Background and objectives: Extended hemodialysis using a high cut-off dialyzer (HCO-HD) removes large quantities of free light chains in patients with multiple myeloma. However, the clinical utility of this method is uncertain. This study assessed the combination of chemotherapy and HCO-HD on serum free light chain concentrations and renal recovery in patients with myeloma kidney (cast nephropathy) and dialysis-dependent acute renal failure.Design, setting, participants, & measurements: An open-label study of the relationship between free light chain levels and clinical outcomes in 19 patients treated with standard chemotherapy regimens and HCO-HD.Results: There were sustained early reductions in serum free light chain concentrations (median 85% [range 50 to 97]) in 13 patients. These 13 patients became dialysis independent at a median of 27 d (range 13 to 120). Six patients had chemotherapy interrupted because of early infections and did not achieve sustained early free light chain reductions; one of these patients recovered renal function (at 105 d) the remaining 5 patients did not recover renal function. Patients who recovered renal function had a significantly improved survival (P < 0.012).Conclusion: In dialysis-dependent acute renal failure secondary to myeloma kidney, patients who received uninterrupted chemotherapy and extended HCO-HD had sustained reductions in serum free light chain concentrations and recovered independent renal function.

Of patients with newly diagnosed multiple myeloma, approximately 10% have dialysis-dependent acute renal failure, with cast nephropathy, caused by monoclonal free light chains (FLC). Of these, 80 to 90% require long-term renal replacement therapy. Early treatment by plasma exchange reduces serum FLC concentrations, but randomized, controlled trials have shown no evidence of renal recovery. This outcome can be explained by the low efficiency of the procedure. A model of FLC production, distribution, and metabolism in patients with myeloma indicated that plasma exchange might remove only 25% of the total amount during a 3-wk period. For increasing FLC removal, extended hemodialysis with a protein-leaking dialyzer was used. In vitro studies indicated that the Gambro HCO 1100 dialyzer was the most efficient of seven tested. Model calculations suggested that it might remove 90% of FLC during 3 wk. This dialyzer then was evaluated in eight patients with myeloma and renal failure. Serum FLC reduced by 35 to 70% within 2 hr, but reduction rates slowed as extravascular re-equilibration occurred. FLC concentrations rebounded on successive days unless chemotherapy was effective. Five additional patients with acute renal failure that was caused by cast nephropathy then were treated aggressively, and three became dialysis independent. A total of 1.7 kg of FLC was removed from one patient during 6 wk. Extended hemodialysis with the Gambro HCO 1100 dialyzer allowed continuous, safe removal of FLC in large amounts. Proof of clinical value now will require larger studies.

Of newly diagnosed patients with multiple myeloma, 12–20% present with acute renal failure caused by monoclonal free light chains (FLCs). Plasma exchange can reduce the pre-renal load of FLCs but randomised controlled trials have shown no clinical benefit. This disappointing outcome can be explained by the low efficiency of the procedure. A model of FLC production, distribution and metabolism in myeloma patients indicated that plasma exchange might remove only 5–10% of the total body FLCs over a three-week period. To improve removal rates we have used prolonged hemodialysis with a protein leaking dialyser. In-vitro studies indicated that the Gambro HCO 1100 dialyser, with pores of 100kDa, was the most efficient of seven tested. This dialyser was used in 10 patients with myeloma and renal failure, as part of their hemodialysis treatment, to assess FLC removal efficiency. Three of the patients were studied at initial clinical presentation with biopsy proven FLC cast nephropathy. Routine chemotherapy was used, together with prolonged daily hemodialysis and multiple measurements of FLCs in serum, urine and dialysate fluid. Serum FLCs were reduced by 40 to 70% within one hour then reduction slowed as extravascular re-equilibration occurred. FLC concentrations rebounded on successive days until chemotherapy was effective. 1.5kg of FLCs was removed from one patient over 6 weeks and another became independent of dialysis. Prolonged hemodialysis allowed removal of 5–10 times more FLCs than plasma exchange without attendant clotting problems and removal of many serum proteins (Figure 1). Proof of clinical value will require further studies. Simulations of aFLC removal by plasma exchange versus hemodialysis on the Gambro HCO 1100. Simulations: 1) 100% tumor kill on day one with only reniculoendothetial removal; 2) 10% tumor kill per day reniculoendothetial removal alone; 3) 10% tumor kill per day with plasma exchange (3.5 liters exchange in 1.5 hrs × 6 over 10 days); 4) 10% tumor kill per day with hemodialysis for 4 hours, 3 times a week; 5) 10% tumor kill per day with hemodialysis for 4 hours per day; 6) 10% tumor kill per day with hemodialysis for 12 hours per day; 7) No tumor kill with 8 hours hemodialysis on alternate days 8) No tumor kill with no direct removal. Simulations of aFLC removal by plasma exchange versus hemodialysis on the Gambro HCO 1100. Simulations: 1) 100% tumor kill on day one with only reniculoendothetial removal; 2) 10% tumor kill per day reniculoendothetial removal alone; 3) 10% tumor kill per day with plasma exchange (3.5 liters exchange in 1.5 hrs × 6 over 10 days); 4) 10% tumor kill per day with hemodialysis for 4 hours, 3 times a week; 5) 10% tumor kill per day with hemodialysis for 4 hours per day; 6) 10% tumor kill per day with hemodialysis for 12 hours per day; 7) No tumor kill with 8 hours hemodialysis on alternate days 8) No tumor kill with no direct removal.

Pulmonary drug disposition after inhalation is complex involving mechanisms, such as regional drug deposition, dissolution, and mucociliary clearance. This study aimed to develop a systems pharmacology approach to mechanistically describe lung disposition in rats and thereby provide an integrated understanding of the system. When drug‐ and formulation‐specific properties for the poorly soluble drug fluticasone propionate were fed into the model, it proved predictive of the pharmacokinetics and receptor occupancy after intravenous administration and nose‐only inhalation. As the model clearly distinguishes among drug‐specific, formulation‐specific, and system‐specific properties, it was possible to identify key determinants of pulmonary selectivity of receptor occupancy of inhaled drugs: slow particle dissolution and slow drug‐receptor dissociation. Hence, it enables assessment of factors for lung targeting, including molecular properties, formulation, as well as the physiology of the animal species, thereby providing a general framework for rational drug design and facilitated translation of lung targeting from animal to man.

The introduction of a comprehensive diagnostic surveillance strategy to exclude invasive fungal infection in high-risk patients with haematological malignancy and those undergoing transplantation can result in improvements in clinical management. There are also potential additional benefits of improved patient survival, decreased morbidity and decreased hospital stay.

A dynamic model is structurally identifiable if it is possible to infer its unknown parameters by observing its output. Structural identifiability depends on the system dynamics, output, and input, as well as on the specific values of initial conditions and parameters. Here we present a symbolic method that characterizes the input that a model requires to be structurally identifiable. It determines which derivatives must be non-zero in order to have a sufficiently exciting input. Our approach considers structural identifiability as a generalization of nonlinear observability and incorporates extended Lie derivatives. The methodology assesses structural identifiability for time-varying inputs and, additionally, it can be used to determine the input profile that is required to make the parameters structurally locally identifiable. Furthermore, it is sometimes possible to replace an experiment with time-varying input with multiple experiments with constant inputs. We implement the resulting method as a MATLAB toolbox named STRIKE-GOLDD2. This tool can assist in the design of new experiments for the purpose of parameter estimation.

Variants identified in genome‐wide association studies have implicated immune pathways in the development of Alzheimer’s disease (AD). Here, we investigated the mechanistic basis for protection from AD associated with PLCγ2 R522, a rare coding variant of the PLCG2 gene. We studied the variant's role in macrophages and microglia of newly generated PLCG2‐R522‐expressing human induced pluripotent cell lines (hiPSC) and knockin mice, which exhibit normal endogenous PLCG2 expression. In all models, cells expressing the R522 mutation show a consistent non‐redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This manifests as enhanced release of cellular calcium ion stores in response to physiologically relevant stimuli like Fc‐receptor ligation or exposure to Aβ oligomers. Expression of the PLCγ2‐R522 variant resulted in increased stimulus‐dependent PIP2 depletion and reduced basal PIP2 levels in vivo. Furthermore, it was associated with impaired phagocytosis and enhanced endocytosis. PLCγ2 acts downstream of other AD‐related factors, such as TREM2 and CSF1R, and alterations in its activity directly impact cell function. The inherent druggability of enzymes such as PLCγ2 raises the prospect of PLCγ2 manipulation as a future therapeutic approach in AD.

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