Renal Transplantation in Patients With Pre-Transplant Donor-Specific Antibodies and Negative Flow Cytometry Crossmatches

The clinical significance of pre-transplant donor-specific antibodies (DSA), despite negative cytotoxicity and flow cytometry crossmatches (FCXMs), is unknown. We performed a retrospective cohort study of 60 living donor renal transplant recipients, all with pre-transplant cytotoxicity and T-cell and B-cell FCXMs that were negative. Twenty recipients had pre-transplant DSA detected by enzyme-linked immunosorbent assays (ELISA) and/or microbead methods. Forty contemporaneous DSA-negative controls were selected. In the DSA-positive group, after a median follow-up of 8.2 months (25-75% range, 5.4-22.8 months), patient survival was 100% and allograft survival was 95.0%. Acute humoral rejection (AHR) developed in four patients (20.0%). Three of the AHR episodes occurred within the first month post-transplant. Median serum creatinine at last follow-up was 1.3 mg/dL (25-75% range, 1.0-1.6 mg/dL), versus 1.1 mg/dL (25-75% range, 0.9-1.4 mg/dL) in the DSA-negative controls (p = 0.29). Only one of the 40 controls developed AHR (2.5%). Pre-transplant DSA was associated with a significantly increased incidence of AHR (p = 0.02 by log-rank test). In conclusion, despite negative pre-transplant cytotoxicity and FCXMs, renal transplant recipients with pre-transplant DSA detected by solid-phase methods may have an increased incidence of AHR and require close monitoring post-transplant.     

Allograft loss in renal transplant recipients with Fabry's disease and activated protein C resistance

INTRODUCTION: Fabry's disease is associated with an increased incidence of thrombotic events and rejection. Spontaneous thrombosis of a functioning cadaveric renal allograft in a recipient with Fabry's disease prompted prospective evaluation of all transplant candidates with Fabry's disease for hypercoagulability. MATERIALS AND METHODS: Transplant candidates with Fabry's disease were tested for hypercoagulability, analyzed for HLA-type and ABO group, and comorbid conditions suggestive of hypercoagulability. RESULTS: A unique association of Fabry's disease with activated protein C Resistance was documented in a cohort of Caucasian male renal transplant recipients with Fabry's disease. Four of five patients were blood group A and had no significant comorbid conditions suggestive of hypercoagulability. The resistance to activation of protein C (APCR)(+) patients shared HLA loci-B8 and Dr3, although the APCR(-) patients shared HLA loci-B27 and -B38. CONCLUSIONS: Due to the observed increase in the incidence of APCR in our Fabry's cohort, we suggest screening all patients with Fabry's disease for APCR. Because factor V and factor Va receptors are found on vascular endothelium and peripheral blood monocytes, APCR in the presence of Fabry's disease may be a nonimmunological stimulus for rejection. Analysis of HLA typing in patients with Fabry's disease may further elucidate HLA-based association of Fabry's disease and resistance to activated protein C with the risk of thrombosis and rejection.     

Conversion From Twice‐Daily Tacrolimus to Once‐Daily Extended Release Tacrolimus (LCPT): The Phase III Randomized MELT Trial

Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice‐daily tacrolimus to a novel extended‐release once‐daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy‐proven acute rejection [BPAR], or loss to follow‐up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4–15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once‐daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels.     

LCPT once‐daily extended‐release tacrolimus tablets versus twice‐daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups

African‐American and elderly kidney transplant recipients (KTR) have increased risk for poor clinical outcomes post‐transplant. Management of immunosuppression may be challenging in these patients and contribute to worse outcomes. A novel once‐daily formulation of tacrolimus (LCPT) has demonstrated noninferiority, similar safety, improved bioavailability, a consistent concentration time profile, and less peak and peak‐trough fluctuations vs. tacrolimus twice‐daily (Tac BID). This pooled analysis of two phase 3 randomized, controlled trials, including 861 (LCPT N = 428; Tac BID N = 433; 38% of patients were stable KTR, and 62% were de novo KTR) patients, examined the efficacy of LCPT in KTR subgroups (blacks, females, and age ≥65). Overall, treatment failure [death, graft failure, centrally read biopsy‐proven acute rejection (BPAR), or lost to follow‐up] at 12 months was as follows: LCPT: 11.9%, BID Tac: 13.4% [?1.48% (?5.95%, 2.99%)]. BPAR rates were as follows: LCPT: 8.2%, Tac BID: 9.5% [?1.29% (?5.14%, 2.55%)]. Numerically, fewer treatment failure events with LCPT were found in the majority of subgroups, with significantly less treatment failure associated with LCPT among black KTR [?13.82% (?27.22%, ?0.31%)] and KTR ≥65 [?13.46% (?25.27%, ?0.78%)]. This pooled analysis suggests numerically lower efficacy failure rates associated with LCPT among high‐risk subgroups, in particular black KTR and KTR ≥65 years old.     

Conversion from calcineurin inhibitor–based immunosuppression to mammalian target of rapamycin inhibitors or belatacept in renal transplant recipients

The calcineurin inhibitors (CNIs) remain the standard of care for maintenance immunosuppression following renal transplantation. CNIs have demonstrated their effectiveness in reducing acute cellular rejection; however, some evidence suggests that these compounds negatively affect native renal function and are associated with allograft injury in renal transplant recipients. CNIs have also been linked with hypertension, new‐onset diabetes after transplantation, tremor, and thrombotic microangiopathy, which have significant consequences for long‐term allograft function and patient health overall. Thus, converting patients to a non‐CNI‐based regimen may improve renal function and also provide extrarenal benefits. A number of studies have been conducted that explore CNI conversion strategies in renal transplant recipients in an effort to improve long‐term allograft function and survival. These include converting to alternative, non‐nephrotoxic, maintenance immunosuppressants, such as the mammalian target of rapamycin inhibitors (sirolimus and everolimus) and the costimulation blocker belatacept. In this review of literature, evidence for the potential renal and extrarenal benefits of conversion to these non‐CNI‐based regimens is evaluated. Clinical challenges, including the adverse event profiles of non‐CNI‐based regimens and the selection of candidates for conversion, are also examined.     

Human Organic Cation Transporters 1 (SLC22A1), 2 (SLC22A2), and 3 (SLC22A3) as Disposition Pathways for Fluoroquinolone Antimicrobials

Fluoroquinolones (FQs) are important antimicrobials that exhibit activity against a wide range of bacterial pathogens and excellent tissue permeation. They exist as charged molecules in biological fluids, and thus, their disposition depends heavily on active transport and facilitative diffusion. A recent review of the clinical literature indicated that tubular secretion and reabsorption are major determinants of their half-life in plasma, efficacy, and drug-drug interactions. In particular, reported in vivo interactions between FQs and cationic drugs affecting renal clearance implicated organic cation transporters (OCTs). In this study, 13 FQs, ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, and sparfloxacin, were screened for their ability to inhibit transport activity of human OCT1 (hOCT1) (SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). All, with the exception of enoxacin, significantly inhibited hOCT1-mediated uptake under initial test conditions. None of the FQs inhibited hOCT2, and only moxifloxacin inhibited hOCT3 (∼30%), even at a 1,000-fold excess. Gatifloxacin, moxifloxacin, prulifloxacin, and sparfloxacin were determined to be competitive inhibitors of hOCT1. Inhibition constants (K_i) were estimated to be 250 ± 18 μM, 161 ± 19 μM, 136 ± 33 μM, and 94 ± 8 μM, respectively. Moxifloxacin competitively inhibited hOCT3-mediated uptake, with a K_i value of 1,598 ± 146 μM. Despite expression in enterocytes (luminal), hepatocytes (sinusoidal), and proximal tubule cells (basolateral), hOCT3 does not appear to contribute significantly to FQ disposition. However, hOCT1 in the sinusoidal membrane of hepatocytes, and potentially the basolateral membrane of proximal tubule cells, is likely to play a role in the disposition of these antimicrobial agents.     

Comparative potency of formulations of mometasone furoate in terms of inhibition of 'PIRHR' in the forearm skin of normal human subjects measured with laser doppler velocimetry

BACKGROUND AND AIMS: Topical glucocorticoid formulations are widely used for effective treatment and control of a variety of dermatoses. Mometasone furoate is a newer corticoid that has high potency but low systemic toxicity. Pharmaceutical factors are known to significantly influence potency and systemic absorption of topically applied glucocorticoids. We studied the potency of "Elocon", a topical formulation of mometasone furoate, compared with two other branded formulations of the same corticoid. METHODS: Corticoid potency was measured by employing a pharmacodynamic parameter of an inhibitory effect of the corticoid on post-ischemic-reactive-hyperemic-response (PIRHR) in human forearm skin under occlusive dressing. The PIRHR was expressed in terms of % increase in the skin blood flow (SBF) as measured with laser doppler velocimetry (LDV). RESULTS : All three active branded formulations of mometasone furoate produced significant inhibition of PIRHR. The AUC(0-2 min) of PIRHR was ( Mean +/- SEM ), Control = 213.52 +/- 11.80, Placebo = 209.77 +/- 19.31, Formulation A = 119.83 +/- 13.71, Formulation C = 53.67 +/- 4.85 and Formulation D = 111.46 +/- 22.87. Formulation "C" exhibited significantly higher topical anti-inflammatory potency than formulations "A" or "D". CONCLUSIONS: Thus, branded formulations of the same glucocorticoid, mometasone furoate significantly differed in their topical anti-inflammatory potency. "Elocon" was significantly more potent than the two other branded formulations studied.     

Stress dose steroids in renal transplant patients undergoing lymphocele surgery

The requirement for perioperative stress dose steroids (SDS) in patients on long-term steroid therapy is controversial, but SDS are given during perioperative care. Studies focusing on surrogate outcomes like cortisol levels indicate a possible requirement for SDS, but clinical results are sparse. We retrospectively compared outcomes of renal or pancreas/kidney transplant patients undergoing surgical lymphocele drainage who did (n=20) or did not (n=38) receive SDS. Patients had similar demographic characteristics (P=NS). No patient developed hypotension (SBP < 80 mmHg), mental status change, unexplained arthralgias, or ileus. Impaired wound healing occurred in one patient in each group (P=NS), and lymphocele recurrence occurred in 25% of the SDS group and 10.5% of the other group (P=.25). SBP decreased from baseline in both groups (P <.001) but did not differ between groups, and maximum blood glucose was higher in the SDS group (P=.04). No difference was observed in other measured parameters. These data indicate that SDS increased the risk of hyperglycemia and provided no apparent benefit. A prospective study is warranted to confirm these findings.