenone treatment. After correction for BP and creatinine clearance differences between the study periods, the mean urinary albumin excretion was 14% [CI: 4,24], P = 0.008 lower during treatment. Mean p-potassium was 0.1 mEq/L [CI: 0.1,0.2] higher during eplerenone treatment, P<0.001. Eplerenone was thus well tolerated and no patients were withdrawn due to hyperkalaemia. LIMITATIONS: Open label, no wash-out period and a moderate sample size. CONCLUSIONS: In non-diabetic CKD patients, the addition of eplerenone to standard antihypertensive treatment including RAS-blockade caused a moderate BP independent fall in albuminuria, a minor fall in creatinine clearance and a 0.1 mEq/L increase in p-potassium. TRIAL REGISTRATION: Clinicaltrials.gov NCT00430924.

[Somatostatin analogues in the treatment of bleeding GI-angiodysplasias]. / Behandling af gastrointestinal blødning fra angiodysplasier med somatostatinanalogen octreotid.

Angiodysplasias account for 2-8% of GI-bleeding episodes. We describe a 75-year-old patient with a history of anaemia for 1 year before being diagnosed with multiple angiodysplasias in the GI-tract. The patient needed weekly blood transfusions until he started treatment with octreotide. After 4 months of treatment the need for transfusions had decreased dramatically and faeces was negative for blood. Treatment was switched to long-acting octreotide (Sandostatin Lar). The case illustrates the usefulness of somatostatin analogues in the treatment of bleeding GI-angiodysplasias.

[Laparoscopic donor nephrectomy at the Herlev University Hospital, Denmark]. / Erfaringer med laparoskopisk donornefrektomi på Herlev Hospital.

INTRODUCTION: The purpose of this investigation was to evaluate the morbidity and convalescence of donors after laparoscopic nephrectomy. Transperitoneal laparoscopy was initiated at Herlev University Hospital in November 2002. MATERIALS AND METHODS: All 24 records from patients who underwent laparoscopic donor nephrectomy were reviewed. Demographic data and perioperative data were collected. RESULTS: Median operation time was 162 min. Estimated blood loss was 200 ml and warm ischemia time 5 min. Postoperative side effects were nausea/vomiting (nine patients) and shoulder pain (two patients). Most serious complication was bleeding, leading to laparotomy the day of surgery in one patient. Other complications were ileus due to herniation of small intestine in porthole 1/24, wound infection 3/24, vaso-vagal episode 1/24, bronchospasms with CO2-retention 1/24, pneumonia 1/24. Length of stay was three days. Return to activities of daily life after 3-4 weeks. Typical analgesics were ketorolac and paracetamol. No laparoscopic procedures were converted to open surgery. There was no mortality. One year graft survival is 96%. CONCLUSION: Transperitoneal laparoscopic donor nephrectomy can be performed safely without serious complications. It is a good alternative to the conventional open approach. No laparoscopic procedures were converted to open nephrectomy. These results are similar to experiences from large centres.