Relationship between renal CD68+ infiltrates and the Oxford Classification of IgA nephropathy.

AIMS: The Oxford Classification E score (endocapillary hypercellularity) predicts renal functional decline in IgA nephropathy (IgAN) patients free from steroid/immunosuppressive (IS) therapy, but is poorly reproducible. We hypothesise that endocapillary hypercellularity reflects glomerular inflammation and that the presence of CD68-positive cells is a more robust marker of E score. METHODS AND RESULTS: CD68-positive cells were quantified in glomeruli and tubulointerstitium in biopsies from 118 IgAN patients, and cell counts were correlated with the criteria of the Oxford Classification, assigned on PAS-stained serial sections. There was a strong correlation between median glomerular CD68 count and the percentage of glomeruli showing endocapillary hypercellularity (r = 0.67; P < 0.001; r2  = 0.45), while there was no correlation between CD68-positive cells and mesangial hypercellularity, % segmental sclerosis, % of crescents and % tubular atrophy/interstitial fibrosis (TA/IF). ROC curve analysis demonstrated that a maximum glomerular CD68 count of 6 is the best cut-off for distinguishing E0 from E1 (sensitivity 94.1%, specificity 71%, area under the curve = 89%). Identification of biopsies with a maximum glomerular CD68-count >6 was reproducible (kappa score 0.8), and there was a strong correlation between glomerular CD68 counts obtained by conventional light microscopy and by image analysis (r = 0.80, r2  = 0.64, P < 0.0001). Digital image analysis revealed that tubulointerstitial CD68-positive cells correlated moderately with % TA/IF (r = 0.59, r2  = 0.35, P < 0.001) and GFR at the time of biopsy (r = 0.54, r2  = 0.29, P < 0.0001), but not with mesangial and endocapillary hypercellularity. CONCLUSIONS: While glomerular CD68-positive cells emerge as markers of endocapillary hypercellularity, their tubulointerstitial counterparts are associated with chronic damage.

What lies downstream: Cellular oxygen delivery during hemodialysis.

Hemodialysis has been linked to structural and functional damage to vital organs such as the brain and heart, possibly via repetitive intradialytic organ ischemia. There is increasing recognition that tissue ischemia can occur without changes in standard hemodynamic parameters such as blood pressure, leading to interest in more direct assessment of the adequacy of oxygen delivery to tissues. In this article, we discuss our current understanding of what happens to cellular oxygen delivery during hemodialysis: we review the underlying physiology, potential measurement techniques, and the clinical literature to date.

Cerebral ischemia during hemodialysis-finding the signal in the noise.

Hemodialysis patients have multiple risk factors for small vessel cerebrovascular disease and cognitive dysfunction. Hemodialysis itself may cause clinically significant neurological injury through repetitive cerebral ischemia. However, supporting evidence to date consists of epidemiological associations, expert opinion, and small, single-centre studies of variable methodological quality. Isolating the impact of intra-dialytic hemodynamic instability from underlying renal and vascular disease on clinically relevant functional outcomes would require very large, controlled studies, given the heterogeneity and confounding comorbidities of the population, and the complex relationship between blood pressure and cerebral oxygen delivery. There has been an increase in complementary physiological studies looking directly at intra-dialytic cerebral oxygen balance, which have provided supporting evidence for the occurrence of cerebral ischemia, often independently of hemodynamics. Data suggesting a relationship between these measures of oxygen balance and functional outcomes is only hypothesis-generating at this stage. We advocate the testing of interventions that aim to reduce intra-dialytic cerebral hypoxia (rather than hypotension) in sufficiently powered studies, followed by correlation with validated, longitudinal assessment of clinically relevant neurological damage.

Relationship between Hypotension and Cerebral Ischemia during Hemodialysis.

The relationship between BP and downstream ischemia during hemodialysis has not been characterized. We studied the dynamic relationship between BP, real-time symptoms, and cerebral oxygenation during hemodialysis, using continuous BP and cerebral oxygenation measurements prospectively gathered from 635 real-world hemodialysis sessions in 58 prevalent patients. We examined the relationship between BP and cerebral ischemia (relative drop in cerebral saturation >15%) and explored the lower limit of cerebral autoregulation at patient and population levels. Furthermore, we estimated intradialytic exposure to cerebral ischemia and hypotension for each patient, and entered these values into multivariate models predicting change in cognitive function. In all, 23.5% of hemodialysis sessions featured cerebral ischemia; 31.9% of these events were symptomatic. Episodes of hypotension were common, with mean arterial pressure falling by a median of 22 mmHg (interquartile range, 14.3-31.9 mmHg) and dropping below 60 mmHg in 24% of sessions. Every 10 mmHg drop from baseline in mean arterial pressure associated with a 3% increase in ischemic events (P<0.001), and the incidence of ischemic events rose rapidly below an absolute mean arterial pressure of 60 mmHg. Overall, however, BP poorly predicted downstream ischemia. The lower limit of cerebral autoregulation varied substantially (mean 74.1 mmHg, SD 17.6 mmHg). Intradialytic cerebral ischemia, but not hypotension, correlated with decreased executive cognitive function at 12 months (P=0.03). This pilot study demonstrates that intradialytic cerebral ischemia occurs frequently, is not easily predicted from BP, and may be clinically significant.

Pitfalls in the management of severe hyponatraemia.

The correction of severe hyponatraemia is complicated by practical and theoretical limitations of formulae used to predict response to treatment, and random errors in the measurement of sodium concentration. We report the case of an elderly woman with a symptomatic serum sodium concentration of 93 mmol/l. Correction of serum sodium unintentionally exceeded conventional targets but, as in the majority of such cases, there were no neurological sequelae.

Heparin versus citrate anticoagulation for continuous renal replacement therapy in intensive care: the RRAM observational study.

BACKGROUND: In the UK, 10% of admissions to intensive care units receive continuous renal replacement therapy with regional citrate anticoagulation replacing systemic heparin anticoagulation over the last decade. Regional citrate anticoagulation is now used in > 50% of intensive care units, despite little evidence of safety or effectiveness. AIM: The aim of the Renal Replacement Anticoagulant Management study was to evaluate the clinical and health economic impacts of intensive care units moving from systemic heparin anticoagulation to regional citrate anticoagulation for continuous renal replacement therapy. DESIGN: This was an observational comparative effectiveness study. SETTING: The setting was NHS adult general intensive care units in England and Wales. PARTICIPANTS: Participants were adults receiving continuous renal replacement therapy in an intensive care unit participating in the Intensive Care National Audit & Research Centre Case Mix Programme national clinical audit between 1 April 2009 and 31 March 2017. INTERVENTIONS: Exposure - continuous renal replacement therapy in an intensive care unit after completion of transition to regional citrate anticoagulation. Comparator - continuous renal replacement therapy in an intensive care unit before starting transition to regional citrate anticoagulation or had not transitioned. OUTCOME MEASURES: Primary effectiveness - all-cause mortality at 90 days. Primary economic - incremental net monetary benefit at 1 year. Secondary outcomes - mortality at hospital discharge, 30 days and 1 year; days of renal, cardiovascular and advanced respiratory support in intensive care unit; length of stay in intensive care unit and hospital; bleeding and thromboembolic events; prevalence of end-stage renal disease at 1 year; and estimated lifetime incremental net monetary benefit. DATA SOURCES: Individual patient data from the Intensive Care National Audit & Research Centre Case Mix Programme were linked with the UK Renal Registry, Hospital Episode Statistics (for England), Patient Episodes Data for Wales and Civil Registrations (Deaths) data sets, and combined with identified periods of systemic heparin anticoagulation and regional citrate anticoagulation (survey of intensive care units). Staff time and consumables were obtained from micro-costing. Continuous renal replacement therapy system failures were estimated from the Post-Intensive Care Risk-adjusted Alerting and Monitoring data set. EuroQol-3 Dimensions, three-level version, health-related quality of life was obtained from the Intensive Care Outcomes Network study. RESULTS: Out of the 188 (94.9%) units that responded to the survey, 182 (96.8%) use continuous renal replacement therapy. After linkage, data were available from 69,001 patients across 181 intensive care units (60,416 during periods of systemic heparin anticoagulation use and 8585 during regional citrate anticoagulation use). The change to regional citrate anticoagulation was not associated with a step change in 90-day mortality (odds ratio 0.98, 95% confidence interval 0.89 to 1.08). Secondary outcomes showed step increases in days of renal support (difference in means 0.53 days, 95% confidence interval 0.28 to 0.79 days), advanced cardiovascular support (difference in means 0.23 days, 95% confidence interval 0.09 to 0.38 days) and advanced respiratory support (difference in means, 0.53 days, 95% CI 0.03 to 1.03 days) with a trend toward fewer bleeding episodes (odds ratio 0.90, 95% confidence interval 0.76 to 1.06) with transition to regional citrate anticoagulation. The micro-costing study indicated that regional citrate anticoagulation was more expensive and was associated with an estimated incremental net monetary loss (step change) of -£2376 (95% confidence interval -£3841 to -£911). The estimated likelihood of cost-effectiveness at 1 year was less than 0.1%. LIMITATIONS: Lack of patient-level treatment data means that the results represent average effects of changing to regional citrate anticoagulation in intensive care units. Administrative data are subject to variation in data quality over time, which may contribute to observed trends. CONCLUSIONS: The introduction of regional citrate anticoagulation has not improved outcomes for patients and is likely to have substantially increased costs. This study demonstrates the feasibility of evaluating effects of changes in practice using routinely collected data. FUTURE WORK: (1) Prioritise other changes in clinical practice for evaluation and (2) methodological research to understand potential implications of trends in data quality. TRIAL REGISTRATION: This trial is registered as ClinicalTrials.gov NCT03545750. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 13. See the NIHR Journals Library website for further project information.

Acute kidney injury, which prevents kidneys from working properly, is common in critically ill patients being treated in an intensive care unit. Patients with acute kidney injury are treated with a machine that takes over kidney functions, a process called continuous renal replacement therapy. Traditionally, as part of continuous renal replacement therapy, heparin (an anticoagulant that stops the blood from clotting) is added to the blood as it enters the continuous renal replacement therapy machine. Recently, citrate anticoagulation (an alternative to heparin) has been increasingly used in intensive care units in the UK. However, the increased use of citrate is happening without evidence that this is better for patients and cost-effective for the NHS. We aimed to find out whether or not changing to citrate anticoagulation for continuous renal replacement therapy is more beneficial than heparin anticoagulation for patients with acute kidney injury treated in an intensive care unit. We also looked at whether or not changing to citrate is cost-effective for the NHS. We used routinely collected data from the Intensive Care National Audit & Research Centre Case Mix Programme national clinical audit to identify 69,001 patients who received continuous renal replacement therapy in an intensive care unit in England or Wales between 1 April 2009 and 31 March 2017. To get a more comprehensive view of the long-term effects of changing to citrate, we 'linked' data from the 69,001 patients together with other routinely collected data sets to get information on their hospital admissions, longer-term kidney problems and survival after leaving the intensive care unit. We combined this information with a survey of anticoagulant use in intensive care units in England and Wales to compare patients who received continuous renal replacement therapy with heparin and citrate. We found that the change to citrate was not associated with a significant change in the death rate at 90 days, but that it was more expensive for hospitals. Our findings suggest that the change to citrate-based anticoagulation may have been premature and should cause clinicians in intensive care units that are still using systemic heparin anticoagulation to pause before making this change.

Renal replacement anticoagulant management: Protocol and analysis plan for an observational comparative effectiveness study of linked data sources.

Acute kidney injury is common in critical illness. In patients with severe acute kidney injury, renal replacement therapy is needed to prevent harm from metabolic and electrolyte disturbances and fluid overload. In the UK, continuous renal replacement therapy (CRRT) is the preferred modality, which requires anticoagulation. Over the last decade, conventional systemic heparin anticoagulation has started being replaced by regional citrate anticoagulation for CRRT, which is now used in approximately 50% of ICUs. This shift towards regional citrate anticoagulation for CRRT is occurring with little evidence of safety or longer term effectiveness. Renal replacement anticoagulant management (RRAM) is an observational comparative effectiveness study, utilising existing data sources to address the clinical and cost-effectiveness of the change to regional citrate anticoagulation for CRRT in UK ICUs. The study will use data from approximately 85,000 patients who were treated in adult, general ICUs participating in the case mix programme national clinical audit between 1 April 2009 and 31 March 2017. A survey of health service providers' anticoagulation practices will be combined with treatment and hospital outcome data from the case mix programme and linked with long-term outcomes from the Civil Registrations (deaths), Hospital Episodes Statistics for England, Patient Episodes Data for Wales, and the UK Renal Registry datasets. The primary clinical effectiveness outcome is all-cause mortality at 90-days. The study will incorporate an economic evaluation with micro-costing of both regional citrate anticoagulation and systemic heparin anticoagulation. Study registration: NCT03545750.

A case of cocaine-induced basilar artery thrombosis.

BACKGROUND: A 40-year-old man presented to an emergency department with slurred speech, diplopia and agitation several hours after cocaine use. His level of consciousness rapidly dropped in the hours following presentation. INVESTIGATIONS: Physical examination, CT scan of the head, cerebral angiography. DIAGNOSIS: Cocaine-induced basilar artery thrombosis. MANAGEMENT: Intra-arterial thombolysis, mechanical clot aspiration, intravenous abciximab, neurointensive care support, rehabilitation at a specialist stroke unit.

Validation of Modelflow Estimates of Cardiac Output in Hemodialysis Patients.

Volume-clamp technology (e.g. Finometer) has become a popular method of collecting continuous, non-invasive, hemodynamic information during hemodialysis. There is minimal data validating the technique in this patient group. A gold standard cardiac output measurement can be obtained using ultrasound dilution in patients with arterio-venous fistulae. Continuous cardiac output was measured in 124 hemodialysis sessions in 27 patients using a volume-clamp device (Finometer PRO). Ultrasound dilution measurement was first taken at baseline (Transonic HD03), then used to calibrate the Finometer. Ultrasound dilution measurement was repeated 2 h into hemodialysis to assess drift following calibration. Pearson's correlation and Bland-Altman statistics, modified for repeated measures, were used to assess agreement between methods. Linear mixed models were constructed to identify factors that could explain session-level and patient-level variation in agreement. For baseline cardiac output before calibration, agreement between volume-clamp and ultrasound dilution measurements was poor, at 25 ± 75% (correlation 0.26, P < 0.001). There was significant variation in agreement between patients, with age, peripheral vascular disease and hemodialysis vintage contributing to poorer agreement. For cardiac output 2 h after calibration, agreement was -5.2 ± 57.5% (correlation 0.6, P < 0.001). Dynamic changes in blood pressure and fluid balance during hemodialysis resulted in greater drift over time after calibration. There was a large error, both random and systematic, in volume-clamp estimates of absolute, pre-calibration cardiac output in this prevalent hemodialysis population. There was minimal bias and reasonable correlation for cardiac output 2 h post-calibration, but limits of agreement remained too wide to meet current clinical standards.

Prognostic value of endocapillary hypercellularity in IgA nephropathy patients with no immunosuppression.

AIM: Interpretation of retrospective clinicopathological studies of IgA nephropathy (IgAN) has been confounded by immunosuppression bias. In published validation studies of the Oxford Classification of IgAN, an average of 33 % of patients received non-randomised steroid and/or cytotoxic therapy. In order to determine the true impact of proliferative lesions on the natural history of IgAN, analysis of patient cohorts that have received no immunosuppression is required. METHODS: We performed a retrospective single centre study of patients with IgAN managed without immunosuppressive therapy. Biopsies were scored according to the Oxford Classification. The primary outcomes were renal survival or a rapid loss of renal function defined as a decline in eGFR of >5 ml/min/year. RESULTS: 237 patients with IgAN were identified with a mean follow-up of 82 months. 200 had biopsies available for review, of which 156 were adequate for scoring using the Oxford Classification. 9/156 patients (5.8 %) received some immunosuppressive therapy, mostly for unrelated conditions: these were excluded. In multivariate COX regression, including histological and clinical data, the only independent predictors of time to ESRD were baseline eGFR (HR 0.96 per ml/min increase, p = 0.018), baseline proteinuria (HR 1.36 per doubling, p = 0.004) and endocapillary hypercellularity (HR 4.75 for E1 compared to E0, p < 0.001). Independent predictors of a rapid decline in eGFR were proteinuria (OR 1.45 per doubling, p = 0.006), endocapillary hypercellularity (OR 3.41 for E1 compared to E0, p = 0.025) and tubular atrophy/interstitial fibrosis (OR 8.77 for T2 compared to T0, p = 0.006). CONCLUSIONS: In a cohort of IgAN patients receiving no immunosuppression, endocapillary proliferation and tubular atrophy/interstitial fibrosis are independent predictors of rate of loss of renal function. The lack of predictive value of E score in other clinicopathological studies is most likely a result of immunosuppression-associated bias. Our findings provide evidence to support immunosuppressive treatment of endocapillary-pattern IgAN.

Circuit life versus bleeding risk: the impact of achieved activated partial thromboplastin time versus achieved filtration fraction.

Whilst prolonging hemofilter (circuit) life, heparin increases bleeding risk. The impact of achieved activated partial thromboplastin time (APTT) on circuit life and bleeding risk has not been assessed in a modern critically ill cohort. Lowering filtration fraction may be an alternative means of prolonging circuit life, but is often overlooked in critical care. An observational study of 309 consecutive circuits in a general intensive care unit was conducted using a wide target APTT range. Multilevel modeling was used to predict circuit life and bleeding according to achieved APTT and filtration fraction. Independent predictors of circuit failure (i.e. unplanned ending of treatment) included filtration fraction (P<0.001, HR 1.07 per 1% increase), peak APTT (P<0.001, HR 0.8 per 10 s increase or 0.3 APTR increase) and baseline PT (P=0.014, HR 0.91 for every 50% increase). The only significant predictor of bleeding was peak APTT (P=0.017, OR 1.05 per 10 s increase). Every 10 s APTT increase was associated with a 20% reduction in circuit failure, but a 5% increase in hemorrhage. A 3% reduction in filtration fraction was associated with the same improvement in circuit life as a 10 s increase in APTT. Increasing APTT prolongs circuit life but carries a substantial risk of bleeding even in modern practice. Filtration fraction has a large impact on circuit life in the critically ill: a 3% reduction in filtration fraction, e.g. by increasing blood flow or delivering some of the clearance via dialysis, would be expected to reduce circuit failure as much as a 10 s increase in APTT.