Comparison of different methods to assess tacrolimus concentration intra-patient variability as potential marker of medication non-adherence.

Background and objective: Non-adherence to tacrolimus commonly manifests as low drug concentrations and/or high intra-patient variability (IPV) of concentrations across multiple measurements. We aimed to compare several methods of tacrolimus IPV calculation and evaluate how well each reflects blood concentration variation due to medication non-adherence in kidney transplant recipients. Methods: This Czech single-center retrospective longitudinal study was conducted in 2019. All outpatients ≥18 years of age, ≥3 months post-transplant, and on tacrolimus-based regimens were approached. After collecting seven consecutive tacrolimus concentrations we asked participating patients to self-report adherence to immunosuppressants (BAASIS© scale). The IPV of tacrolimus was calculated as the medication level variability index (MLVI), the coefficient of variation (CV), the time-weighted CV, and via nonlinearly modeled dose-corrected trough levels. These patient-level variables were analyzed using regression analysis. Detected nonlinearities in the dose-response curve were controlled for by adding tacrolimus dosing and its higher-order terms as covariates, along with self-reported medication adherence levels. Results: Of 243 patients using tacrolimus, 42% (n = 102) reported medication non-adherence. Non-adherence was associated with higher CVs, higher time-weighted CVs, and lower dose-corrected nonlinearly modeled trough levels; however, it was not associated with MLVIs. All of the significant operationalizations suggested a weak association that was similar across the applied methods. Discussion and conclusion: Implementation non-adherence was reflected by higher CV or time-weighted CV and by lower blood concentrations of tacrolimus. As an additional tool for identifying patients at risk for non-adherence, simple IPV calculations incorporated into medical records should be considered in everyday clinical practice.

Bone disesase in end-stage kidney disease - renal and non-renal components.

Metabolic bone disease in chronic kidney disease and end-stage renal failure represents one of the most severe clinical complication in kidney patients, namely those on maintenance dialysis. Traditionally, bone changes are induced by secondary hyperparathyroidism. The CKD-MBD concept reflects the link between bone and cardiovascular disease in these patients. Studies documented also other bone pathological pathways in renal patients, such as osteoporosis, as in kidney and dialysis patients its risk factors are present as well as in general population. Resulting bone disease in renal disease and failure is far more complex than previously seen. However, the secondary hyperparathyroidism still represents the main pathological pathway.

Immunosuppressive therapy related adherence, beliefs and self-management in kidney transplant outpatients.

PURPOSE: Kidney transplant (KTx) recipients should strictly adhere to their lifelong complex therapeutic regimen, and any barriers to medication adherence can weaken correct patient behavior. This study aimed to determine the adherence to immunosuppressive therapy (IS) in KTx adult outpatients in the Czech Republic, and attempted to gain a greater insight into their attitudes toward IS and self-management tasks. MATERIALS AND METHODS: Pharmacist-led structured interviews were conducted to assess self-reported adherence to IS using the Czech version of the Medication Adherence Report Scale, in the context of attitudes toward IS in terms of necessity and concern scale of the Beliefs about Medicines Questionnaire. A specific questionnaire was developed to target IS self-management tasks. Medication records were also reviewed for IS serum levels, reflecting direct adherence measurement. Descriptive statistics were used to calculate adherence and self-management variables, and were analyzed by univariate and multivariate correlations, including the decision-tree method. RESULTS: The interview was completed by 211 (male 123; mean age 55.0±12.4 years, mean time 6.6±5.9 years after KTx) of the total of 235 patients. Full adherence to IS was reported by 173 (82.0%) patients. Most of them had IS serum levels within the therapeutic range, however, cyclosporine was associated with the highest variability (P<0.001). Non-adherence and concerns increased over time after KTx (P<0.05). Despite the more common unintentional non-adherence (P<0.001), relatively high concerns signified the risk of not taking IS as prescribed. Concerns also correlated with the perception of impaired health status (P<0.01), as well as the occurrence of IS-related adverse effects (P<0.001). The patients' awareness of their therapy was insufficient, and main gaps in self-management comprised inadequate sun protection, incorrect administration of IS, and unfamiliarity with the IS name, or their indications. CONCLUSION: Although self-reported adherence to IS therapy was satisfactory, the comprehensive evaluation enabled the detection of greater concerns about IS, as well as underestimated self-management tasks that posttransplant interventions should target in the future.

Molecular patterns of diffuse and nodular parathyroid hyperplasia in long-term hemodialysis.

Secondary hyperparathyroidism is a well-known complication of end-stage renal disease (ESRD). Both nodular and diffuse parathyroid hyperplasia occur in ESRD patients. However, their distinct molecular mechanisms remain poorly understood. Parathyroid tissue obtained from ESRD patients who had undergone parathyroidectomy was used for Illumina transcriptome screening and subsequently for discriminatory gene analysis, pathway mapping, and gene annotation enrichment analysis. Results were further validated using quantitative RT-PCR on the independent larger cohort. Microarray screening proved homogeneity of gene transcripts in hemodialysis patients compared with the transplant cohort and primary hyperparathyroidism; therefore, further experiments were performed in hemodialysis patients only. Enrichment analysis conducted on 485 differentially expressed genes between nodular and diffuse parathyroid hyperplasia revealed highly significant differences in Gene Ontology terms and the Kyoto Encyclopedia of Genes and Genomes database in ribosome structure (P = 3.70 × 10-18). Next, quantitative RT-PCR validation of the top differently expressed genes from microarray analysis proved higher expression of RAN guanine nucleotide release factor (RANGRF; P < 0.001), calcyclin-binding protein (CACYBP; P < 0.05), and exocyst complex component 8 (EXOC8; P < 0.05) and lower expression of peptidylprolyl cis/trans-isomerase and NIMA-interacting 1 (PIN1; P < 0.01) mRNA in nodular hyperplasia. Multivariate analysis revealed higher RANGRF and lower PIN1 expression along with parathyroid weight to be associated with nodular hyperplasia. In conclusion, our study suggests the RANGRF transcript, which controls RNA metabolism, to be likely involved in pathways associated with the switch to nodular parathyroid growth. This transcript, along with PIN1 transcript, which influences parathyroid hormone secretion, may represent new therapeutical targets to cure secondary hyperparathyroidism.

Changes of serum calcium, magnesium and parathyroid hormone induced by hemodialysis with citrate-enriched dialysis solution.

BACKGROUND/AIMS: In recent years, one of technical attempts to improve biocompatibility and tolerability of the hemodialysis procedure is the substitution of acetate in dialysis solution with citrate. The aim of our study was to compare two dialysis solutions: traditional bicarbonate dialysis solution containing acetate (3 mmol/L) (solution A); and (solution C) commercially produced citrate-enriched bicarbonate dialysis solution (0.8 mmol/L citrate). METHODS: Patients from a single hemodialysis center (N=126) were included in the study. Both conventional low-flux hemodialysis and on-line hemodiafiltration procedures were studied. Both dialysis solutions contained identical calcium (1.5 mmol/L) and magnesium (0.5 mmol/L) concentrations. RESULTS: Parathyroid hormone (iPTH) concentration decreased during procedures with solution A by 64%. On the contrary, when solution C was used, iPTH concentration increased insignificantly by 4%. For solution A, serum calcium and magnesium increased during procedures in patients with predialysis concentrations lower than 2.33 and 0.76 mmol/L, respectively. In procedures with dialysis solution C these concentrations were significantly lower: 2.19 mmol/L for Ca and 0.68 mmol/L for Mg. CONCLUSION: Our study clearly shows that the substitution of part of acetate with citrate in dialysis solution significantly influences changes of serum calcium, magnesium and parathyroid hormone concentrations during hemodialysis and hemodiafiltration procedures.

Skin wounds associated with calciphylaxis in end-stage renal disease patients on dialysis.

Calciphylaxis is a rare complication of chronic renal failure mostly with poor prognosis. Painful lesions on various skin surface areas are the most prominent feature of this serious disease. Subsequent infection of necrotic skin tissue is associated with the risk of sepsis. Pathophysiology is unclear, but several risk factors are known. The most important risk factor is impaired calcium-phosphate metabolism. Our paper describes two cases of different forms of calciphylaxis in patients with chronic renal failure. In the first case, pamidronate and cinacalcet were used for treatment. In the second described case, calciphylaxis was associated with secondary hyperparathyroidism and immediate subtotal parathyroidectomy was performed. Both patients were successfully treated, using systemic approach as well as dedicated local care for healing of skin wounds.

Resting energy expenditure and thermal balance during isothermic and thermoneutral haemodialysis--heat production does not explain increased body temperature during haemodialysis.

BACKGROUND: During routine haemodialysis (HD) body temperature increases, which contributes to haemodynamic instability. The relative roles of increased heat production and/or incomplete heat transfer are not fully elucidated. Concomitant measurement of heat production and heat transfer may help to assess the factors determining thermal balance during HD. METHODS: Thirteen stable non-diabetic maintenance HD patients were investigated during two HD procedures (isothermic, dT = 0, no change of body temperature; thermoneutral, dE = 0, no energy transfer between blood and dialysate), using a blood temperature monitor (BTM) in active mode. Energy transfer, blood and dialysate temperature, and relative blood volume change (dBV) were continuously recorded, and resting energy expenditure (REE; Deltatrac Datex) was measured repeatedly during each procedure. Fourteen healthy persons served as controls for REE comparison. RESULTS: In isothermic HD, median energy removal was 218 kJ/4 h HD (= heat flow -15.1 W). This cooling correlated with dBV induced by ultrafiltration (rho = 0.731, P < 0.01). There was no difference in dBV between isothermic (7.7%) and thermoneutral (8.1%) HD. Predialysis REE was 82.8 W/1.73 m(2), not different from controls. No variation in REE during HD was observed, except a small and transient increase after a light meal (5 and 4%). In the time course of REE, no difference between the procedures was found. CONCLUSIONS: Our findings suggest that stable maintenance HD patients have REE not different from healthy controls, that HD procedure per se does not significantly increase REE and that neither isothermic nor thermoneutral regimen has any influence on metabolic rate. Therefore, body temperature elevation during routine HD may rather be due to decreased heat removal. With the use of BTM in active mode, body temperature can be kept stable (isothermic HD), which requires active cooling. This negative energy transfer is proportional to decrease in blood volume induced by ultrafiltration.