Comparison of the hemoglobin variability in non-chronic kidney disease or end-stage renal disease participants and patients with CKD and ESRD.

INTRODUCTION: Hemoglobin (Hb) variability occurs frequently in hemodialysis (HD) patients during erythropoietin (EPO) therapy. Guidelines define a narrow target range for the anemia treatment in these patients that is difficult to adhere to in practice. Our aim was to evaluate whether the Hb variability in HD patients is higher compared to non-chronic kidney disease or end-stage renal disease (ESRD) participants and patients with CKD stage I or II. MATERIALS AND METHODS: Monthly blood samples were assessed prospectively in 100 non-CKD or ESRD participants and 57 patients with CKD stage I or II, and retrospectively in 74 HD patients without changes in EPO or iron dose for 6 months. Variability was calculated and compared between the different groups. RESULTS: Hb variability was significantly higher in HD patients compared to the other groups, corresponding to results of previous studies. There were no significant differences between non-CKD or ESRD participants and patients with CKD stage I or II in terms of standard deviation (SD), residual SD, fluctuations across threshold, Hb cycling, and mean absolute change of Hb every 30 days (p > 0.05), but a significant difference compared to HD patients (p < 0.001). There were no significant differences between the groups in time in target and area under the curve (AUC) (p > 0.05). CONCLUSION: Hb variability is a common phenomenon in all groups independently of the method used for assessment and even without EPO therapy. The target range is difficult to achieve for HD patients and should be reconsidered in the future to avoid unsettling both the patients and the staff.

Development of a list with renally relevant drugs as a tool to increase medicines optimisation in patients with chronic kidney disease.

OBJECTIVES: Chronic kidney disease (CKD) is a common disorder all over the world. Therapeutic goals are early detection of declining renal function and implementation of adequate pharmacological treatments regarding underlying and secondary diseases. As therapy becomes more complex with increasing stages of CKD, a decision-making tool for healthcare professionals could help to ensure safe drug treatment in patients with CKD in the outpatient setting. Therefore, a list of renally relevant drugs as a decision-making tool was developed to improve medicines optimisation for CKD patients in the outpatient setting long term. METHODS: A renally relevant drug list (RRD-list) with renally relevant drugs, based on data from a study on medicines optimisation in patients with CKD from June 2015 to March 2018, was developed at the nephrological outpatient clinic at the Klinikum Fulda, Germany. The whole study is published elsewhere. A clinical pharmacist reviewed the patients' medications, current drug-related problems and all nephrologists' recommendations, and categorised all detected drugs into renally relevant and non-renally relevant groups. The 10 most frequently detected renally relevant drug groups were summarised in the RRD-list and extended by treatment alternatives and advice. RESULTS: The medication of 160 patients, who were receiving overall 1376 drugs, was analysed; 831 drugs were defined as renally relevant. Drug-related problems were caused by 543 renally relevant drugs. The nephrologists made 292 recommendations regarding 28 drug classes. Considering the 10 most frequent drug groups, in total 16 renally relevant drug groups with 36 drug classes were added to the RRD-list. CONCLUSIONS: The RRD-list could be an essential tool for all healthcare professionals in their daily work, such as general practitioners and community pharmacists, for the treatment of patients with renal insufficiency.

Medicines optimization for patients with chronic kidney disease in the outpatient setting: the role of the clinical pharmacist.

OBJECTIVES: Medicines optimization (MO) in patients with chronic kidney disease (CKD) is at high risk at transition points of different ambulatory care levels such as nephrologists in outpatient clinics and general practitioners (GPs). We examined if adding a clinical pharmacist to the therapeutic team promotes implementation of nephrologists' drug therapy recommendations by GPs' and reduces drug-related problems (DRPs). METHODS: A prospective, controlled intervention study was conducted in the nephrology outpatient clinic of the Klinikum Fulda, Germany. The control and intervention phases took place successively. Patients with CKD stage 3-5 and at least one concomitant disease, for example, arterial hypertension or type-2 diabetes were recruited consecutively in three subgroups (naive, 1 contact, ≥2 contacts with nephrologist) from June 2015 to May 2019. GPs' acceptance and frequency of DRPs without (control group [CG]) and with (intervention group [IG]) pharmacist's interventions were compared after 6 months. Interventions include educational training events for GPs between control- and intervention phase, medication therapy management and pharmaceutical patient counselling. KEY FINDINGS: In total, 256 patients (CG = 160, IG = 96) were recruited into the study. GPs' acceptance of nephrologists' medication recommendations increased significantly among naive patients and those with one prior contact with the nephrologist (CG/IG: naive = 72.8%/95.5%, 1 contact = 81.1%/94.4%; P < 0.001). DRPs per patient were significantly reduced in all subgroups (P < 0.001). CONCLUSIONS: Interdisciplinary collaboration between the nephrologist, GPs and clinical pharmacist resulted in better MO for patients with CKD.

Pre-transplant HLA Antibodies and Delayed Graft Function in the Current Era of Kidney Transplantation.

Delayed graft function (DGF) occurs in a significant proportion of deceased donor kidney transplant recipients and was associated with graft injury and inferior clinical outcome. The aim of the present multi-center study was to identify the immunological and non-immunological predictors of DGF and to determine its influence on outcome in the presence and absence of human leukocyte antigen (HLA) antibodies. 1,724 patients who received a deceased donor kidney transplant during 2008-2017 and on whom a pre-transplant serum sample was available were studied. Graft survival during the first 3 post-transplant years was analyzed by multivariable Cox regression. Pre-transplant predictors of DGF and influence of DGF and pre-transplant HLA antibodies on biopsy-proven rejections in the first 3 post-transplant months were determined by multivariable logistic regression. Donor age ≥50 years, simultaneous pre-transplant presence of HLA class I and II antibodies, diabetes mellitus as cause of end-stage renal disease, cold ischemia time ≥18 h, and time on dialysis >5 years were associated with increased risk of DGF, while the risk was reduced if gender of donor or recipient was female or the reason for death of donor was trauma. DGF alone doubled the risk for graft loss, more due to impaired death-censored graft than patient survival. In DGF patients, the risk of death-censored graft loss increased further if HLA antibodies (hazard ratio HR=4.75, P < 0.001) or donor-specific HLA antibodies (DSA, HR=7.39, P < 0.001) were present pre-transplant. In the presence of HLA antibodies or DSA, the incidence of biopsy-proven rejections, including antibody-mediated rejections, increased significantly in patients with as well as without DGF. Recipients without DGF and without biopsy-proven rejections during the first 3 months had the highest fraction of patients with good kidney function at year 1, whereas patients with both DGF and rejection showed the lowest rate of good kidney function, especially when organs from ≥65-year-old donors were used. In this new era of transplantation, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increase the risk of DGF. Measures to prevent the strong negative impact of DGF on outcome are necessary, especially during organ allocation for presensitized patients.

[Pharmaceutical care of a patient with oral anticoagulation and renal impairment]. / Pharmazeutische Betreuung eines Patienten mit chronischer Niereninsuffizienz unter oraler Antikoagulation.

Atrial fibrillation is one of the most important indications for oral anticoagulation. Besides vitamin K antagonists, the novel oral anticoagulants dabigatran, apixaban, edoxaban and rivaroxaban are one therapy option in patients with atrial fibrillation. The following case report describes an 83-year-old female patient treated with dabigatran for secondary stroke prevention. Due to different factors, the renal function of the patient decreases significantly (acute on chronic renal failure), resulting in a re-evaluation of the current treatment. This case report is an example of decision-making 'for and against' novel oral anticoagulants versus vitamin K antagonists.

[Novel oral anticoagulants--issues in clinical practice]. / Neue orale Antikoagulanzien.

The novel oral anticoagulants (NOAC) dabigatran, apixaban, edoxaban and rivaroxaban target either thrombin or factor Xa for the prevention and treatment of thrombosis. A short introduction of the main indications for an oral anticoagulation is followed by the pharmacology of each drug, their effectiveness, selected drug-drug interactions and adverse drug events, especially bleeding. The article represents clinical aspects for the perioperative management, the possibilities for monitoring of each drug, the application in patients with renal impairment as well as different advantages and disadvantages.

Pharmacogenetic analyses of cisplatin-induced nephrotoxicity indicate a renoprotective effect of ERCC1 polymorphisms.

AIM: We investigated whether genetic polymorphisms may contribute to the interpatient variability of cisplatin-induced nephrotoxicity. PATIENTS & METHODS: Polymorphisms in the candidate genes GSTM1, GSTT1, OCT1, OCT2, LARP2, ERCC1, XRCC1 and EPO were analyzed for associations with nephrotoxicity in 79 cancer patients receiving cisplatin-containing chemotherapy. RESULTS: Higher cisplatin dose was associated with strongly decreased estimated glomerular filtration rates (eGFR) (r(2) = 0.205). Two highly genetically linked polymorphisms in the ERCC1 gene, 8092C>A and Asn118Asn, were significantly associated with change in eGFR, accounting for an additional 13% of interindividual variability. Homozygous carriers of the 8092A allele in ERCC1 showed no reduction in eGFR, compared with the 11.5% mean eGFR decrease in C allele carriers (p = 0.004). Homozygous carriers of the C allele of Asn118Asn showed no reduction in eGFR, compared with the 12.8% mean eGFR decrease seen in T allele carriers (p = 0.047). Polymorphisms in the other candidate genes were not associated with cisplatin-induced nephrotoxicity. CONCLUSION: Genetic polymorphisms in ERCC1 may be valuable predictors of cisplatin-induced nephrotoxicity.

Regulation of renal adenosine excretion in humans--role of sodium and fluid homeostasis.

BACKGROUND: Adenosine is a vasoactive metabolite of ATP hydrolysis that is involved in the regulation of renal haemodynamics, tubular reabsorption and renin release. Elevated tissue levels are found under conditions of increased metabolic load, ischaemia or renal injury. Urinary adenosine excretion (EADO) may therefore provide a sensitive marker of renal functional impairment in allograft rejection and kidney disease. To provide a basis for evaluation of EADO in clinical settings, we investigated, in an intra-individual, crossover clinical trial the physiological variability and regulation of EADO in response to altered sodium and fluid balance. METHODS: Twelve healthy volunteers were randomized to normal (ad libitum), low (<5 g/day) or high (supplementation of 100 mg/kg/day) sodium chloride diets for 8 days prior to assessment of renal haemodynamics and tubular function in standard clearance investigations. Following baseline periods, fluid homeostasis was altered independently by acute oral water load. EADO was determined in 24 h urine collections and during clearance investigations. RESULTS: Mean EADO in humans was 3.2+/-0.2 micromol/ 24 h during euvolaemia and normal sodium intake. A weak correlation was found between sodium load and EADO. In clearance experiments, variation in EADO was <1.3-fold, despite profound alterations in sodium intake. EADO was independent of urinary flow rate. Renal haemodynamics were not significantly altered by dietary regimen or by acute volume load. CONCLUSION: In summary, the physiological variability of EADO is remarkably small in humans. We demonstrate that even profound alterations in sodium and fluid homeostasis do not significantly affect EADO. These data provide a basis for evaluation of elevated EADO as a marker of renal injury in various clinical settings.

Electrophysiological and molecular characterization of the inward rectifier in juxtaglomerular cells from rat kidney.

Renin, the key element of the renin-angiotensin-aldosterone system, is mainly produced by and stored in the juxtaglomerular cells in the kidney. These cells are situated in the media of the afferent arteriole close to the vessel pole and can transform into smooth muscle cells and vice versa. In this study, the electrophysiological properties and the molecular identity of the K+ channels responsible for the resting membrane potential (approximately -60 mV) of the juxtaglomerular cells were examined. In order to increase the number of juxtaglomerular cells, afferent arterioles from NaCl-depleted rats were used, and > 90% of the afferent arterioles were renin positive at the distal end of the arteriole. Whole-cell and cell-attached single-channel patch-clamp experiments showed that juxtaglomerular cells are endowed with a strongly inwardly rectifying K+ channel (Kir). The channel was highly sensitive to inhibition by Ba2+ (inhibition constant 37 microM at 0 mV), but relatively insensitive to Cs+ and, with 142 mM K+ in the pipette, had a single-channel conductance of 31.5 pS. Immunocytochemical studies showed the presence of Kir2.1 but no signal for Kir2.2 in the media of the afferent arteriole. In PCR analyses using isolated juxtaglomerular cells, the mRNA for Kir2.1 and Kir2.2 was detected. Collectively, the results show that Kir2.1 is the dominant component of the channel. The current carried by these channels plays a decisive role in setting the membrane potential of juxtaglomerular cells.

Does angiotensin II modulate erythropoietin production in HepG2 cells?

BACKGROUND: In humans, infusion of angiotensin II increases erythropoietin (EPO) serum levels in a dose-dependent manner. However, it is not known whether angiotensin II stimulates EPO-producing renal fibroblasts directly via a receptor or by alteration of renal hemodynamics with a consecutive decrease of renal blood flow. The purpose of this study was to investigate EPO secretion and gene expression under direct angiotensin II stimulation in a cell model thereby excluding hemodynamic effects. METHODS: In an established EPO-secreting cell line (HepG2), EPO concentrations were measured under various conditions (normoxia and hypoxia) and different angiotensin II concentrations. mRNA levels of EPO were analyzed by LightCycler quantitative PCR after reverse transcription normalized to the housekeeping gene cyclophilin. RESULTS: Angiotensin II did not affect EPO production in any concentration (1 nM or 100 microM) under conditions of normoxia. Reduced oxygen tension (1% O2) led to the expected increase of EPO and EPO gene expression. EPO secretion stimulated by hypoxia is not significantly changed by any concentration of angiotensin II. CONCLUSION: In summary, this study shows that angiotensin II does not alter EPO production in HepG2 cell culture under normoxic or hypoxic conditions. This might point towards the hypothesis that in vivo renal cortical blood flow and consecutively the decrease of oxygen tension may lead to an increase of EPO secretion.

Proinflammatory role of fractalkine (CX3CL1) in rheumatoid arthritis.

OBJECTIVE: Fractalkine (CX3CL1) represents the sole member of the so-called CX3C chemokines. In rheumatoid arthritis (RA), functional studies suggest a role for this chemokine in monocyte chemotaxis and angiogenesis in the rheumatoid synovium. We analyzed the expression of fractalkine within different T cell subsets of the peripheral blood and expression of its receptor CX3CR1 within the rheumatoid synovium to further characterize its pathogenic role in RA. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from 17 patients with RA and analyzed by flow cytometry in comparison to healthy blood donors. To identify the T helper cell cytokine profile of fractalkine-expressing cells, flow cytometric analysis of PBMC was performed after stimulation with PMA and ionomycin. Expression of fractalkine and its receptor was characterized in RA synovium by immunohistochemistry and laser capture microdissection microscopy. RESULTS: Flow cytometric analysis of fractalkine-expressing T cell subsets revealed a low proportion of fractalkine-expressing CD4+ and CD8+ T cells in both RA patients and controls. In addition, fractalkine was predominantly expressed in CD4+ T cells with a Th1-type cytokine expression profile. In RA synovium, fractalkine was detected in synovial macrophages, dendritic cells, endothelial cells, and a small proportion of T cells. The fractalkine receptor CX3CR1 was found in synovial macrophages, dendritic cells, and T cells as well as in synovial fibroblasts. Fractalkine stimulation of cultured synovial fibroblasts resulted in a marked upregulation of matrix metalloproteinase-2 (MMP-2) production. CONCLUSION: The results suggest that fractalkine may represent a Th1-type chemokine. Upregulation of MMP-2 production in synovial fibroblasts upon fractalkine stimulation in vitro supports the hypothesis of a proinflammatory role of this chemokine in RA.