A careful management of antimicrobials is essential in the critically ill with acute kidney injury, especially if renal replacement therapy is required. Acute kidney injury may lead per se to clinically significant modifications of drugs' pharmacokinetic parameters, and the need for renal replacement therapy represents a further variable that should be considered to avoid inappropriate antimicrobial therapy. The most important pharmacokinetic parameters, useful to determine the significance of extracorporeal removal of a given drug, are molecular weight, protein binding, and distribution volume. In many cases, the extracorporeal removal of antimicrobials can be relevant, with a consistent risk of underdosing-related treatment failure and/or potential onset of bacterial resistance. It should also be taken into account that renal replacement therapies are often not standardized in critically ill patients, and their impact on plasma drug concentrations may substantially vary in relation to membrane characteristics, treatment modality, and delivered dialysis dose. Thus, in this clinical scenario, the knowledge of the pharmacokinetic and pharmacodynamic properties of different antimicrobial classes is crucial to tailor maintenance dose and/or time interval according to clinical needs. Finally, especially for antimicrobials known for a tight therapeutic range, therapeutic drug monitoring is strongly suggested to guide dosing adjustment in complex clinical settings, such as septic patients with acute kidney injury undergoing renal replacement therapy. The most important factors able to affect drug PK during RRT are volume of distribution (V), protein binding, and molecular weight (MW); the knowledge of these parameters, along with total body clearance (CL TB ), allows determination of the significance of extracorporeal removal of a given drug.The volume of distribution corresponds to the ratio of the amount of drug in the body at a given time and plasma concentration at that time (11). In other terms, it represents the theoretical volume necessary to contain the total amount of an administered drug at the same concentration measured in plasma (12), and it should be regarded as a proportionality factor between a plasma concentration and the corresponding amount of drug in the whole body (11). As snapshot plasma drug concentrations may vary according to the state of drug disposition (i.e., just after intravenous [i.v.] administration, during the distribution phase, during the terminal phase of drug disposition, or at equilibrium), the proportionality ratio between the amount of drug in the body and the plasma concentration will change; thus, several V will be obtained in different situations (11). In clinical practice, V at equilibrium (V ss ), obtained when plasma concentrations are measured under steady-state conditions (i.e., during continuous i.v. drug infusion or multiple-drug administration once steady-state plasma concentrations have been achieved), represents the most appropriate V to compute a "loading dose" (11)...

Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β–induced podocyte injury, potentially identifying new therapeutic targets.

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AA: African American; ADPKD: autosomal dominant polycystic kidney disease; HLA, human leukocyte antigen; PRA: panel reactivity antibody. Continuous variables represented as mean AE SD. Categorical variables as numbers (percentage). c l i n i c a l i n v e s t i g a t i o n M Fribourg et al.: T-cell exhaustion in transplantation