John Schollum

Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function

To better understand the diagnostic and predictive performance of urinary biomarkers of kidney injury, we evaluated γ-glutamyltranspeptidase (GGT), alkaline phosphatase (AP), neutrophil-gelatinase-associated lipocalin (NGAL), cystatin C (CysC), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in a prospective observational study of 529 patients in 2 general intensive care units (ICUs). Comparisons were made using the area under the receiver operator characteristic curve (AUC) for diagnosis or prediction of acute kidney injury (AKI), dialysis, or death, and reassessed after patient stratification by baseline renal function (estimated glomerular filtration rate, eGFR) and time after renal insult. On ICU entry, no biomarker had an AUC above 0.7 in the diagnosis or prediction of AKI. Several biomarkers (NGAL, CysC, and IL-18) predicted dialysis (AUC over 0.7), and all except KIM-1 predicted death at 7 days (AUC between 0.61 and 0.69). Performance was improved by stratification for eGFR or time or both. With eGFR <60 ml/min, CysC and KIM-1 had AUCs of 0.69 and 0.73, respectively, within 6 h of injury, and between 12 and 36 h, CysC (0.88), NGAL (0.85), and IL-18 (0.94) had utility. With eGFR >60 ml/min, GGT (0.73), CysC (0.68), and NGAL (0.68) had the highest AUCs within 6 h of injury, and between 6 and 12 h, all AUCs except AP were between 0.68 and 0.78. Beyond 12 h, NGAL (0.71) and KIM-1 (0.66) performed best. Thus, the duration of injury and baseline renal function should be considered in evaluating biomarker performance to diagnose AKI.

Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).

We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.

Dietary salt loading impairs arterial vascular reactivity

BACKGROUND Studies of sodium have shown improvements in vascular function and blood pressure (BP). The effect of chronic sodium loading from a low-sodium diet to a Western diet on vascular function and BP has been less well studied. OBJECTIVE The objective was to examine the effects of dietary salt intake on vascular function and BP. DESIGN Thirty-five hypertensive volunteers met the inclusion criteria. After a 2-wk run-in with a low-sodium diet (60 mmol/d), the participants maintained their diets and were randomly assigned to receive sequentially 1 of 3 interventions for 4 wk, with a 2-wk washout between interventions: sodium-free tomato juice (A), tomato juice containing 90 mmol Na (B), and tomato juice containing 140 mmol Na (C). The outcomes were changes in pulse wave velocity (PWV), systolic BP (SBP), and diastolic BP (DBP). RESULTS The difference in PWV between interventions B and A was 0.39 m/s (95% CI: 0.18, 0.60 m/s; P < or = 0.001) and between C and A was 0.35 m/s (95% CI: 0.13, 0.57 m/s; P < or = 0.01). Differences in SBP and DBP between interventions B and A were 4.4 mm Hg (95% CI: 1.2, 7.8 mm Hg; P < or = 0.01) and 2.4 mm Hg (95% CI: 0.8, 4.1 mm Hg; P < or = 0.001), respectively, and between interventions C and A were 5.6 mm Hg (95% CI: 2.7, 8.4 mm Hg; P < or = 0.01) and 3.3 mm Hg (95% CI: 1.5, 5.0 mm Hg; P < or = 0.001), respectively. Changes in PWV correlated with changes in SBP (r = 0.52) and DBP (r = 0.58). CONCLUSIONS Dietary salt loading produced significant increases in PWV and BP in hypertensive volunteers. Correlations between BP and PWV suggest that salt loading may have a BP-independent effect on vascular wall function. This further supports the importance of dietary sodium restriction in the management of hypertension. This trial was registered with the Australian and New Zealand Clinical Trials Registry as ACTRN12609000161224.

Red Blood Cell Survival in Long-term Dialysis Patients

BACKGROUND Shortening of red blood cell (RBC) survival contributes to the anemia of chronic kidney disease. The toxic uremic environment accounts for the decreased RBC life span. The contribution of mechanical damage caused by hemodialysis to the shortened life span is unclear. Reductions up to 70% in RBC survival have been reported in uremic patients. To date, no accurate well-controlled RBC survival data exist in dialysis patients treated using different dialysis modalities and receiving erythropoiesis-stimulating agent (ESA) therapy. The aim of this study was to determine RBC survival in hemodialysis (HD) and peritoneal dialysis (PD) patients compared with healthy persons. STUDY DESIGN Observational study. SETTING & PARTICIPANTS 14 HD patients and 5 PD patients were recruited from the dialysis unit. Healthy volunteers (n = 14) age- and sex-matched to HD participants were included. All dialysis patients received either ESA therapy or regular iron supplementation. PREDICTOR Dialysis patients versus age- and sex-matched healthy controls. OUTCOMES RBC survival. MEASUREMENTS RBC survival was determined using radioactive chromium labeling. RESULTS More than 85% of dialysis patients were anemic (hemoglobin, 12.0 ± 1.1 g/dL); hemoglobin concentrations were not significantly different between HD and PD patients. Median RBC survival was significantly decreased by 20% in HD patients compared with healthy controls: 58.1 (25th-75th percentile, 54.6-71.2) versus 72.9 (25th-75th percentile, 63.4-87.8) days (P = 0.02). No difference was shown between the PD and HD groups: 55.3 (25th-75th percentile, 49.0-60.2) versus 58.1 (25th-75th percentile, 54.6-71.2) days (P = 0.2). LIMITATIONS Label loss from RBCs associated with the chromium 51 labeling technique needs to be accounted for in the interpretation of RBC survival data. CONCLUSIONS Despite current ESA therapy, decreased RBC survival contributes to chronic kidney disease-related anemia, although the reduction is less than previously reported. There does not appear to be net mechanical damage associated with HD therapy resulting in decreased RBC life span.

Assessment of markers of glycaemic control in diabetic patients with chronic kidney disease using continuous glucose monitoring.

Aim:  Due to altered red blood cell survival and erythropoietin therapy glycated haemoglobin (HbA1c) may not accurately reflect long‐term glycaemic control in patients with diabetes and chronic kidney disease (CKD). Glycated albumin (GA) and fructosamine are alternative markers of glycaemia. The aim of this study was to investigate the accuracy of HbA1c, GA and fructosamine as indicators of glycaemic control using continuous glucose monitoring.

Dietary sodium loading in normotensive healthy volunteers does not increase arterial vascular reactivity or blood pressure

Background:  Studies of dietary sodium on vascular function and blood pressure in normotensive volunteers have shown conflicting results. There are very limited data available on the effect of chronic sodium loading from a low‐sodium diet to a high‐sodium diet on vascular function and blood pressure in normotensive volunteers.

Glycated albumin is the preferred marker for assessing glycaemic control in advanced chronic kidney disease

Diabetic nephropathy is the most common aetiology of end-stage kidney disease (ESKD). Strict glycaemic control reduces the development and progression of diabetes-related complications, and there is evidence that improved metabolic control improves outcomes in diabetic subjects with advanced chronic kidney disease (CKD). Glycaemic control in people with kidney disease is complex. Changes in glucose and insulin homeostasis may occur as a consequence of loss of kidney function and dialysis. The reliability of measures of long-term glycaemic control is affected by CKD and the accuracy of glycated haemoglobin (HbA1c) in the setting of CKD and ESKD is questioned. Despite the altered character of diabetes in CKD, current guidelines for diabetes management are not specifically adjusted to this patient group. The validity of indicators of longer term glycaemic control has been the focus of increased recent research. This review discusses the current understanding of commonly used indicators of metabolic control (HbA1c, fructosamine, glycated albumin) in the setting of advanced CKD (Stages 4 and 5, glomerular filtration rate <30 mL/min/1.73m2).

Older peoples' satisfaction with home-based dialysis.

Background:  The proportion of older people receiving dialysis is rapidly increasing. The typical choice for older patients is between home‐based peritoneal dialysis (PD) and clinic‐based haemodialysis (HD). Some centres have been successful in encouraging all patients – including older patients – to have home‐based self‐administered PD or HD.

Chronic interstitial fibrosis in the rat kidney induced by long-term (6-mo) exposure to lithium

There is a lack of suitable animal models that replicate the slowly progressive chronic interstitial fibrosis that is characteristic of many human chronic nephropathies. We describe a chronic long-term (6-mo) model of lithium-induced renal fibrosis, with minimal active inflammation, which mimics chronic kidney interstitial fibrosis seen in the human kidney. Rats received lithium via their chow (60 mmol lithium/kg food) daily for 6 mo. No animals died during the exposure. Nephrogenic diabetes insipidus was established by 3 wk and persisted for the 6 mo. Following metabolic studies, the animals were killed at 1, 3, and 6 mo and the kidneys were processed for histological and immunohistochemical studies. Progressive interstitial fibrosis, characterized by increasing numbers of myofibroblasts, enhanced transforming growth factor-β(1) expression and interstitial collagen deposition, and a minimal inflammatory cellular response was evident. Elucidation of the underlying mechanisms of injury in this model will provide a greater understanding of chronic interstitial fibrosis and allow the development of intervention strategies to prevent injury.

Nephrotoxicity of recreational party drugs

N‐benzylpiperazine (BZP) is the active ingredient in recreational ‘party’ pills with a stimulant, euphoric mechanism of action akin to that of 3,4‐methylenedioxymethamphetamine (MDMA or ecstasy). Many people (ab)use BZP‐based party pills usually without any significant toxic effects. However, nephrotoxicity secondary to hyperthermia and rhabdomyolysis has been reported. Another serious renal‐related side‐effect is hyponatraemia with acute cerebral oedema. There is also evidence that these agents may have a specific toxic effect producing acute kidney injury. Thus, acute kidney injury either direct or secondary to the effects of BZP or MDMA need to be considered when any individual presents with symptoms of a recreational party drug overdose.