Increased burden of rare variants in genes of the endosomal Toll-like receptor pathway in patients with systemic lupus erythematosus.

OBJECTIVE: To compare the frequency of rare variants in genes of the pathophysiologically relevant endosomal Toll-like receptor (eTLR) pathway and any quantifiable differences in variant rarity, predicted deleteriousness, or molecular proximity in patients with systemic lupus erythematosus (SLE) and healthy controls. PATIENTS AND METHODS: 65 genes associated with the eTLR pathway were identified by literature search and pathway analysis. Using next generation sequencing techniques, these were compared in two randomised cohorts of patients with SLE (n = 114 and n = 113) with 197 healthy controls. Genetically determined ethnicity was used to normalise minor allele frequencies (MAF) for the identified genetic variants and these were then compared by their frequency: rare (MAF < 0.005), uncommon (MAF 0.005-0.02), and common (MAF >0.02). This was compared to the results for 65 randomly selected genes. RESULTS: Patients with SLE are more likely to carry a rare nonsynonymous variant affecting proteins within the eTLR pathway than healthy controls. Furthermore, individuals with SLE are more likely to have multiple rare variants in this pathway. There were no differences in rarity, Combined Annotation Dependent Depletion (CADD) score, or molecular proximity for rare eTLR pathway variants. CONCLUSIONS: Rare non-synonymous variants are enriched in patients with SLE in the eTLR pathway. This supports the hypothesis that SLE arises from several rare variants of relatively large effect rather than many common variants of small effect.

Clinical Pharmacokinetics in Kidney Disease: Application to Rational Design of Dosing Regimens.

A change in pharmacokinetics can alter drug exposure and predispose the patient to either over- or underdosing, potentially resulting in adverse drug reactions or therapeutic failure. Kidney disease is characterized by multiple physiologic effects, which induce clinically significant changes in pharmacokinetics. These vary between individuals and may be quantitated in certain instances. An understanding of pharmacokinetic concepts is, therefore, important for a rational approach to the design of drug dosing regimens for the delivery of personalized medical care. Whether kidney disease is acute or chronic, drug clearance decreases and the volume of distribution may remain unchanged or increase. AKI is defined by dynamic changes in kidney function, which complicates attempts to accurately quantify drug clearance. In contrast, changes in drug clearance progress more slowly with CKD. In general, kidney replacement therapies increase drug clearance, but the extent to which this occurs depends on the modality used and its duration, the drug's properties, and the timing of drug administration. However, the changes in drug handling associated with kidney disease are not isolated to reduced kidney clearance and an appreciation of the scale of potential derangements is important. In most instances, the first dose administered in patients with kidney disease is the same as in patients with normal kidney function. However, in some cases, a higher (loading) initial dose is given to rapidly achieve therapeutic concentrations, followed by a lower maintenance dose, as is well described when prescribing anti-infectives to patients with sepsis and AKI. This review provides an overview of how pharmacokinetic principles can be applied to patients with kidney disease to personalize dosage regimens. Patients with kidney disease are a vulnerable population and the increasing prevalence of kidney disease means that these considerations are important for all prescribers.

Clinical Pharmacokinetics in Kidney Disease: Fundamental Principles.

Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Prescribing to patients with kidney disease requires knowledge about the drug, the extent of the patient's altered physiology, and pharmacokinetic principles that influence the design of dosing regimens. There are multiple physiologic effects of impaired kidney function, and the extent to which they occur in an individual at any given time can be difficult to define. Although some guidelines are available for dosing in kidney disease, they may be on the basis of limited data or not widely applicable, and therefore, an understanding of pharmacokinetic principles and how to apply them is important to the practicing clinician. Whether kidney disease is acute or chronic, drug clearance decreases, and the volume of distribution may remain the same or increase. Although in CKD, these changes progress relatively slowly, they are dynamic in AKI, and recovery is possible depending on the etiology and treatments. This, and the use of kidney replacement therapies further complicate attempts to quantify drug clearance at the time of prescribing and dosing in AKI. The required change in the dosing regimen can be estimated or even quantitated in certain instances through the application of pharmacokinetic principles to guide rational drug dosing. This offers an opportunity to provide personalized medical care and minimizes adverse drug events from either under- or overdosing. We discuss the principles of pharmacokinetics that are fundamental for the design of an appropriate dosing regimen in this review.

Simplifying the hemodialysis prescription in patients with ethylene glycol poisoning.

The management of ethylene glycol poisoning is multimodal and usually includes hemodialysis. The usual approach for guiding treatment duration is iterative, based on serial measurements of ethylene glycol concentration and routine biochemistry. In this issue, Iliuta et al. present a simplified approach to determining the duration of hemodialysis based on a single ethylene glycol concentration. Although this appears reasonable in many cases, there are circumstances in which further consideration is warranted and it only applies to high-efficiency intermittent hemodialysis.

MMP2 and MMP9 associate with crescentic glomerulonephritis.

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiple organ involvement. Lupus nephritis (LN) is a common manifestation with a wide variety of histological appearances. Matrix metalloproteinases (MMP) 2 and 9 are gelatinases capable of degrading glomerular basement membrane type IV collagen, which have been associated with LN. We examine the expression of MMP2 and MMP9 in different classes of LN. Methods: MMP2 and MMP9 expression was detected by immunohistochemistry in sections from renal biopsy specimens with class III, class IV and class V LN (total n = 31), crescentic immunoglobulin A nephropathy (n = 6), pauci-immune glomerulonephritis (n = 7), minimal change disease (n = 2), mesangiocapillary glomerulonephritis (n = 7), diabetic nephropathy (n = 12) and histologically normal controls (n = 8). Results: MMP2 and MMP9 were not expressed in all classes of LN, but were observed in LN with cellular and fibrocellular crescents. MMP2/MMP9 was expressed in cellular and fibrocellular crescents regardless of glomerulonephritis but not observed in inactive fibrous crescents or with mesangial proliferation. This suggests that MMP2 and MMP9 are involved in the development of extracapillary proliferative lesions. Conclusions: MMP2/MMP9 is expressed with active extracapillary proliferation. Further study is necessary to define whether the expression of MMP2/MMP9 reflects a role in glomerular repair after injury, a role in organ-level immune responses or a role as a marker of epithelialization.

Simian immunodeficiency virus confounds T follicular helper T cells and the germinal centre.

Yamamoto et al. have studied T follicular helper (TFH) and germinal centre (GC) responses after infection of rhesus macaques (RM) infected with simian immunodeficiency virus (SIV). In this study the authors examined the behaviour of TFH, reproducing infection-associated TFH accumulation and their association with the quality of antibody responses against cross-clade viral epitopes. The authors correlate TFHIL4 and CD154 expression with superior antibody responses. Accumulation of TFH was accompanied by aberrant expression of non-TFH transcriptional regulators such as BLIMP1 in TFH, suggesting viral induced abnormalities may affect TFH function.