A systematic review of the efficacy and safety of anticoagulants in advanced chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) have an increased risk of venous thromboembolism (VTE) and atrial fibrillation (AF). Anticoagulants have not been studied in randomised controlled trials with CrCl < 30 ml/min. The objective of this review was to identify the impact of different anticoagulant strategies in patients with advanced CKD including dialysis. METHODS: We conducted a systematic review of randomized controlled trials and cohort studies, searching electronic databases from 1946 to 2022. Studies that evaluated both thrombotic and bleeding outcomes with anticoagulant use in CrCl < 50 ml/min were included. RESULTS: Our initial search yielded 14,503 papers with 53 suitable for inclusion. RCTs comparing direct oral anticoagulants (DOACs) versus warfarin for patients with VTE and CrCl 30-50 ml/min found no difference in recurrent VTE events (RR 0.68(95% CI 0.42-1.11)) with reduced bleeding (RR 0.65 (95% CI 0.45-0.94)). Observational data in haemodialysis suggest lower risk of recurrent VTE and major bleeding with apixaban versus warfarin. Very few studies examining outcomes were available for therapeutic and prophylactic dose low molecular weight heparin for CrCl < 30 ml/min. Findings for patients with AF on dialysis were that warfarin or DOACs had a similar or higher risk of stroke compared to no anticoagulation. For patients with AF and CrCl < 30 ml/min not on dialysis, anticoagulation should be considered on an individual basis, with limited studies suggesting DOACs may have a preferable safety profile. CONCLUSION: Further studies are still required, some ongoing, in patients with advanced CKD (CrCl < 30 ml/min) to identify the safest and most effective treatment options for VTE and AF.

Extracellular resistance is sensitive to tissue sodium status; implications for bioimpedance-derived fluid volume parameters in chronic kidney disease.

Multifrequency bioimpedance spectroscopy (BIS) is an established method for assessing fluid status in chronic kidney disease (CKD). However, the technique is lacking in predictive value and accuracy. BIS algorithms assume constant tissue resistivity, which may vary with changing tissue ionic sodium concentration (Na+). This may introduce significant inaccuracies to BIS outputs. To investigate this, we used 23Na magnetic resonance imaging (MRI) to measure Na+ in muscle and subcutaneous tissues of 10 healthy controls (HC) and 20 patients with CKD 5 (not on dialysis). The extracellular (Re) and intracellular (Ri) resistance, tissue capacitance, extracellular (ECW) and total body water (TBW) were measured using BIS. Tissue water content was assessed using proton density-weighted MRI with fat suppression. BIS-derived volume indices were comparable in the two groups (OH: HC - 0.4 ± 0.9 L vs. CKD 0.5 ± 1.9 L, p = 0.13). However, CKD patients had higher Na+ (HC 21.2 ± 3.0, CKD 25.3 ± 7.4 mmol/L; p = 0.04) and significantly lower Re (HC 693 ± 93.6, CKD 609 ± 74.3 Ohms; p = 0.01); Ri and capacitance did not vary. Na+ showed a significant inverse linear relationship to Re (rs = - 0.598, p < 0.01) but not Ri. This relationship of Re (y) and Na+ (x) is described through equation y = - 7.39x + 814. A 20% increase in tissue ionic Na+ is likely to overestimate ECW by 1.2-2.4L. Tissue Na+ concentration has a significant inverse linear relationship to Re. BIS algorithms to account for this effect could improve prediction accuracy of bioimpedance derived fluid status in CKD.

Salt and Water Retention Is Associated with Microinflammation and Endothelial Injury in Chronic Kidney Disease.

BACKGROUND: Progressive chronic kidney disease (CKD) inevitably leads to salt and water retention and disturbances in the macro-and microcirculation. OBJECTIVES: We hypothesize that salt and water dysregulation in advanced CKD may be linked to inflammation and microvascular injury pathways. METHODS: We studied 23 CKD stage 5 patients and 11 healthy controls (HC). Tissue sodium concentration was assessed using 23Sodium magnetic resonance (MR) imaging. Hydration status was evaluated using bioimpedance spectroscopy. A panel of inflammatory and endothelial biomarkers was also measured. RESULTS: CKD patients had fluid overload (FO) when compared to HC (overhydration index: CKD = 0.5 ± 1.9 L vs. HC = -0.5 ± 1.0 L; p = 0.03). MR-derived tissue sodium concentrations were predominantly higher in the subcutaneous (SC) compartment (median [interquartile range] CKD = 22.4 mmol/L [19.4-31.3] vs. HC = 18.4 mmol/L [16.6-21.3]; p = 0.03), but not the muscle (CKD = 24.9 ± 5.5 mmol/L vs. HC = 22.8 ± 2.5 mmol/L; p = 0.26). Tissue sodium in both compartments correlated to FO (muscle: r = 0.63, p < 0.01; SC: rs = 0.63, p < 0.01). CKD subjects had elevated levels of vascular cell adhesion molecule (p < 0.05), tumor necrosis factor-alpha (p < 0.01), and interleukin (IL)-6 (p = 0.01) and lower levels of vascular endothelial growth factor-C (p = 0.04). FO in CKD was linked to higher IL-8 (r = 0.51, p < 0.05) and inversely associated to E-selectin (r = -0.52, p = 0.01). Higher SC sodium was linked to higher intracellular adhesion molecule (ICAM; rs = 0.54, p = 0.02). CONCLUSION: Salt and water accumulation in CKD appears to be linked with inflammation and endothelial activation pathways. Specifically IL-8, E-Selectin (in FO), and ICAM (in salt accumulation) may be implicated in the pathophysiology of FO and merit further investigation.

Migration of antigen presenting cells from periphery to the peritoneum during an inflammatory response: role of chemokines and cytokines.

We demonstrate the migration of antigen presenting cells (APCs), macrophages, and dendritic cells from the subcutaneous site to the peritoneum after they have picked up the antigen, using cell tracking dye. The migration of the APCs is more universal as it was also observed after injection of MethA tumor, DH-5alpha cells, and leishmania parasites, in addition to AK-5 tumor cells. Cellular migration is mediated by several chemokines and cytokines that also induce heavy influx of immune cells into the peritoneum. MIP-3beta secreted by the mesothelial cells is involved in the cellular influx into the peritoneum, whereas IL-12 and IFN-gamma produced by the APCs induced activation of immune cells in the peritoneum. Our results suggest an antigen presentation function for the APCs in the peritoneum as studied by lymphoproliferation assays. These studies indicate antigen presentation function of the activated migratory APCs from the distant subcutaneous site to the peritoneum, suggesting it acts as an important lymphoid organ involved in the enhancement of effector cell function.

Suppression of macrophage function in AK-5 tumor transplanted animals: role of TGF-beta1.

Transforming growth factor-beta 1 (TGF-beta1), a multifunctional cytokine secreted by various cell types has been implicated in diverse physiologic and pathophysiologic functions, including immunological, inflammatory, and neoplastic processes. AK-5 tumor cells when injected intraperitoneally grow as ascites, causing 100% mortality. Peritoneal macrophages cocultured with AK-5 cells, in vitro showed specific suppression of tumoricidal function. We report that AK-5 cells secrete the latent form of TGF-beta1, which is converted to its active homodimeric form, causing suppression of the secretion of cytocidal molecule by macrophages thereby inhibiting their cytotoxic capabilities. When macrophages are cocultured with AK-5 cells in the presence of antibodies against TGF-beta1 or the receptor II for TGF-beta, there is significant recovery in the secretion of nitric oxide and macrophage cytotoxic potential. These results suggest a major role for TGF-beta produced by the tumor cells, in the immune escape mechanisms adopted by the AK-5 tumor cells.

Antitumour immune responses.

The role of the immune system in combating tumour progression has been studied extensively. The two branches of the immune response - humoral and cell-mediated - act both independently and in concert to combat tumour progression, the success of which depends on the immunogenicity of the tumour cells. The immune system discriminates between transformed cells and normal cells by virtue of the presence of unique antigens on tumour cells. Despite this, the immune system is not always able to detect and kill cancerous cells because neoplasms have also evolved various strategies to escape immune surveillance. Attempts are being made to trigger the immune system into an early and efficient response against malignant cells, and various therapeutic modalities are being developed to enhance the strength of the immune response against tumours. This review aims to elucidate the tumoricidal role of various components of the immune system, including macrophages, lymphocytes, dendritic cells and complement.

Role of reactive nitrogen intermediates and protein nitration during immune response against a rat histiocytoma.

The ability of macrophages to produce reactive nitrogen species, particularly nitric oxide (NO) is correlated with an enhanced microbicidal or tumoricidal activity during pathogenic or tumoral invasion, respectively. NO reacts in water with oxygen and its reactive intermediates to yield, among others, nitrite and nitrate, which are relatively, stable anions. In this study, we show the varying concentrations of nitrite and nitrate present in different body fluids during AK-5 tumor growth and regression in Wistar rats. We have followed the tumor progression profile and the corresponding levels of nitrite and nitrate present in three major body compartments: the tumor mass; the serum which is the intermediary site; and the peritoneal compartment which is the priming ground for the macrophages. We are thus able to show that the status of the tumor has a direct correlation with macrophage activation and motility to different sites in the body. We also demonstrate after in vitro coculture, that the levels of nitrite and nitrate secreted by the macrophages correlate with their cytocidal capacity.

Differential modulation of host macrophage function by AK-5 tumor is dependent on the site of tumor transplantation.

We have studied the mechanisms involved in the activation or suppression of the immune response by the tumor cells, which is also dependent on the site of tumor transplantation. AK-5 tumor cells when transplanted s.c. activated peritoneal macrophages through the induction of different cytokines, whereas tumor cells when transplanted i.p. suppressed the activity of macrophages as well as the production of cytokines. Suppression of macrophage function was also observed when they were cocultured with tumor cells in vitro. Our studies suggest the capability of AK-5 tumor in driving the immune response either towards activated status or towards immune suppression, depending on the site of transplantation. Activated macrophages produced free radicals, which were cytotoxic to the tumor cells.