Nicholas Fluck

Long-term prognosis after acute kidney injury (AKI): what is the role of baseline kidney function and recovery? A systematic review

Objectives To summarise the evidence from studies of acute kidney injury (AKI) with regard to the effect of pre-AKI renal function and post-AKI renal function recovery on long-term mortality and renal outcomes, and to assess whether these factors should be taken into account in future prognostic studies. Design/Setting A systematic review of observational studies listed in Medline and EMBASE from 1990 to October 2012. Participants All AKI studies in adults with data on baseline kidney function to identify AKI; with outcomes either stratified by pre-AKI and/or post-AKI kidney function, or described by the timing of the outcomes. Outcomes Long-term mortality and worsening chronic kidney disease (CKD). Results Of 7385 citations, few studies met inclusion criteria, reported baseline kidney function and stratified by pre-AKI or post-AKI function. For mortality outcomes, three studies compared patients by pre-AKI renal function and six by post-AKI function. For CKD outcomes, two studies compared patients by pre-AKI function and two by post-AKI function. The presence of CKD pre-AKI (compared with AKI alone) was associated with doubling of mortality and a fourfold to fivefold increase in CKD outcomes. Non-recovery of kidney function was associated with greater mortality and CKD outcomes in some studies, but findings were inconsistent varying with study design. Two studies also reported that risk of poor outcome reduced over time post-AKI. Meta-analysis was precluded by variations in definitions for AKI, CKD and recovery. Conclusions The long-term prognosis after AKI varies depending on cause and clinical setting, but it may also, in part, be explained by underlying pre-AKI and post-AKI renal function rather than the AKI episode itself. While carefully considered in clinical practice, few studies address these factors and with inconsistent study design. Future AKI studies should report pre-AKI and post-AKI function consistently as additional factors that may modify AKI prognosis.

Characterization of a Factor H Mutation That Perturbs the Alternative Pathway of Complement in a Family with Membranoproliferative GN

Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.

Prothrombotic changes in platelet, endothelial and coagulation function following hemodialysis.

Purpose Patients on hemodialysis (HD) have an increased risk of thrombotic events, including myocardial infarction and vascular access thrombosis. The study hypothesis is that a single session of dialysis leads to platelet, endothelial & coagulation activation. Our aim is to determine the effect of a single HD session on prothrombotic vascular biomarkers before and after a single session of hemodialysis. Methods Blood samples were taken from the vascular access of 55 patients immediately before and after a hemodialysis session. Platelet function was assessed by (1) flow cytometric measurement of P-selectin expression and fibrinogen binding ± ADP stimulation, (2) Ultegra rapid platelet function assay (RPFA) using the agonists thrombin receptor activating peptide (TRAP) and arachidonic acid (AA), (3) soluble P-selectin, and (4) soluble CD40L. Coagulation (thrombin-antithrombin III [TAT] and D-dimer), endothelial von Willebrand factor (vWF) and high sensitivity C-Reactive protein (hsCRP) were assessed by ELISA. Results Unfractionated heparin was given to all patients during dialysis and 30 patients (55%) were on antiplatelet agents. Post-hemodialysis there were significant increases in unstimulated platelet P-selectin (p=.037), stimulated P-selectin (p<.001), soluble P-selectin (p<.001) and soluble CD40L (p=.036). Stimulated platelet fibrinogen binding was increased post-hemodialysis (p<.001) but unstimulated fibrinogen binding was unchanged. TRAP- (p<.001) and AA-(p=.009) stimulated aggregation were reduced post-hemodialysis. There were increases post-hemodialysis in TAT (p<.001), D-dimer (p<.001), vWF (p<.001) and hsCRP (p=.011). Conclusion This study has shown that despite heparin therapy, a single session of HD induced increases in platelet, endothelial, and coagulation activation. More effective medical strategies to reduce the prothrombotic state of patients on hemodialysis should be investigated.

Chronic kidney disease, a useful trigger for proactive primary care? Mortality results from a large UK cohort

BACKGROUND Much of the emphasis for primary care management of chronic kidney disease (CKD) has focused on cardiovascular risk; however, many patients die of other causes. Aim. In order to guide future primary care management of CKD, we report the causes of death from a large U.K. CKD cohort linked to health care administrative data. DESIGN, SETTING AND METHODS The Grampian Laboratory Outcomes Mortality and Morbidity Study (GLOMMS-1) is a community cohort of people with established CKD, identified in 2003 and followed up for 6 years. Causes of death were available from death certificates. The relative likelihood of different causes of death was compared to the general population. RESULTS When standardized for age and sex, mortality was 4.7 (95% confidence interval 4.5-4.9) times higher in GLOMMS-1 than the general population. Non-cardiovascular diseases accounted for 1076 (50.9%) of deaths, 3.7 times more common than in the age- and sex-matched general population. For those with stages 3 and 4 CKD, without cardiovascular disease at baseline, a non-cardiovascular cause accounted for almost two-thirds of deaths. In those 75 years and older, dementia and falls were among the main non-cardiovascular causes of death. CONCLUSIONS Mortality in those with CKD is high, with non-cardiovascular diseases accounting for more than half of all deaths. While there is evidence that intervention may benefit those at risk of cardiovascular death, most of the non-cardiovascular causes of death identified were not readily amenable to prevention. A mechanism to identify which patients may benefit from intervention to prevent cardiovascular disease or renal disease progression is needed.

Thrombin-Anti-Thrombin Levels and Patency of Arterio-Venous Fistula in Patients Undergoing Haemodialysis Compared to Healthy Volunteers: A Prospective Analysis

Background Patients on haemodialysis (HD) are at an increased risk of sustaining thrombotic events especially to their vascular access which is essential for maintenance of HD. Objectives To assess whether 1) markers of coagulation, fibrinolysis or endothelial activation are increased in patients on HD compared to controls and 2) if measurement of any of these factors could help to identify patients at increased risk of arteriovenous (AVF) access occlusion. Patients/Methods Venous blood samples were taken from 70 patients immediately before a session of HD and from 78 resting healthy volunteers. Thrombin-antithrombin (TAT), D-dimer, von Willebrand factor (vWF), plasminogen activator inhibitor-1 antigen (PAI-1) and soluble p-selectin were measured by ELISA. C-reactive protein (hsCRP) was measured by an immunonephelometric kinetic assay. Determination of the patency of the AVF was based upon international standards and was prospectively followed up for a minimum of four years or until the AVF was non-functioning. Results A total of 70 patients were studied with a median follow-up of 740 days (range 72-1788 days). TAT, D-dimer, vWF, p-selectin and hsCRP were elevated in patients on HD compared with controls. At one year follow-up, primary patency was 66% (46 patients). In multivariate analysis TAT was inversely associated with primary assisted patency (r= -0.250, p= 0.044) and secondary patency (r = -0.267, p= 0.031). Conclusions The novel finding of this study is that in patients on haemodialysis, TAT levels were increased and inversely correlated with primary assisted patency and secondary patency. Further evaluation is required into the possible role of TAT as a biomarker of AVF occlusion.

Platelet activation, coagulation activation and C‐reactive protein in simultaneous samples from the vascular access and peripheral veins of haemodialysis patients

Introduction:  Most studies of haemodialysis (HD) patients compare venous blood samples from controls with samples from the vascular access (VA) of HD patients. We hypothesised that VA samples may be more prothrombotic compared with venous samples.

Antiphospholipid syndrome presenting with acute digital ischaemia, avascular necrosis of the femoral head and superior mesenteric artery thrombus

This case illustrates a rare and unique case of a 73-year-old woman who presents with a rapidly developing digital ischaemia, superior mesenteric artery thrombus with positive-lupus anticoagulant. She then developed avascular necrosis of the femoral head. Discussion of the process of diagnosis and management of antiphospholipid syndrome and catastrophic antiphospholipid syndrome are reported.

Is routine hospital episode data sufficient for identifying individuals with chronic kidney disease? A comparison study with laboratory data

Internationally, investment in the availability of routine health care data for improving health, health surveillance and health care is increasing. We assessed the validity of hospital episode data for identifying individuals with chronic kidney disease compared to biochemistry data in a large population-based cohort, the Grampian Laboratory Outcomes, Morbidity and Mortality Study-II (n = 70,435). Grampian Laboratory Outcomes, Morbidity and Mortality Study-II links hospital episode data to biochemistry data for all adults in a health region with impaired kidney function and random samples of individuals with normal and unmeasured kidney function in 2003. We compared identification of individuals with chronic kidney disease by hospital episode data (based on International Classification of Diseases-10 codes) to the reference standard of biochemistry data (at least two estimated glomerular filtration rates <60 mL/min/1.73 m2 at least 90 days apart). Hospital episode data, compared to biochemistry data, identified a lower prevalence of chronic kidney disease and had low sensitivity (<10%) but high specificity (>97%). Using routine health care data from multiple sources offers the best opportunity to identify individuals with chronic kidney disease.

Pro-thrombotic changes in platelet, endothelial and coagulation function following haemodialysis

Purpose: Patients on hemodialysis (HD) have an increased risk of thrombotic events, including myocardial infarction and vascular access thrombosis. The study hypothesis is that a single session of dialysis leads to platelet, endothelial & coagulation activation. Our aim is to determine the effect of a single HD session on prothrombotic vascular biomarkers before and after a single session of hemodialysis. Methods: Blood samples were taken from the vascular access of 55 patients immediately before and after a hemodialysis session. Platelet function was assessed by (1) flow cytometric measurement of P-selectin expression and fibrinogen binding ± ADP stimulation, (2) Ultegra rapid platelet function assay (RPFA) using the agonists thrombin receptor activating peptide (TRAP) and arachidonic acid (AA), (3) soluble P-selectin, and (4) soluble CD40L. Coagulation (thrombin-antithrombin III [TAT] and D-dimer), endothelial von Willebrand factor (vWF) and high sensitivity C-Reactive protein (hsCRP) were assessed by ELISA. Results: Unfractionated heparin was given to all patients during dialysis and 30 patients (55%) were on antiplatelet agents. Post-hemodialysis there were significant increases in unstimulated platelet P-selectin (p=.037), stimulated P-selectin (p<.001), soluble P-selectin (p<.001) and soluble CD40L (p=.036). Stimulated platelet fibrinogen binding was increased post-hemodialysis (p<.001) but unstimulated fibrinogen binding was unchanged. TRAP- (p<.001) and AA-(p=.009) stimulated aggregation were reduced post-hemodialysis. There were increases post-hemodialysis in TAT (p<.001), D-dimer (p<.001), vWF (p<.001) and hsCRP (p=.011). Conclusion: This study has shown that despite heparin therapy, a single session of HD induced increases in platelet, endothelial, and coagulation activation. More effective medical strategies to reduce the prothrombotic state of patients on hemodialysis should be investigated.

Activated platelets and coagulation in patients on haemodialysis

(→ = +0·56, p = 0·003 and → = +0·38, p < 0·0·001, respectively). RCF had an independent inverse correlation with bk-PWV (→ = −0·01, p = 0·01). Systolic blood pressure showed an independent positive correlation with ba-PWV only after adjustment for other biomarkers (→ = +0·1, p = 0·04). Cholesterol/HDL had an independent inverse correlation with ABPI (→ = −0·08, p = 0·046). There was no significant association between the other biomarkers and ABPI or PWV. Conclusion: Hypercholesterolaemia and hypertension need aggressive treatment in this population. Plasma Hcy and RCF levels correlated well with severity of PAD. They are easily measured markers of disease and provide possible targets for further risk factor modification.