High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study

Background The optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80–85 mmHg) and a low-target period (65–70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula. Results 26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (− 10 (95% CI − 17, − 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine–plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results. Conclusions In the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function.

Role of mTor signaling for tubular function and disease

The mechanistic target of rapamycin (mTOR) forms two distinct intracellular multiprotein complexes that control a multitude of intracellular processes linked to metabolism, proliferation, actin cytoskeleton and survival. Recent studies have identified the importance of these complexes for transport regulation of ions and nutrients along the entire nephron. First reports could link altered activity of these complexes to certain disease entities i.e. diabetic nephropathy, AKI or hyperkalemia.

MO622IMPAIRED PROTEIN-BOUND UREMIC TOXIN EXCRETION SUGGESTS TUBULAR DYSFUNCTION IN DIABETIC NEPHROPATHY

Background and Aims Kidney tubular damage is an important prognostic determinant in diabetic nephropathy (DN) (1). Proximal tubular secretion is a vital homeostatic function that is responsible for excretion of waste, such as protein bound uremic toxins (PBUTs) that are minimally eliminated via glomerular filtration. PBUTs are potentially harmful waste products of endogenous metabolism that are efficiently excreted by tubular secretion via organic anion transporters (OATs). Currently available diagnostic methods cannot accurately detect tubular dysfunction. We hypothesize that renal PBUT clearance may be a sensitive tubular function marker. Here, we measured PBUTs in long-term streptozotocin (STZ)-induced murine diabetic nephropathy (DN), which was characterized by severe tubular atrophy and interstitial fibrosis (2). Method Diabetes mellitus was induced in C57Bl/6 mice by a single intraperitoneal injection of 200 mg/kg STZ which resulted in substantial kidney damage after 6 months evaluated by histopathology and conventional markers (2). Indoxyl sulfate (IS), hippuric acid (HA), kynurenic acid (KA), kynurenine (Kyn), p-cresol glucuronide (pCG), p-cresol sulfate (pCS) and indole acetic acid (IAA) were measured in plasma and urine after 6 and 8 months by LC-MS/MS. Results Among the PBUTs with the highest OAT affinity, viz. IS, HA and KA, plasma concentrations were 2.2-, 2.3- and 1.5-fold higher (p=0.005, 0.0006, 0.03; Fig 1A-C) after 6 months and 1.9-, 2.1- and 2-fold higher (p=0.008, 0.0005, 0.001; Fig 2A-C) after 8 in DN, and urinary excretions (normalized for plasma concentrations) were 3.3-, 2.3- and 3.0-fold lower (p=0.012, 0.16, 0.03; Fig 1G-I) after 6 months and 2.5-, 1.6-, 2.3-fold lower (p=0.028, 0.046, 0.0005; Fig 2G-I) after 8 months in DN. Other PBUTS, viz. IAA, Kyn, pCS and pCG, were not significantly affected. Conclusion Our findings suggest that OAT function is compromised in murine long-term DN. Renal clearance of IS, HA and KA may be a marker of tubular function in DN. Future studies should focus on correlations with histology and validation in other species.

Renal effects of the serine protease inhibitor aprotinin in healthy conscious mice

Treatment with aprotinin, a broad-spectrum serine protease inhibitor with a molecular weight of 6512 Da, was associated with acute kidney injury, which was one of the reasons for withdrawal from the market in 2007. Inhibition of renal serine proteases regulating the epithelial sodium channel ENaC could be a possible mechanism. Herein, we studied the effect of aprotinin in wild-type 129S1/SvImJ mice on sodium handling, tubular function, and integrity under a control and low-salt diet. Mice were studied in metabolic cages, and aprotinin was delivered by subcutaneously implanted sustained release pellets (2 mg/day over 10 days). Mean urinary aprotinin concentration ranged between 642 ± 135 (day 2) and 127 ± 16 (day 8) µg/mL . Aprotinin caused impaired sodium preservation under a low-salt diet while stimulating excessive hyperaldosteronism and unexpectedly, proteolytic activation of ENaC. Aprotinin inhibited proximal tubular function leading to glucosuria and proteinuria. Plasma urea and cystatin C concentration increased significantly under aprotinin treatment. Kidney tissues from aprotinin-treated mice showed accumulation of intracellular aprotinin and expression of the kidney injury molecule 1 (KIM-1). In electron microscopy, electron-dense deposits were observed. There was no evidence for kidney injury in mice treated with a lower aprotinin dose (0.5 mg/day). In conclusion, high doses of aprotinin exert nephrotoxic effects by accumulation in the tubular system of healthy mice, leading to inhibition of proximal tubular function and counterregulatory stimulation of ENaC-mediated sodium transport.

995. Safety and Efficacy of F/TAF and F/TDF for PrEP in DISCOVER Participants Taking F/TDF for PrEP at Baseline

Background DISCOVER is an ongoing trial comparing emtricitabine plus tenofovir alafenamide (F/TAF) or tenofovir disoproxil fumarate (F/TDF) for HIV pre-exposure prophylaxis (PrEP). DISCOVER included some participants already taking F/TDF for PrEP at baseline (BL) creating a unique opportunity to study outcomes after switching from F/TDF to F/TAF. Methods Men who have sex with men and transgender women at risk of HIV were randomized to receive blinded daily F/TAF or F/TDF and followed for at least 96 weeks; participants taking BL F/TDF for PrEP could enroll without a washout period. Laboratory assessments included estimated glomerular filtration rate (eGFR), markers of renal proximal tubular function (RBP and β2M to creatinine ratios), and fasting cholesterol levels; these were analyzed by 2-sided Wilcoxon rank sum test. Bone mineral density (BMD) was assessed in a subset of participants and analyzed by ANOVA. Results 905 of 5387 (16.8%) participants were on BL F/TDF for PrEP for a median duration of 399 days; baseline characteristics are found in Table 1. There was one HIV infection among BL PrEP users, in a participant randomized to F/TDF who had intermittent low adherence. Participants on BL PrEP randomized to F/TAF had improvements in eGFR and markers of proximal tubular function compared to F/TDF. Median change in BMD was not statistically different for BL PrEP users assigned to F/TAF vs F/TDF, however de novo F/TAF participants had improved BMD profiles compared to F/TDF. BL PrEP users in the F/TAF arm had increases in LDL cholesterol (median +6mg/dL) compared to F/TDF, while changes in HDL and total:HDL ratio were similar. Lipid-modifying agent (LMA) initiation in BL PrEP users was more frequent in the F/TAF arm, while LMA initiation in de novo PrEP participants was similar between arms (Table 2). Table 1. Characteristics of DISCOVER participants Table 2. Efficacy and safety results Conclusion HIV incidence was low in participants taking BL PrEP. Participants who switched from F/TDF to F/TAF had improvements in renal biomarkers. There was no statistical difference in BMD among BL PrEP users, although numbers were small. The observed lipid changes in BL PrEP users are consistent with the LDL and HDL suppressive effect of TDF, and the small but higher rate of LMA initiation with F/TAF is likely related to withdrawal of this effect. Disclosures Thomas Campbell, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Amanda Clarke, MD, Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Other Financial or Material Support, Conference attendance sponsorship)Viiv Healthcare (Consultant, Other Financial or Material Support, Conference travel sponsorship) Benoit Trottier, MD, AbbVie (Grant/Research Support, Other Financial or Material Support, Personal fees)Bristol-Myers Squibb (Grant/Research Support, Other Financial or Material Support, Personal fees)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Other Financial or Material Support, Personal fees)Janssen (Grant/Research Support, Other Financial or Material Support, Personal fees)Merck (Grant/Research Support, Other Financial or Material Support, Personal fees)Viiv Healthcare (Grant/Research Support, Other Financial or Material Support, Personal fees) Christoph C. Carter, MD, Gilead Sciences Inc. (Employee, Shareholder) Yongwu Shao, PhD, Gilead Sciences Inc. (Employee, Shareholder) Ramin Ebrahimi, MSc, Gilead Sciences Inc. (Employee, Shareholder) Moupali Das, MD, Gilead Sciences Inc. (Employee, Shareholder) Diana M. Brainard, MD, Gilead Sciences (Employee) Jay Gladstein, MD, Gilead Sciences Inc. (Scientific Research Study Investigator)