Hemophagocytic syndromes comprise a cluster of hyperinflammatory disorders, including hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Overwhelming macrophage activation has long been considered a final common pathway in the pathophysiology of hemophagocytic syndromes leading to the characteristic cytokine storm, laboratory abnormalities, and organ injuries that define the clinical spectrum of the disease. So far, it is unknown whether primary macrophage activation alone can induce the disease phenotype. In this study, we established a novel mouse model of a hemophagocytic syndrome by treating mice with an agonistic anti-CD40 antibody (Ab). The response in wild-type mice is characterized by a cytokine storm, associated with hyperferritinemia, high soluble CD25, erythrophagocytosis, secondary endothelial activation with multiple organ vaso-occlusion, necrotizing hepatitis, and variable cytopenias. The disease is dependent on a tumor necrosis factor-α–interferon-γ–driven amplification loop. After macrophage depletion with clodronate liposomes or in mice with a macrophage-selective deletion of the CD40 gene (CD40flox/flox/LysMCre), the disease was abolished. These data provide a new preclinical model of a hemophagocytic syndrome and reinforce the key pathophysiological role of macrophages.
Background Cancer risk is increased by two- to four-fold in kidney transplant recipients (KTRs) compared to the general population. Little attention, however, has been given to KTRs with ultra long-term survival >20 years. Methods We studied 293 of 1241 KTRs (23.6%), transplanted between 1981 and 1999, who showed kidney allograft survival >20 years. These long-term survivors were analyzed for cancer development, cancer type, cancer-associated risk factors, patient and allograft outcomes. Results By 10, 20, and 30 years post-transplantation, these long-term KTRs showed a cancer rate of 4.4%, 14.6%, and 33.2%, and a nonmelanoma skin cancer (NMSC) rate of 10.3%, 33.5%, and 76.8%. By recipient ages of 40, 60, and 80 years KTRs showed a cancer rate of 3.4%, 14.5%, 55.2%, and a NMSC rate of 1.7%, 31.6%, and 85.2%. By 30 years post-transplant, PTLD showed the highest incidence of 8.5%, followed by renal cell carcinoma (RCC) with 5.1%. Risk factors associated with the development of cancer were only recipient age(p = 0.016). Smoking history was associated with the risk of lung cancer (p = 0.018). Risk factors related to the development of NMSC included recipient age (p = 0.001) and thiazide diuretics (p = 0.001). Cancer increased the risk of death by 2.4-fold (p = 0.002), and PTLD increased the risk of kidney allograft loss by 6.5-fold (p = 0.001). No differences were observed concerning the development of donor-specific antibodies (p>0.05). Conclusions In long-term KTRs cancer is a leading cause of death. PTLD remains the most common cancer type followed by RCC. These results emphasize the need for focused long-term cancer surveillance protocols.
Background and Aims Kidneys have an intrinsic reserve capacity to respond to a higher workload by increasing filtration in their nephrons, called renal functional reserve (RFR). Despite the high clinical relevance of RFR, the necessary dynamic measurements are rarely done in the clinical routine, due to time- and workload as well as lack of standardized protocols. Method We developed a novel RFR protocol using 99mTc-DTPA (DTPA-Cl) before and after an oral protein load performed in an outpatient clinical setting within one day. Following a weak of low protein diet and using standardized hydration baseline and post-stimulation GFR were measured. 50 MBq activity were given i.v. at 0 and 240 mins, the plasma clearance was calculated based on the activity course at 13 time-points over 480 mins. RFR was expressed as the difference of post-protein stimulation peak mGFR to baseline mGFR in fasting state. Results In the pilot study we measured RFR in 7 healthy participants. The results showed a high heterogeneity. Therefore, we modified the study protocol for the next 16 patients by (a) extending the time of measurements to 330 min post-stimulation and (b) increasing the frequency of activity measurements to every 30 mins. In addition, we used a protein load of 1.5 g/kg bwt of beef protein. These standardized measurements showed inter-individual time differences in reaching the peak GFR values post-protein load, the peaks detectable between 150 to 270 mins after the protein meal. The mean RFR (±SD) was 14 (±13) ml/min/1.73 m2 corresponding to 16 (±15)% [Fig. 1]. All participants demonstrated a significant fall in DTPA-Cl 60 mins post-stimulation. Conclusion RFR can be measured with a same day pre- and post-stimulation DTPA-clearance protocol. Using a high oral load of beef protein and a long, post-stimulation period of measurements demonstrates inter-individual differences in reaching the hyperfiltration peak and a significant, previously not appreciated, post-prandial drop in GFR.
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