The impact of peritoneal dialysis on oxypurinol and urate elimination in people with gout.

Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CLk) and peritoneal (CLpd) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy.

Does the intact nephron hypothesis provide a reasonable model for metformin dosing in chronic kidney disease?

This research explored the intact nephron hypothesis (INH) as a model for metformin dosing in patients with chronic kidney disease (CKD). The INH assumes that glomerular filtration rate (GFR) will account for all kidney drug handling even for drugs eliminated by tubular secretion like metformin. We conducted two studies: (1) a regression analysis to explore the relationship between metformin clearance and eGFR metrics, and (2) a joint population pharmacokinetic analysis to test the relationship between metformin renal clearance and gentamicin clearance. The relationship between metformin renal clearance and eGFR metrics and gentamicin clearance was found to be linear, suggesting that a proportional dose reduction based on GFR in patients with CKD is reasonable.

The pharmacokinetics of meropenem and piperacillin-tazobactam during sustained low efficiency haemodiafiltration (SLED-HDF).

OBJECTIVE: We analysed the pharmacokinetics of meropenem and piperacillin-tazobactam in patients undergoing a standardised session of sustained low efficiency haemodiafiltration (SLED-HDF) to inform the dosing of these drugs in an acute setting. PARTICIPANTS: Six stable patients with end-stage kidney disease. METHODS: An open-label pilot pharmacokinetic study of meropenem and piperacillin-tazobactam. SLED-HDF was undertaken for 4 h. Plasma drug concentrations were measured pre- and post-filter and in the effluent at multiple time points. The pharmacokinetic data was analysed using non-compartmental methods. The fraction of time that individual plasma concentration profiles were predicted to remain above the MIC break-points for commonly isolated gram-negative pathogens during a prolonged SLED-HDF session was assessed using two targets; fT > MIC (fraction of time above the MIC) and the more aggressive fT > 4 × MIC (fraction of time above 4 × MIC). RESULTS: Meropenem total and SLED-HDF clearance ranged from 141 to 180 mL/min and 126-205 mL/min, respectively. Piperacillin total and SLED-HDF clearance values ranged from 131 to 252 mL/min and 135-162 mL/min, respectively. Our results suggest that prolonged SLED-HDF (12 h) will only maintain a sufficient meropenem and piperacillin-tazobactam plasma concentration to achieve a target of fT > MIC for gram-negative pathogens (MIC 2 mg/L-meropenem, 8 mg/L-piperacillin-tazobactam) for less than 40% of the time. Plasma concentrations would be inadequate to achieve the more aggressive target of 100 % fT > 4xMIC target recommended for critically unwell patients. CONCLUSIONS: The pharmacokinetic data obtained from this pilot study demonstrate significant quantities of meropenem and piperacillin are removed during a SLED-HDF session. This may lead to subtherapeutic concentrations of piperacillin and meropenem over the duration of HDF session. TRIAL REGISTRATION: Australasian Clinical Trials Registry Network (ACTRN12616000078459).

Metformin doses to ensure efficacy and safety in patients with reduced kidney function.

We aimed to develop a metformin dosing strategy to optimise efficacy and safety in patients with reduced kidney function. Metformin data from two studies stratified by kidney function were analysed. The relationship between metformin clearance and kidney function estimates was explored using a regression analysis. The maintenance dose range was predicted at different bands of kidney function to achieve an efficacy target of 1 mg/L for steady-state plasma concentrations. The dosing strategy was evaluated using simulations from a published metformin pharmacokinetic model to determine the probability of concentrations exceeding those associated with lactic acidosis risk, i.e. a steady-state average concentration of 3 mg/L and a maximum (peak) concentration of 5 mg/L. A strong relationship between metformin clearance and estimated kidney function using the Cockcroft and Gault (r2 = 0.699), MDRD (r2 = 0.717) and CKD-Epi (r2 = 0.735) equations was found. The probability of exceeding the safety targets for plasma metformin concentration was <5% for most doses and kidney function levels. The lower dose of 500 mg daily was required to maintain concentrations below the safety limits for patients with an eGFR of 15-29 mL/min. Our analysis suggests that a maximum daily dose of 2250, 1700, 1250, 1000, and 500 in patients with normal kidney function, CKD stage 2, 3a, 3b and 4, respectively, will provide a reasonable probability of achieving efficacy and safety. Our results support the cautious of use metformin at appropriate doses in patients with impaired kidney function.

Refinement of a protocol to induce reliable muscle cramps in the abductor hallucis.

OBJECTIVE: To test the reliability of immediate replication of muscle cramp characteristics induced with different electrical stimulation protocols. APPROACH: Five (age 33.8 ± 5.7 y, 60% male) and ten (age 47.4 ± 11.7 y, 60% male) participants completed independent discovery and validation cohorts, respectively. This was to identify a protocol that resulted in consistent muscle cramp characteristics (discovery), and to examine the test-retest reliability of the identified protocol (validation). Electrical stimulation (150 burst) at abductor hallucis motor-point was used to induce muscle cramps with 4 Hz increments in stimulation frequency (8-32 Hz) or until muscle cramp was first evident, followed by refinement (2 and 1 Hz) until at least two muscle cramps occurred. This defined the cramp threshold frequency, and concurrent electromyogram activity and duration of the cramp were quantified. The discovery cohort involved three separate randomised sessions where intervals between stimulation was 60, 90, and 120 s respectively. In each session, four randomised electrical stimulation protocols were completed. Stimulation current was fixed at 10, 20, and 30% higher than m-wave stimulation current (protocols 1-3 respectively), or randomised within 4 Hz steps (protocol 4) to minimise any order effect. MAIN RESULTS: We were able to immediately replicate tolerable muscle cramp at least twice. Discovery cohort demonstrated (i) incremental changes in stimulation frequency (protocols 1-3 vs. protocol 4, i.e. order effect), and (ii) changes in stimulation current with differing protocols did not significantly alter the prevailing muscle cramp characteristics, and (iii) defining the muscle cramp characteristics elicits good-to-excellent inter-observer reliability. The validation cohort's test-retest reliability and the minimum detectable change were improved for all muscle cramp characteristics when immediately replicated more than twice at the lowest stimulation frequency. SIGNIFICANCE: This study provides evidence for a reliable method for inducing repeatable muscle cramps in abductor hallucis.

Endovascular Renal Denervation in End-Stage Kidney Disease Patients: Cardiovascular Protection-A Proof-of-Concept Study.

INTRODUCTION: Sympathetic neural activation is markedly increased in end-stage kidney disease (ESKD). Catheter-based renal denervation (RDN) reduces sympathetic overactivity and blood pressure in resistant hypertension. We investigated the effect of RDN on sympathetic neural activation and left ventricular mass in patients with ESKD. METHODS: Nine ESKD (6 hemodialysis and 3 peritoneal dialysis) patients with dialysis vintage of ≥11 months were treated with RDN (EnligHTN system). Data were obtained on a nondialysis day; at baseline, 1, 3, and 12 months post-RDN. RESULTS: At baseline sympathetic neural activation measured by muscle sympathetic nervous activity (MSNA) and plasma norepinephrine concentrations were markedly elevated. Left ventricular hypertrophy (LVH) was evident in 8 of the 9 patients. At 12 months post-RDN, blind analysis revealed that MSNAfrequency (-12.2 bursts/min1, 95% CI [-13.6, -10.7]) and LV mass (-27 g/m2, 95% CI [-47, -8]) were reduced. Mean ambulatory BP (systolic: -24 mm Hg, 95% CI [-42, -5] and diastolic: -13 mm Hg, 95% CI [-22, -4]) was also reduced at 12 months. Office BP was reduced as early as 1 month (systolic: -25 mm Hg, 95% CI [-45, -5] and diastolic: -13 mm Hg, 95% CI [-24, -1]). Both ambulatory and office BP had clinically significant reductions in at least 50% of patients out to 12 months. DISCUSSION: Catheter-based RDN significantly reduced MSNA and LV mass as well as systemic BP in this group of patients with ESKD.

A Population Pharmacokinetic Model for 51Cr EDTA to Estimate Renal Function.

BACKGROUND AND OBJECTIVES: 51Cr EDTA clearance (CL) from plasma is used to estimate glomerular filtration rate (GFR). We propose that current methods for analysing the raw 51Cr EDTA measurements over-simplifies the disposition of 51Cr EDTA and therefore could produce biased GFR estimates. The aim of this study was to develop a population pharmacokinetic model for 51Cr EDTA disposition and to compare model-predicted GFR to other methods of estimating renal function. PATIENTS AND METHODS: Data from 40 individuals who received ~7.4 MBq of 51Cr EDTA, as an intravenous bolus, were available for analysis. Plasma radioactivity (counts/min) was measured from timed collection points at 2, 4, 6 and 24 h after the dose. A population analysis was conducted using NONMEM® version 7.2. Model-predicted GFR was compared with other methods for estimating renal function using mean prediction error (MPE). RESULTS: A two-compartment pharmacokinetic model with first-order elimination best fit the data. Compared with the model predictions, creatinine CL from 24 h urine data was unbiased. The commonly used 'slope-intercept' method for estimating isotopic GFR was positively biased compared with the model (MPE 15.5 mL/min/1.73 m2 [95% confidence interval {CI} 8.9-22.2]. The Cockcroft Gault, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equations led to negatively biased GFR estimates (MPE -19.0 [95% CI -25.4 to -12.7], -20.1 [95% CI -27.2 to -13.1] and -16.5 [95% CI -22.2 to -10.1] mL/min/1.73 m2, respectively). CONCLUSIONS: The biased GFR estimates were most obvious in patients with relatively normal renal function. This may lead to inaccurate dosing in patients who are receiving drugs with a narrow therapeutic range where dosing is adjusted according to GFR estimates (e.g. carboplatin). STUDY REGISTRATION: The study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number: ACTRN 12611000035921.

Endovascular renal denervation: a novel sympatholytic with relevance to chronic kidney disease.

Endovascular renal denervation (sympathectomy) is a novel procedure developed for the treatment of resistant hypertension. Evidence suggests that it reduces both afferent and efferent sympathetic nerve activity, which may offer clinical benefit over and above any blood pressure-lowering effect. Studies have shown objective improvements in left ventricular mass, ventricular function, central arterial stiffness, central haemodynamics, baroreflex sensitivity and arrhythmia frequency. Benefits have also been seen in insulin resistance, microalbuminuria and glomerular filtration rate. In chronic kidney disease, elevated sympathetic activity has been causally linked to disease progression and cardiovascular sequelae. Effecting a marked reduction in sympathetic hyperactivity may herald a significant step in the management of this and other conditions. In this in-depth review, the pathophysiology and clinical significance of the sympatholytic effects of endovascular renal denervation are discussed.