Adherence to, and patient convenience of, prolonged-release tacrolimus in stable kidney and liver transplant recipients after conversion from immediate-release tacrolimus in routine clinical practice in Switzerland.

AIMS OF THE STUDY: Non-adherence to immunosuppressive therapy in patients following solid organ transplantation is associated with an increased risk of transplant rejection and graft loss. A high pill burden can adversely affect patients’ implementation of their treatment regimens and may lead to omitting doses of medication. The aim of this study was to investigate medication implementation adherence in liver and kidney transplant recipients converted from twice-daily, immediate-release tacrolimus to once-daily, prolonged-release tacrolimus. METHODS: This multicentre, non-interventional, observational, 12-month study evaluated implementation adherence in routine practice at five hospitals in Switzerland. Patients attended four clinical visits: at baseline (pre-conversion), and then at week 2, month 6 and month 12 post-conversion. Implementation was defined as consistently taking medication at the correct time and at the correct dose in order to achieve target tacrolimus trough levels. Implementation adherence was evaluated in three ways: using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) interview questionnaire (at baseline and month 12), investigator-rated patient adherence (recorded at all visits), and tacrolimus trough levels (assessed throughout the study; sub-therapeutic levels were predefined by the investigator on an individual patient basis, over-therapeutic levels were defined as tacrolimus trough levels >15 ng/ml). The primary composite endpoint was non-adherence according to the BAASIS at month 12, any post-conversion investigator adherence rating of “poor”, or sub-therapeutic or over-therapeutic tacrolimus trough levels at month 6 or 12. Secondary endpoints included: individual components of the composite non-adherence primary endpoint, tacrolimus pill burden, patient satisfaction, and adverse drug reactions. RESULTS: Seventy-five patients received prolonged-release tacrolimus; 68 patients (46 kidney and 22 liver transplant recipients) completed the study. Of these 68 patients, 24 had missing data for at least one component of the primary endpoint; therefore, data for the primary composite endpoint were evaluable for 44 patients. Most (81.8%; 36/44) patients were non-adherent for the composite endpoint. Sub-therapeutic tacrolimus trough levels outside of the predefined therapeutic range were the largest contributor to the composite endpoint, and were detected in 62.0% (31/50) of patients. Overall non-adherence according to the BAASIS was similar pre-conversion (30.7%) and at 12 months post-conversion (28.3%). Investigators rated adherence as “poor” for two patients. Prolonged-release tacrolimus decreased tacrolimus pill burden in 66.7% of patients. All patients were very satisfied / satisfied with prolonged-release tacrolimus; 75.0% found it easier to remember to take prolonged-release versus immediate-release tacrolimus. Twenty percent of patients reported adverse drug reactions, with infections being the most frequently reported (9.3%). CONCLUSION: Overall, 1-year non-adherence rates were similar following conversion from immediate-release to prolonged-release tacrolimus; however, prolonged-release tacrolimus intake was more convenient. No new safety signals were detected.

Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial.

BACKGROUND: Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. However, evidence for benefits and harms of thiazides in the prevention of calcium containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known. METHODS: The NOSTONE trial is an investigator-initiated 3-year prospective, multicenter, double-blind, placebo-controlled trial to assess the efficacy of standard and low dose hydrochlorothiazide treatment in the recurrence prevention of calcium containing kidney stones. We plan to include 416 adult (≥ 18 years) patients with recurrent (≥ 2 stone episodes in the last 10 years) calcium containing kidney stones (containing ≥50% of calcium oxalate, calcium phosphate or a mixture of both). Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo. The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome, safety and tolerability of hydrochlorothiazide treatment, changes in urinary biochemistry elicited by hydrochlorothiazide treatment and impact of baseline disease severity, biochemical abnormalities and stone composition on treatment response. DISCUSSION: The NOSTONE study will provide long-sought information on the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones. Strengths of the study include the randomized, double-blind and placebo-controlled design, the large amount of patients studied, the employment of high sensitivity and high specificity imaging and the exclusive public funding support. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03057431 . Registered on February 20 2017.

Assessment of intradialysis calcium mass balance by a single pool variable-volume calcium kinetic model.

INTRODUCTION: A reliable method of intradialysis calcium mass balance quantification is far from been established. We herein investigated the use of a single-pool variable-volume Calcium kinetic model to assess calcium mass balance in chronic and stable dialysis patients. METHODS: Thirty-four patients on thrice-weekly HD were studied during 240 dialysis sessions. All patients were dialyzed with a nominal total calcium concentration of 1.50 mmol/L. The main assumption of the model is that the calcium distribution volume is equal to the extracellular volume during dialysis. This hypothesis is assumed valid if measured and predicted end dialysis plasma water ionized calcium concentrations are equal. A difference between predicted and measured end-dialysis ionized plasma water calcium concentration is a deviation on our main hypothesis, meaning that a substantial amount of calcium is exchanged between the extracellular volume and a nonmodeled compartment. FINDINGS: The difference between predicted and measured values was 0.02 mmol/L (range -0.08:0.16 mmol/L). With a mean ionized dialysate calcium concentration of 1.25 mmol/L, calcium mass balance was on average negative (mean ± SD -0.84 ± 1.33 mmol, range -5.42:2.75). Predialysis ionized plasma water concentration and total ultrafiltrate were the most important predictors of calcium mass balance. A significant mobilization of calcium from the extracellular pool to a nonmodeled pool was calculated in a group of patients. DISCUSSION: The proposed single pool variable-volume Calcium kinetic model is adequate for prediction and quantification of intradialysis calcium mass balance, it can evaluate the eventual calcium transfer outside the extracellular pool in clinical practice.

A prospective observational study comparing a non-operator dependent automatic PWV analyser to pulse pressure, in assessing arterial stiffness in hemodialysis.

BACKGROUND: Chronic kidney disease (CKD) accelerates vascular stiffening related to age. Arterial stiffness may be evaluated measuring the carotid-femoral pulse wave velocity (PWV) or more simply, as recommended by KDOQI, monitoring pulse pressure (PP). Both correlate to survival and incidence of cardiovascular disease. PWV can also be estimated on the brachial artery using a Mobil-O-Graph; a non-operator dependent automatic device. The aim was to analyse whether, in a dialysis population, PWV obtained by Mobil-O-Graph (MogPWV) is more sensitive for vascular aging than PP. METHODS: A cohort of 143 patients from 4 dialysis units has been followed measuring MogPWV and PP every 3 to 6 months and compared to a control group with the same risk factors but an eGFR > 30 ml/min. RESULTS: MogPWV contrarily to PP did discriminate the dialysis population from the control group. The mean difference translated in age between the two populations was 8.4 years. The increase in MogPWV, as a function of age, was more rapid in the dialysis group. 13.3% of the dialysis patients but only 3.0% of the control group were outliers for MogPWV. The mortality rate (16 out of 143) was similar in outliers and inliers (7.4 and 8.0%/year). Stratifying patients according to MogPWV, a significant difference in survival was seen. A high parathormone (PTH) and to be dialysed for a hypertensive nephropathy were associated to a higher baseline MogPWV. CONCLUSIONS: Assessing PWV on the brachial artery using a Mobil-O-Graph is a valid and simple alternative, which, in the dialysis population, is more sensitive for vascular aging than PP. As demonstrated in previous studies PWV correlates to mortality. Among specific CKD risk factors only PTH is associated with a higher baseline PWV. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02327962.

Frequency and severity of pain and symptom distress among patients with chronic kidney disease receiving dialysis.

QUESTION UNDER STUDY: Data on pain management in haemodialysis patients with end-stage renal disease are scanty. Our study aimed to collect information on the frequency and severity of pain and symptom distress among long-term dialysis patients in southern Switzerland. METHODS: Patients with chronic kidney disease stage 5, on dialysis, treated in five nephrology units in southern Switzerland, who had given informed consent and were able to complete the survey, were interviewed to assess pain and correlated symptoms using a Visual Analogue Scale (VAS), the Brief Pain Inventory and the Edmonton Symptom Assessment System. To evaluate the impact of symptoms, the Instrumental Activities of Daily Living questionnaire was used. RESULTS: One hundred and twenty-three patients, aged 36-90 years and with a mean time on dialysis of 3.5 years, were interviewed. Pain was experienced by 81 patients during the 4 weeks before the interview: 68 had chronic pain; 66 reported pain intensity higher than 5 on the VAS; 35 identified musculoskeletal pain as the most disturbing pain. Five patients used drugs to cope with pain during the night. Asthenia and fatigue were prevalent concomitant symptoms. Asthenia, fatigue, sleep disturbances, dyspnoea, loss of appetite, nausea/vomiting and anxiety were correlated with pain. The majority of the patients reported that their pain limited their daily life activities. CONCLUSIONS: Pain severity and symptom distress in dialysis patients are important, but underestimated and undertreated. They interfere with sleep quality and daily living. Routine assessment of pain burden, pain management similar to that used in palliative care, and adequate analgesic use to treat specific dialysis-associated pain syndromes should be considered in guidelines.

High prevalence in Switzerland of pure red-cell aplasia due to anti-erythropoietin antibodies in chronic dialysis patients: report of five cases.

BACKGROUND: Pure red-cell aplasia (PRCA) after erythropoietin (Epo) administration due to the appearance of neutralizing anti-Epo antibodies has been reported in over 200 cases between 1998 and 2002. However, large intercountry disparities were observed in the occurrence of this syndrome. METHODS: On behalf of the Swiss Society of Nephrology, a survey was conducted in all the dialysis units of Switzerland in order to collect information on the occurrence, diagnostic and evolution data of the cases observed. A questionnaire was send to the nephrologists in charge of each of the 69 dialysis units in January 2003. The clinical and biological data of the suspected cases were analysed and compared with the data provided to health authorities and pharmaceutical companies. RESULTS: A total of five cases were identified as true PRCA with demonstrated positive anti-Epo antibodies. They occurred between November 1998 and February 2002, were all treated by haemodialysis and had received Epo subcutaneously. The median appearance time of refractory anaemia after Epo initiation was 10 months (range: 7-54 months). Two cases had been treated exclusively with epoietin-alpha, one solely with epoietin-beta and the two others with a combination of both. With five cases out of a total of about 2500 dialysis patients and 2300 Epo-treated dialysis patients or an exposure rate to Epo of 9900 dialysis patient-years during a 4.3 year period, this prevalence is among the highest of those reported in European countries. CONCLUSIONS: The prevalence of PRCA after Epo administration in dialysis patients appears particularly high in Switzerland. Among the potential explanations, the most plausible are the high percentage of dialysis patients treated with Epo, the almost exclusive subcutaneous administration, the larger market distribution of the epoietin-alpha brand, the eventual disruption of the cold chain and the setting-up of a systematic national survey.

Does monitoring of pre-/post-dialyzer pressure difference improve efficiency in intermittent hemodialysis?

BACKGROUND: Continuous monitoring of pre-/post-dialyzer pressure difference (DeltaP) is widely used in continuous renal replacement therapies to monitor extracorporeal circuit function. The aim of this study was to verify whether DeltaP may help to identify chronic subclinical worsening of dialysis quality due to incomplete dialyzer clotting in intermittent hemodialysis. METHODS: Nine chronic hemodialysis patients were enrolled in the study and dialyzed twice (high-flux polysulfone dialyzer) with DeltaP and urea-clearance monitoring: the first session with a standard anticoagulation and the second without. To verify whether a visible clotting of the dialyzer precedes or follows a significant DeltaP increase, we checked the dialyzers for the presence of red clots after a saline flush performed when a 50% increase in DeltaP was registered. RESULTS: In the second dialysis session after a 50% increase in DeltaP (documented in 7/9 patients), all dialyzers, after saline flush, showed a visible fiber clotting but not a significant reduction (>15%) in urea clearance. In the majority of the patients (6/7), until a few minutes before complete occlusion of the extracorporeal circuit, the urea clearance did not change significantly (-8.9 +/- 12.7%). CONCLUSIONS: The usual check of the presence or absence of red clots in the dialyzer at the end of the dialysis session is enough, in the absence of red clots, to ensure that dialyzer efficiency is maintained during the whole treatment. Contrary to what is applied in CRRT, a continuous monitoring of DeltaP during intermittent hemodialysis would not significantly help to unmask unnoticed inefficient hemodialysis sessions.

Does continuous venovenous hemodiafiltration concomitant with radiological procedures provide a significant and safe removal of the iodinated contrast ioversol?

BACKGROUND: The purpose of our study was to investigate whether continuous venovenous hemodiafiltration (CVVHDF) concomitant with radiological procedures (RxP) was feasible, well tolerated and could significantly remove iodinated contrast media (CM). METHODS: 26 patients with various degrees of renal insufficiency who were submitted to RxP were included in the study. The CVVHDF session was started immediately before CM administration. All the patients were evaluated for feasibility and tolerability; furthermore a pharmacokinetic study was done on 12 patients to calculate the amount of CM eliminated. The baseline incidence of CM nephropathy was studied in 25 consecutive historical controls. RESULTS: The CM administered was 208 +/- 146 g; the fractional removal of CM was 9.2 +/- 4.9% during RxP and 30.9 +/- 20.7% during the whole CVVHDF session. Hemodynamic tolerance was excellent. The incidence of CM nephropathy in the experimental and control groups was 37 and 24%, respectively. CONCLUSIONS: CVVHDF during RxP is feasible and well tolerated but ioversol removal is modest. This fact together with the high incidence of renal function impairment, the complexity of the procedure and its intrinsic risks, and the large amount of resources needed discourage the routine use of CVVHDF as a prophylactic tool to avoid CM nephropathy.

Citrate anticoagulation in continuous venovenous hemodiafiltration: a metabolic challenge.

OBJECTIVE: Feasibility and safety evaluation of regional citrate anticoagulation (RCA) versus systemic heparinization for continuous venovenous hemodiafiltration. DESIGN AND SETTING: Combined retrospective and prospective observational study performed in a secondary multidisciplinary intensive care unit of the Ospedale Civico Lugano Switzerland. PATIENTS AND INTERVENTIONS: Twelve hemodynamically unstable patients (median APACHE II score 26, interquartile range 22-29) in whom heparin was judged to be at least temporarily contraindicated. A switch from RCA (predilution setting; same iso-osmotic replacement and dialysis fluid) to heparinization or vice versa was recommended for the final evaluation; 56 dialyzers were used for RCA (1,400 h) and 39 for heparinization (1,271 h). MEASUREMENTS AND RESULTS: Median dialyzer life span was 24.2 h (interquartile range 17.4-42.3) for RCA and 42.5 h (20.6-69.1) for heparinization. Fluid control and dialysis quality were similar in the two groups and required no additional intervention. The risk of significant hypocalcemia and metabolic alkalosis was higher at the beginning of the RCA program and decreased with the further training of the staff. Seven bleeding episodes occurred with heparinization vs. three in RCA. CONCLUSIONS: RCA may be a safe and useful form of anticoagulation which is more expensive than heparinization but helps to minimize bleeding risk. The risk of metabolic complications is higher at the beginning of a new RCA program. For centers lacking experienced staff we suggest reserving this technique for patients with rapid clotting of the extracorporeal circuit if treated without anticoagulation.