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.

Autosomal dominant hypercalciuric hypocalcaemia: the calcium-sensing receptor in renal calcium homeostasis and the impact of renal transplantation.

Calcium-sensing receptors (CaSRs) are G protein-coupled receptors that help maintain Ca2+ concentrations, modulating calciotropic hormone release (parathyroid hormone (PTH), calcitonin and 1,25-dihydroxyvitamin D) by direct actions in the kidneys, gastrointestinal tract and bone. Variability in population calcium levels has been attributed to single nucleotide polymorphisms in CaSR genes, and several conditions affecting calcium and phosphate homeostasis have been attributed to gain- or loss-of-function mutations. An example is autosomal dominant hypercalciuric hypocalcaemia, because of a missense mutation at codon 128 of chromosome 3, as reported in our specific case and her family. As a consequence of treating symptomatic hypocalcaemia as a child, this female subject slowly developed progressive end-stage kidney failure because of nephrocalcinosis and nephrolithiasis. After kidney transplantation, she remains asymptomatic, with decreased vitamin D and elemental calcium requirements, stable fluid and electrolyte homeostasis during intercurrent illnesses and has normalised urinary calcium and phosphate excretion, reducing the likelihood of hypercalciuria-induced graft impairment. We review the actions of the CaSR, its role in regulating renal Ca2+ homeostasis along with the impact of a proven gain-of-function mutation in the CaSR gene resulting in autosomal dominant hypercalciuric hypocalcaemia before and after kidney transplantation.

FTO-mediated m6A mRNA demethylation aggravates renal fibrosis by targeting RUNX1 and further enhancing PI3K/AKT pathway.

Chronic kidney disease (CKD) is a global health burden, with ineffective therapies leading to increasing morbidity and mortality. Renal interstitial fibrosis is a common pathway in advanced CKD, resulting in kidney function and structure deterioration. In this study, we investigate the role of FTO-mediated N6-methyladenosine (m6A) and its downstream targets in the pathogenesis of renal fibrosis. M6A modification, a prevalent mRNA internal modification, has been implicated in various organ fibrosis processes. We use a mouse model of unilateral ureteral obstruction (UUO) as an in vivo model and treated tubular epithelial cells (TECs) with transforming growth factor (TGF)-ß1 as in vitro models. Our findings revealed increased FTO expression in UUO mouse model and TGF-ß1-treated TECs. By modulating FTO expression through FTO heterozygous mutation mice (FTO+/- ) in vivo and small interfering RNA (siRNA) in vitro, we observed attenuation of UUO and TGF-ß1-induced epithelial-mesenchymal transition (EMT), as evidenced by decreased fibronectin and N-cadherin accumulation and increased E-cadherin levels. Silencing FTO significantly improved UUO and TGF-ß1-induced inflammation, apoptosis, and inhibition of autophagy. Further transcriptomic assays identified RUNX1 as a downstream candidate target of FTO. Inhibiting FTO was shown to counteract UUO/TGF-ß1-induced RUNX1 elevation in vivo and in vitro. We demonstrated that FTO signaling contributes to the elevation of RUNX1 by demethylating RUNX1 mRNA and improving its stability. Finally, we revealed that the PI3K/AKT pathway may be activated downstream of the FTO/RUNX1 axis in the pathogenesis of renal fibrosis. In conclusion, identifying small-molecule compounds that target this axis could offer promising therapeutic strategies for treating renal fibrosis.

Is It Time to Integrate Frailty Assessment in Onconephrology?

Onconephrology has emerged as a novel sub-specialty of nephrology dedicated to the intersection between the kidney and cancer. This intersection is broad and includes a number of important areas of focus, including concurrent chronic kidney disease (CKD) and cancer, acute kidney complications of cancer, and cancer-treatment-induced nephrotoxicity. The importance of onconephrology is even more evident when considering the global growth in the population of older adults, many of whom are living with some degree of frailty. Furthermore, a considerable proportion of older adults have CKD (some of whom eventually progress to kidney failure) and are at high risk of developing solid tumour and hematologic malignancies. Specific to kidney disease, the association between frailty status and kidney disease has been explored in depth, and tools to capture frailty can be used to guide the management and prognostication of older adults living with kidney failure. Whilst there is emerging data regarding the assessment and impact of frailty in onconephrology, there remains a relative paucity of knowledge within this topic. In this article, we evaluate the definition and operationalization of frailty and discuss the significance of frailty within onconephrology. We review evidence on current approaches to assessing frailty in onconephrology and discuss potential developments and future directions regarding the utilization of frailty in this patient population. A greater awareness of the intersections and interactions between frailty and onconephrology and further efforts to integrate frailty assessment in onconephrology to optimize the delivery of realistic and goal-directed management strategies for patients is needed.

Reduction of lithium induced interstitial fibrosis on co-administration with amiloride.

Long-term administration of lithium is associated with chronic interstitial fibrosis that is partially reduced with exposure to amiloride. We examined potential pathways of how amiloride may reduce interstitial fibrosis. Amiloride was administered to a rat model of lithium induced interstitial fibrosis over a long term (6 months), as well as for short terms of 14 and 28 days. Kidney cortical tissue was subjected to RNA sequencing and microRNA expression analysis. Gene expression changes of interest were confirmed using immunohistochemistry on kidney tissue. Pathways identified by RNA sequencing of kidney tissue were related to 'promoting inflammation' for lithium and 'reducing inflammation' for amiloride. Validation of candidate genes found amiloride reduced inflammatory components induced by lithium including NF-κB/p65Ser536 and activated pAKTSer473, and increased p53 mediated regulatory function through increased p21 in damaged tubular epithelial cells. Amiloride also reduced the amount of Notch1 positive PDGFrß pericytes and infiltrating CD3 cells in the interstitium. Thus, amiloride attenuates a multitude of pro-inflammatory components induced by lithium. This suggests amiloride could be repurposed as a possible anti-inflammatory, anti-fibrotic agent to prevent or reduce the development of chronic interstitial fibrosis.

Predictors of Health Deterioration Among Older New Zealanders Undergoing Dialysis: A Three-Year Accelerated Longitudinal Cohort Study.

BACKGROUND: Patient involvement in dialysis decision-making is crucial, yet little is known about patient-reported outcomes over time on dialysis. OBJECTIVE: To examine health-related outcomes over 24 and 36 months in an older cohort of dialysis patients. DESIGN: The "Dialysis outcomes in those aged ≥65 years study" is a prospective longitudinal cohort study of New Zealanders with kidney failure. SETTING: Three New Zealand nephrology units. PATIENTS: Kidney failure (dialysis and predialysis) patients aged 65 or above. We have previously described outcomes after 12 months of dialysis therapy relative to baseline. MEASUREMENTS: Patient-reported social and health factors using the SF-36, EQ-5D, and Kidney Symptom Score questionnaires. METHODS: This article describes and compares characteristics of 120 older kidney failure patients according to whether they report "Same/better" or "Worse" health 24 and 36 months later, and identifies predictors of "worse health." Modified Poisson regression modeling estimated relative risks (RR) of worse health. RESULTS: Of 120 patients at 12 months, 47.5% had worse health or had died by 24 months. Of those surviving at 24 months (n = 80), 40% had "Worse health" or had died at 36 months. Variables independently associated with reduced risk of "Worse health" (24 months) were as follows: Maori ethnicity (RR = 0.44; 95% CI = 0.26-0.75), Pacific ethnicity (RR = 0.39; 95% CI = 0.33-0.46); greater social satisfaction (RR = 0.57; 95% CI = 0.46-0.7). Variables associated with an increased risk of "Worse health" were as follows: problems with usual activities (RR = 1.32; 95% CI = 1.04-1.37); pain or discomfort (RR = 1.48; 95% CI = 1.34, 1.63). At 36 months, lack of sense of community (RR = 1.41; 95% CI = 1.18-1.69), 2 or more comorbidities (RR = 1.21; 95% CI = 1.13-1.29), and problems with poor health (RR = 1.47; 95% CI = 1.41-1.54) were associated with "Worse health." LIMITATIONS: Participant numbers restricted the number of variables able to be included in the multivariable model, and hence there may have been insufficient power to detect certain associations. CONCLUSIONS: In this study, the majority of older dialyzing patients report "Same/better health" at 24 and 36 months. Maori and Pacific people report better outcomes on dialysis. Social and/or clinical interventions aimed at improving social satisfaction, sense of community, and help with usual activities may impact favorably on the experiences for older dialysis patients. TRIAL REGISTRATION: Australian and New Zealand clinical trials registry: ACTRN12611000024943.

CONTEXTE: La participation des patients à la prise de décisions est essentielle en contexte de traitements de dialyse. On en sait toutefois peu sur les résultats observés par les patients en cours de traitement. OBJECTIF: Examiner les résultats liés à la santé sur une période de 24 et de 36 mois dans une cohorte de patients âgés suivant des traitements de dialyse. TYPE D'ÉTUDE: Cette étude intitulée Dialysis outcomes in those aged ≥65 years est une étude de cohorte prospective et longitudinale menée auprès de Néo-Zélandais atteints d'insuffisance rénale. CADRE: Trois unités de néphrologie en Nouvelle-Zélande. SUJETS: Des patients âgés de plus de 65 ans atteints d'insuffisance rénale (dialyse et prédialyse). Nous avions antérieurement décrit les résultats observés après 12 mois de dialyse par rapport au début de l'étude. MESURES: Les facteurs sociaux et l'état de santé déclarés par les patients par l'entremise des questionnaires SF-36, EQ-5D et Kidney Symptom Score. MÉTHODOLOGIE: Dans cet article, nous décrivons et comparons les caractéristiques de 120 patients âgés atteints d'insuffisance rénale selon qu'ils avaient déclaré un état de santé « inchangé/meilleur ¼ ou « empiré ¼ après 24 et 36 mois. Nous discutons également des facteurs prédictifs d'un état de santé jugé « empiré ¼. Un modèle de régression de Poisson corrigé a servi à estimer le risque relatif (RR) de progresser vers un état de santé « empiré ¼. RÉSULTATS: Des 120 patients évalués après 12 mois, 47,5 % avaient déclaré un état de santé « empiré ¼ ou étaient décédés après 24 mois. Parmi les survivants à 24 mois d'étude (n = 80), 40 % avaient déclaré un état de santé « empiré ¼ ou étaient décédés après 36 mois. Les variables associées de façon indépendante à un risque réduit de voir l'état de santé empiré (24 mois) étaient : le fait d'être Maori (RR = 0,44; IC 95% = 0.26-0.75) ou issu d'une population du Pacifique (RR = 0.39; IC 95% = 0.33-0.46) et une satisfaction sociale plus élevée (RR = 0.57; IC 95% = 0.46-0.7) constituent les variables qui ont été associées de façon indépendante à un risque réduit de voir un état de santé empiré après 24 mois. Parmi les variables associées à un risque accru d'aggravation de l'état de santé, on compte des difficultés à pratiquer les activités quotidiennes (RR = 1.32; IC 95% = 1.04-1.37) et la douleur ou l'inconfort (RR = 1.48; IC 95% = 1.34-1.63). Après 36 mois de traitement, l'absence d'un sentiment de communauté (RR = 1,41; IC 95% = 1.18-1.69), le fait de présenter au moins deux maladies concomitantes (RR = 1.21; IC 95% = 1.13-1.29) et des problèmes liés à une mauvaise santé (RR = 1.47; IC 95% = 1.41-1.54) ont été associés à un état de santé jugé « empiré ¼. LIMITES: Le faible nombre de participants a restreint le nombre de variables pouvant être incluses dans le modèle multivarié, il est donc possible que la puissance de détection de certaines associations soit insuffisante. CONCLUSION: Dans cette étude, la majorité des patients âgés sous dialyse ont déclaré avoir un état de santé « inchangé/meilleur ¼ après 24 et 36 mois de traitement. Les patients Maoris et ceux qui sont originaires du Pacifique ont déclaré de meilleurs résultats de dialyse. Les interventions sociales ou cliniques visant à améliorer la satisfaction sociale, le sentiment d'appartenance à la communauté et l'aide aux activités quotidiennes pourraient avoir un effet bénéfique sur le vécu des patients âgés suivant des traitements de dialyse.

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.

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.

A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD).

BACKGROUND: Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain. METHODS: To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism. RESULTS: A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings. CONCLUSIONS: In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Australian Clinical Trials Registry, ACTRN12610000650099.

Report on the First Symposium on Invertebrate Neuroscience held on 13-17th August 2019 at the Balaton Limnological Institute, MTA Centre for Ecological Research, Tihany, Hungary.

This meeting report provides an overview of the oral and poster presentations at the first international symposium for invertebrate neuroscience. The contents reflect the contributions of invertebrate neuroscience in addressing fundamental and fascinating challenges in understanding the neural substrates of animal behaviour.

Effects of Allopurinol on the Progression of Chronic Kidney Disease.

BACKGROUND: Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known. METHODS: In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m2 of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULTS: Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m2; median urine albumin:creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m2 per year [95% confidence interval {CI}, -4.11 to -2.55] and -3.23 ml per minute per 1.73 m2 per year [95% CI, -3.98 to -2.47], respectively; mean difference, -0.10 ml per minute per 1.73 m2 per year [95% CI, -1.18 to 0.97]; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group. CONCLUSIONS: In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.).

Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat.

Hypertension plays an important role in the development and progression of chronic kidney disease. Studies to date, with mineralocorticoid receptor antagonists (MRA), have demonstrated varying degrees of results in modifying the development of renal fibrosis. This study aimed to investigate whether treatment with a MRA commenced following the establishment of hypertension, a situation more accurately representing the clinical setting, modified the progression of renal fibrosis. Using male Cyp1a1Ren2 rats (n = 28), hypertension was established by addition of 0.167% indole-3-carbinol (w/w) to the rat chow, for 2 weeks prior to treatment. Rats were then divided into normotensive, hypertensive (H), or hypertensive with daily oral spironolactone treatment (H + SP) (human equivalent dose 50 mg/day). Physiological data and tissue were collected after 4 and 12 weeks for analysis. After 4 weeks, spironolactone had no demonstrable effect on systolic blood pressure (SBP), proteinuria, or macrophage infiltration in the renal cortex. However, glomerulosclerosis and renal cortical fibrosis were significantly decreased. Following 12 weeks of spironolactone treatment, SBP was lowered (not back to normotensive levels), proteinuria was reduced, and the progression of glomerulosclerosis and renal cortical fibrosis was significantly blunted. This was associated with a significant reduction in macrophage and myofibroblast infiltration, as well as CTGF and pSMAD2 expression. In summary, in a model of established hypertension, spironolactone significantly blunted the progression of renal fibrosis and glomerulosclerosis, and downregulated the renal inflammatory response, which was associated with reduced proteinuria, despite only a partial reduction in systolic blood pressure. This suggests a blood pressure independent effect of MRA on renal fibrosis.

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.

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).

Myocardial global longitudinal strain: An early indicator of cardiac interstitial fibrosis modified by spironolactone, in a unique hypertensive rat model.

OBJECTIVES: Is global longitudinal strain (GLS) a more accurate non-invasive measure of histological myocardial fibrosis than left ventricular ejection fraction (LVEF) in a hypertensive rodent model. BACKGROUND: Hypertension results in left ventricular hypertrophy and cardiac dysfunction. Speckle-tracking echocardiography has emerged as a robust technique to evaluate cardiac function in humans compared with standard echocardiography. However, its use in animal studies is less clearly defined. METHODS: Cyp1a1Ren2 transgenic rats were randomly assigned to three groups; normotensive, untreated hypertensive or hypertensive with daily administration of spironolactone (human equivalent dose of 50 mg/day). Cardiac function and interstitial fibrosis development were monitored for three months. RESULTS: The lower limit of normal LVEF was calculated to be 75%. After three months hypertensive animals (196±21 mmHg systolic blood pressure (SBP)) showed increased cardiac fibrosis (8.8±3.2% compared with 2.4±0.7% % in normals), reduced LVEF (from 81±2% to 67±7%) and impaired myocardial GLS (from -17±2% to -11±2) (all p<0.001). Myocardial GLS demonstrated a stronger correlation with cardiac interstitial fibrosis (r2 = 0.58, p<0.0001) than LVEF (r2 = 0.37, p<0.006). Spironolactone significantly blunted SBP elevation (184±15, p<0.01), slowed the progression of cardiac fibrosis (4.9±1.4%, p<0.001), reduced the decline in LVEF (72±4%, p<0.05) and the degree of impaired myocardial GLS (-13±1%, p<0.01) compared to hypertensive animals. CONCLUSIONS: This study has demonstrated that, myocardial GLS is a more accurate non-invasive measure of histological myocardial fibrosis compared to standard echocardiography, in an animal model of both treated and untreated hypertension. Spironolactone blunted the progression of cardiac fibrosis and deterioration of myocardial GLS.

The Association between Metformin Therapy and Lactic Acidosis.

INTRODUCTION AND OBJECTIVES: There is increasing evidence to suggest that therapeutic doses of metformin are unlikely to cause lactic acidosis. The aims of this research were (1) to formally evaluate the association between metformin therapy and lactic acidosis in published case reports using two causality scoring systems, (2) to determine the frequency of pre-existing independent risk factors in published metformin-associated lactic acidosis cases, (3) to investigate the association between risk factors and mortality in metformin-associated lactic acidosis cases, and (4) to explore the relationship between prescribed metformin doses, elevated metformin plasma concentrations and the development of lactic acidosis in cases with chronic renal impairment. METHODS: A systematic review was conducted to identify metformin-associated lactic acidosis cases. Causality was assessed using the World Health Organisation-Uppsala Monitoring Centre system and the Naranjo adverse drug reaction probability scale. Compliance to dosing guidelines was investigated for cases with chronic renal impairment as well as the association between steady-state plasma metformin concentrations prior to admission. RESULTS: We identified 559 metformin-associated lactic acidosis cases. Almost all cases reviewed (97%) presented with independent risk factors for lactic acidosis. The prescribed metformin dose exceeded published guidelines in 60% of cases in patients with impaired kidney function. Metformin steady-state plasma concentrations prior to admission were predicted to be below the proposed upper limit of the therapeutic range of 5 mg/L. CONCLUSIONS: Almost all cases of metformin-associated lactic acidosis reviewed presented with independent risk factors for lactic acidosis, supporting the suggestion that metformin plays a contributory role. The prescribed metformin dose, on average, exceeded the dosing recommendations by 1000 mg/day in patients with varying degrees of renal impairment but the predicted pre-admission plasma concentrations did not exceed the therapeutic range.

Chronic Kidney Disease in New Zealand Maori and Pacific People.

Chronic kidney disease (CKD) disproportionately affects Maori (the indigenous people of New Zealand [NZ]) as well as Pacific people, particularly from Samoa, Tonga, and Fiji. As New Zealand is home to the largest population of Pacific people, New Zealand and the Pacific Islands fulfil the definition of a CKD 'hotspot'. Although diabetic nephropathy is the major cause of CKD, with disproportionately higher rates in NZ Maori and Pacific people, there is increasing evidence that there is a familial predisposition to CKD that is not due to diabetes. Further studies are required to understand the reasons for this pre-disposition.

Recruitment and participant baseline characteristics in the dialysis outcomes in those aged 65 years or older study.

BACKGROUND: Despite an increasing number of older people commencing dialysis the impact of dialysis on their quality of life and survival, remains unclear. The Dialysis Outcomes in those aged over 65 years or older study is an accelerated prospective cohort longitudinal design study, designed to obtain sufficient health related quality of life data, linked to clinical data, to inform clinicians' and patients' decision-making with respect to end stage kidney disease (ESKD), outcomes, and options for management in New Zealand (NZ). METHODS: The study has an accelerated prospective cohort longitudinal design, comprised of cross-sectional and longitudinal components. We report the baseline data on the 225 participants enrolled in the study. Dialysis duration was grouped in tertiles from less than one year (incident patients), 1-3 years and greater than 3 years. Health related quality of life data was obtained from self-reported questionnaires including KDQoL-36, EQ-5D-3 L, FACIT, WHODAS II, and the Personal Well-being Score. RESULTS: The median age of the cohort was 71 years and two thirds were male. Three quarters of the participants were on dialysis at the baseline, with 42% of those on home dialysis (haemodialysis or peritoneal dialysis). Maori and Pacific people were over represented (20% Maori and 24% Pacific) in the sample, when compared to the general NZ population of the same age group (where 5% are Maori and 2% are Pacific). At baseline, there were no differences observed in sociodemographic, quality of life or health characteristics between the dialysis groups either by modality or duration of dialysis. CONCLUSIONS: We report the baseline characteristics of participants enrolled prospectively into a longitudinal cohort observational study examining health related quality of life factors with clinical characteristics on dialysis outcomes in a group of New Zealanders aged 65 years or older who are either on dialysis or have been educated about dialysis (BMC Nephrol 14:175, 2013). Subsequent publications are planned, analysing the prospective longitudinal data to identify key factors that determine both outcome and quality of life for individuals of this age group. TRIAL REGISTRATION: ACTRN12611000024943 .

Sympathetic overactivity in dialysis patients-Underappreciated and clinically consequential.

Cardiovascular morbidity and mortality remain frustratingly common in dialysis patients. A dearth of established evidence-based treatment calls for alternative therapeutic avenues to be embraced. Sympathetic hyperactivity, predominantly due to afferent nerve signaling from the diseased native kidneys, has been established to be prognostic in the dialysis population for over 15 years. Despite this, tangible therapeutic interventions have, to date, been unsuccessful and the outlook for patients remains poor. This narrative review summarizes established experimental and clinical data, highlighting recent developments, and proposes why interventions to ameliorate sympathetic hyperactivity may well be beneficial for this high-risk population.

The intact nephron hypothesis as a model for renal drug handling.

PURPOSE: The intact nephron hypothesis (INH) states that impaired renal function results from a reduction in the number of complete (intact) nephrons. Under this model, renal drug clearance is assumed to be a linear function of glomerular filtration while tubular handling is ignored. The aims of this study were to systematically review published studies designed to test the INH and to assess the strength of the study designs used. METHODS: A systematic literature search was conducted in MEDLINE, EMBASE and Google Scholar. Studies specifically designed to understand the relationship between glomerular and tubular function across different levels of renal function were included. Studies that found a linear relationship between GFR and tubular clearance were deemed to support the INH while studies that found a non-linear relationship did not support the INH. Study design was accessed using a bespoke strength of evidence score. RESULTS: Thirty studies met the criteria for inclusion. Of these, 24 did not support the INH. Studies that did not support the INH used methods for measuring tubular clearance that were more robust and included subjects with a wider range of GFR values than studies that supported the INH. DISCUSSION: Our results suggest that the INH may not be a suitable general model for renal drug handling, particularly for drugs that are eliminated by tubular mechanisms. Further studies to assess the clinical importance of a non-linear relationship between drug clearance and GFR are warranted.