Optimizing the dosing of vancomycin in patients receiving intermittent haemodialysis with low-flux filters, and the potential impact of dosing software.

AIM: Iterative approaches to vancomycin dosing (e.g., dosing when trough concentrations <15-20 mg/L) can be inadequate. Computer-guided dosing may be superior but has not been evaluated in patients with kidney failure receiving replacement therapy. We evaluated vancomycin concentrations using a hospital protocol and a pharmacokinetic software. We measured vancomycin clearance by the FX8 low-flux filter because data are absent. METHODS: We retrospectively reviewed records of adults with kidney failure requiring replacement therapy receiving vancomycin and dialysed with the FX8 low-flux filter, and calculated the proportion of pre-dialysis concentrations that were within, above or below a specified range. One and two-compartment models in the pharmacokinetic software were assessed by computing mean prediction error (MPE) and root mean square error (RMSE) of observed versus predicted concentrations. Vancomycin extracorporeal clearance was prospectively determined using the extraction method. RESULTS: In 24 patients (34 courses; 139 paired observed and predicted concentrations), 62/139 (45%) pre-dialysis concentrations were 15-25 mg/L, 29/139 (21%) were above, and 48/139 (35%) were below. MPE for the one-compartment model was -0.2 mg/L, RMSE 5.3 mg/L. MPE for the two-compartment model was 2.0 mg/L, RMSE 5.6 mg/L. Excluding the first paired concentrations, the subsequent MPE (n = 105) using one-compartment model was -0.5 mg/L, RMSE 5.6 mg/L. The MPE for the two-compartment model was 2.1 mg/L, RMSE 5.8 mg/L. The median extracorporeal clearance was 70.7 mL/min (range: 10.3-130.3; n = 22). CONCLUSIONS: Vancomycin dosing was suboptimal and the pharmacokinetic software was not sufficiently predictive. These may improve with a loading dose. The substantial removal of vancomycin by low-flux filters is not accounted for by the models tested.

Value of Renal Histology in Predicting Cardiorenal Outcomes in Heart Transplant-listed Patients.

Cardiorenal syndrome (CRS) contributes significantly to morbidity and mortality in patients requiring mechanical circulatory support and transplantation. There are no validated markers to predict major adverse kidney events (MAKEs), for which simultaneous heart-kidney transplant (SHKT) could offer improved survival. We evaluate renal histology in predicting MAKEs in transplant-listed patients. Methods: We identified 18 patients with renal histology consistent with CRS from 655 consecutive heart transplant-listed patients between 2010 and 2019. Biopsies were analyzed for glomerular, tubular, interstitial, and arteriolar changes tallied to give a biopsy chronicity score. The primary outcome, MAKE, was a composite of death, need for renal replacement therapy (RRT), or estimated glomerular filtration rate decline >50%. These were evaluated at 2 time points: before and following the transplant. Secondary outcomes included the individual components of the composite outcomes and the need for short-term RRT following the transplant. Results: The mean age was 52.3 y, 22% were female. Five patients did not survive to transplant. One patient underwent successful SHKT. MAKE occurred in 8 of 18 before the transplant and in 8 of 13 following the transplant. Neither outcome was predicted by baseline biochemistry. The biopsy chronicity score was significantly higher in patients with MAKE before transplant (4.3 versus 1.7, P = 0.024) and numerically higher in patients requiring short-term RRT following transplant (3.2 versus 0.7, P = 0.075). Contrary to limited previous literature, interstitial fibrosis did not predict any outcome, whereas tubular atrophy and arteriosclerosis were associated with MAKE before transplant. Conclusions: A higher biopsy chronicity score was associated with adverse kidney endpoints, raising its potential utility over standard biochemistry in considering SHKT referral.

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.

Life-Saving Combined Heart-Kidney Transplantation in a Previous Sequential Heart and Kidney Transplant Recipient.

PURPOSE: Solid organ re-transplantation in the context of allograft failure is a challenging clinical and ethical problem. Ideally, solid organ re-transplantation after initial allograft failure should be performed in all recipients, but this is often not clinically or logistically feasible. METHODS: This report details what we believe is the first combined heart-kidney transplant in a recipient of a previous sequential heart and kidney transplant. RESULTS: Eight years after a combined heart and kidney transplant after initially receiving a sequential heart and kidney transplant, a 31-year-old man is doing extremely well, with no rejection episodes or significant complications after transplantation. SUMMARY: This case confirms that combined heart and kidney transplantation is a viable option for tackling the complex issue of graft failure in recipients of previous cardiac and renal grafts. LEARNING POINTS: Good short- and long-term outcomes following combined heart-kidney transplantation can be achieved in patients with multi-system end-organ dysfunction.Advances in immunosuppressant therapy have enabled multiple transplantation procedures from different donors in a single recipient.We describe the first recipient in the world of combined heart-kidney transplantation on a background of previous sequential heart-kidney transplantation.

A consensus statement on the renal monitoring of Australian patients receiving tenofovir based antiviral therapy for HIV/HBV infection.

A number of antiviral agents used against Human Immunodeficiency Virus (HIV) infection and hepatitis B virus (HBV) mono or co-infection have been associated with real nephrotoxicity (including tenofovir disoproxil fumarate (TDF), atazanavir, indinavir and lopinavir) or apparent changes in renal function (e.g. cobicistat, ritonavir, rilpivirine and dolutegravir). Patients with HIV are at higher risk of acute and chronic renal dysfunction, so baseline assessment and ongoing monitoring of renal function is an important part of routine management of patients with HIV. Given the paucity of evidence in this area, we sought to establish a consensus view on how routine monitoring could be performed in Australian patients on ART regimens, especially those involving TDF. A group of nephrologists and prescribers (an HIV physician and a hepatologist) were assembled by Gilead to discuss practical and reasonable renal management strategies for patients particularly those on TDF-based combination regimens (in the case of those with HIV-infection) or on TDF-monotherapy (in the case of HBV-mono infection). The group considered which investigations should be performed as part of routine practice, their frequency, and when specialist renal referral is warranted. The algorithm presented suggests testing for serum creatinine along with plasma phosphate and an assessment of urinary protein (rather than albumin) and glucose. Here we advocate baseline tests of renal function at initiation of therapy. If creatinine excretion inhibitors (e.g. cobicistat or rilpivirine) are used as part of the ART regimen, we suggest creatinine is rechecked at 4 weeks and this value used as the new baseline. Repeat testing is suggested at 3-monthly intervals for a year and then at least yearly thereafter if no abnormalities are detected. In patients with abnormal baseline results, renal function assessment should be performed at least 6 monthly. In HBV mono-infected patients advocate that a similar testing protocol may be logical.

Surviving calciphylaxis.

Calciphylaxis is a rare disorder with high mortality, which commonly occurs, but not limited to, patients with end-stage renal disease. We present a successful case in which a patient survived this serious disorder of vasculopathy, highlighting the physical and emotional morbidities associated with this condition and alerting physicians of the key elements in its management. Further understanding of calciphylaxis may advance our knowledge in endotheliopathy and vascular ossification.

Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury.

Ischemia/reperfusion (IR) injury is a leading cause of acute renal failure and an important contributor to allograft damage. Tissue factor (TF) is up-regulated during IR, and TF inhibition reduces renal injury. However, the underlying mechanisms by which TF contributes to injury have not been elucidated. We postulated that TF contributes to IR injury by production of coagulation proteases and subsequent signaling by protease activated receptor (PARs). We compared renal injury after 25 minutes of bilateral renal ischemia and varying periods of reperfusion in C57BL/6 mice, those expressing low levels of TF (low-TF), hirudin-treated C57BL/6, and mice lacking either PAR-1 or PAR-2. C57BL/6 mice developed severe renal failure and died within 48 hours of reperfusion. In contrast, low-TF, hirudin-treated C57BL/6, and PAR-1-/- mice were protected from renal failure and had reduced mortality, tubular injury, neutrophil accumulation, and lower levels of the chemokines KC and MIP-2. Importantly, PAR-1-/- mice had lower chemokine levels despite up-regulation of TF and fibrin deposition. In addition, treating PAR-1-/- mice with hirudin conferred no additional benefit. Somewhat surprisingly, PAR-2 deficiency did not protect from renal failure. These experiments indicate that increased TF activity after renal IR leads to increased CXC chemokine expression and subsequent neutrophil-mediated injury predominantly by thrombin-dependent PAR-1 signaling.

Fibromuscular hyperplasia as a cause of transplant renal artery stenosis.

There are several causes of transplant renal artery stenosis, resulting in hypertension and renal dysfunction. Rarely, fibromuscular hyperplasia may cause such a presentation, and this case report discusses the historical, diagnostic and management issues pertaining to this rare situation.