Cardiovascular and renal outcomes following percutaneous coronary intervention in a population with renal disease: a case-control study.

BACKGROUND: Patients with renal disease are less likely to undergo percutaneous coronary intervention (PCI) due to concerns about poor outcomes. AIM: We describe outcomes following PCI in individuals with chronic kidney disease (CKD), as compared with matched controls with comparable CKD who did not undergo PCI. We also identified factors predictive of poor outcomes following PCI amongst patients with CKD. DESIGN: Retrospective observational case-control study. METHODS: Cases were individuals with CKD (stages 1-5) undergoing PCI between 2008 and 2014. Controls were age, gender and creatinine-matched individuals not requiring PCI. We compared mortality between groups using Kaplan-Meier curves and Cox regression modelling. We assessed changes in serum creatinine using Wilcoxon Rank testing. We explored the relationship between biochemical and haematological measures (baseline creatinine, calcium, phosphate, calcium-phosphate product, parathyroid hormone, white cell count, haemoglobin, platelet count, c-reactive protein and total cholesterol) and post-PCI mortality, using logistic regression. RESULTS: We identified 144 cases and 144 controls. Mortality was significantly lower amongst cases compared with controls [hazard ratio 0.46 (95% confidence intervals 0.31, 0.69)]. PCI did not result in a significant change in renal function (P=0.52). Amongst cases, serum creatinine and calcium-phosphate product were predictors of mortality following PCI. CONCLUSION: Cases undergoing PCI had lower mortality, and PCI was not associated with accelerated CKD progression. On this data, PCI should not be deferred as a treatment option in patients with CKD. Serum creatinine and calcium-phosphate product predict mortality following PCI in this cohort, and may be useful in risk-stratifying patients with CKD being considered for PCI.

Y-box protein-1 controls transforming growth factor-beta1 translation in proximal tubular cells.

Transforming growth factor-beta1 (TGF-beta1) mRNA has low basal translational efficiency in proximal tubule cells; however, its translation is stimulated by profibrotic cytokines. We studied the role of the multifunctional Y-box protein-1 (YB-1) in regulating proximal tubule cell TGF-beta1 translation. Using RNA-electrophoretic mobility shift assays and ultraviolet crosslinking, we found two protein complexes of 50 and 100 kDa, which bound to the TGF-beta1 mRNA 5'-untranslated region. Supershift studies using antibodies to YB-1 showed that both sites contained YB-1 as did studies with recombinant YB-1, which demonstrated that it was sufficient to form both complexes. RNA competition experiments confirmed YB-1 binding to the two predicted binding sites; one with high affinity and the other with lower affinity. Strong basal YB-1 association with TGF-beta1 mRNA was found in proximal tubule cells, which decreased when platelet-derived growth factor was used to activate TGF-beta1 translation. In contrast, knockdown of proximal tubule cell YB-1 expression abrogated TGF-beta1 synthesis. Our results suggest that TGF-beta1 translation in proximal tubule cells requires YB-1 binding to a high-affinity site in the 5'-untranslated region of its mRNA; however, binding to a low-affinity site inhibits basal translation.

Adding a new dimension to the weekend effect: an analysis of a national data set of electronic AKI alerts.

BACKGROUND: Increased mortality related to differences in delivery of weekend clinical care is the subject of much debate. AIM: We compared mortality following detection of acute kidney injury (AKI) on week and weekend days across community and hospital settings. DESIGN: A prospective national cohort study, with AKI identified using the Welsh National electronic AKI reporting system. METHODS: Data were collected on outcome for all cases of adult AKI in Wales between 1 November 2013 and 31 January 2017. RESULTS: There were a total of 107 298 episodes. Weekday detection of AKI was associated with 28.8% (26 439); 90-day mortality compared to 90-day mortality of 31.9% (4551) for AKI detected on weekdays (RR: 1.11, 95% CI: 1.08-1.14, P < 0.001, HR: 1.16 95% CI: 1.12-1.20, P < 0.001). There was no 'weekend effect' for mortality associated with hospital-acquired AKI. Weekday detection of community-acquired AKI (CA-AKI) was associated with a 22.6% (10 356) mortality compared with weekend detection of CA-AKI, which was associated with a 28.6% (1619) mortality (RR: 1.26, 95% CI: 1.21-1.32, P < 0.001, HR: 1.34, 95%CI: 1.28-1.42, P < 0.001). The excess mortality in weekend CA-AKI was driven by CA-AKI detected at the weekend that was not admitted to hospital compared with CA-AKI detected on weekdays which was admitted to hospital (34.5% vs. 19.1%, RR: 1.8, 95% CI: 1.69-1.91, P < 0.001, HR: 2.03, 95% CI: 1.88-2.19, P < 0.001). CONCLUSION: 'Weekend effect' in AKI relates to access to in-patient care for patients presenting predominantly to hospital emergency departments with AKI at the weekend.

The influence of socioeconomic status on presentation and outcome of acute kidney injury.

AIM: Although socioeconomic background is known to impact on the incidence and progression of chronic kidney disease, its influence of on the presentation and outcome for acute kidney injury is not known and is the subject of this study. DESIGN: The Welsh National electronic AKI reporting system was used to identify all cases of AKI in patients >18 years of age between March 2015 and November 2017. METHODS: Socioeconomic classification of patients was derived from the Welsh Index Multiple Deprivation score (WIMD). Patients were grouped according to the WIMD score by their postcode, and the ranked data were categorized into percentiles and correlated with incidence and measures of AKI severity and outcome. RESULTS: Date was collected on a total of 57 654 patients. Increased deprivation was associated with higher AKI incidence rates, more episodes of AKI per patient and more severe AKI at presentation. In contrast 90-day mortality was highest in the most affluent areas. Mortality in affluent areas was driven by increased patient age. Corrected for age 90-day mortality was higher in areas of increased deprivation. CONCLUSION: This study highlights that AKI incidence presentation and outcomes are adversely affected by social deprivation. Further studies are required to understand the extent to which these differences reflect patient related factors or regional differences in provision and access to care.

Community acquired acute kidney injury: findings from a large population cohort.

BACKGROUND: The extent of patient contact with medical services prior to development of community acquired-acute kidney injury (CA-AKI)is unknown. AIM: We examined the relationship between incident CA-AKI alerts, previous contact with hospital or primary care and clinical outcomes. DESIGN: A prospective national cohort study of all electronic AKIalerts representing adult CA-AKI. METHODS: Data were collected for all cases of adult (≥18 years of age) CA-AKI in Wales between 1 November 2013 and 31 January 2017. RESULTS: There were a total of 50 560 incident CA-AKI alerts. In 46.8% there was a measurement of renal function in the 30 days prior to the AKI alert. In this group, in 63.8% this was in a hospital setting, of which 37.6% were as an inpatient and 37.5% in Accident and Emergency. Progression of AKI to a higher AKI stage (13.1 vs. 9.8%, P < 0.001) (or for AKI 3 an increase of > 50% from the creatinine value generating the alert), the proportion of patients admitted to Intensive Care (5.5 vs. 4.9%, P = 0.001) and 90-day mortality (27.2 vs. 18.5%, P < 0.001) was significantly higher for patients with a recent test. 90-day mortality was highest for patients with a recent test taken in an inpatient setting prior to CA-AKI (30.9%). CONCLUSION: Almost half of all patients presenting with CA-AKI are already known to medical services, the majority of which have had recent measurement of renal function in a hospital setting, suggesting that AKI for at least some of these may potentially be predictable and/or avoidable.

Acute kidney injury electronic alerts in primary care - findings from a large population cohort.

BACKGROUND: Electronic reporting of AKI has been used to aid early AKI recognition although its relevance to CA-AKI and primary care has not been described. AIMS: We described the characteristics and clinical outcomes of patients with CA-AKI, and AKI identified in primary care (PC-AKI) through AKI e-Alerts. DESIGN: A prospective national cohort study was undertaken to collect data on all e-alerts representing adult CA-AKI. METHOD: The study utilized the biochemistry based AKI electronic (e)-alert system that is established across the Welsh National Health Service. RESULTS: 28.8% of the 22 723 CA-AKI e-alerts were classified as PC-AKI. Ninety-day mortality was 24.0% and lower for PC-AKI vs. non-primary care (non-PC) CA-AKI. Hospitalization was 22.3% for PC-AKI and associated with greater disease severity, higher mortality, but better renal outcomes (non-recovery: 18.1% vs. 21.6%; progression of pre-existing CKD: 40.5% vs. 58.3%). 49.1% of PC-AKI had a repeat test within 7 days, 42.5% between 7 and 90 days, and 8.4% was not repeated within 90 days. There was significantly more non-recovery (24.0% vs. 17.9%) and progression of pre-existing CKD (63.3% vs. 47.0%) in patients with late repeated measurement of renal function compared to those with early repeated measurement of renal function. CONCLUSION: The data demonstrate the clinical utility of AKI e-alerts in primary care. We recommend that a clinical review, or referral together with a repeat measurement of renal function within 7 days should be considered an appropriate response to AKI e-alerts in primary care.

A new antibody capture enzyme linked immunoassay specific for transforming growth factor beta 1.

Previous studies which examined Transforming Growth Factor beta 1 (TGF-beta 1) generation have relied on the identification of TGF-beta 1 mRNA or measurement of TGF-beta 1 by bioassay. Quantitation of TGF-beta 1 message alone however is inadequate since the regulation of TGF-beta 1 synthesis is often post-transcriptional. TGF-beta 1 is poorly immunogenic, and sensitive and specific immunoassays for this peptide have proved difficult to develop. Bioassays depend on stimulation or inhibition of cell proliferation in a TGF-beta 1 dependent manner, and are very rigid in their requirements for optimal performance. The aims of this work was therefore to develop a sensitive and reproducible immunoassay for TGF-beta 1. Microtitre plates were coated with human recombinant TGF-beta 1, unbound protein was discarded from the wells prior to blocking with bovine serum albumin. Chicken anti-human TGF-beta 1 antibody was incubated with the test solution overnight at 4 degrees C and then added to the coated wells. Bound antibody was detected with alkaline phosphatase conjugated anti-chicken antibody. The assay is sensitive to 0.2 ng/ml with a range to 100 ng/ml. The assay detects the mature form of human recombinant TGF-beta 1, natural platelet extracted TGF-beta 1, and TGF-beta 1 derived from human monocytes stimulated with Phorbol myristate acetate (PMA). Active TGF-beta 1 is measured directly and latent TGF-beta 1 can be measured indirectly following acid activation of samples. Inter-assay precision ranged from 4.3 to 9.6%, (coefficient of variation, %CV) and intraassay precision ranged from 2.8 to 8.6% (CV).(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of renal proximal tubular epithelial cell fibroblast growth factor-2 generation by heparin.

Progression of renal disease is closely correlated to the degree of renal interstitial fibrosis, and evidence is increasing that epithelial cells of the renal proximal tubule (PTCs) may contribute to its pathogenesis. Such cytokines as basic fibroblast growth factor (FGF-2) have been implicated in progressive renal injury, and we previously showed that PTCs are a source of this cytokine. FGF-2 is characterized by its high affinity for heparin, and numerous studies have suggested that heparin may modify the progression of renal disease. The current study examined how heparin influenced FGF-2 generation and bioactivity in the human renal epithelial PTC line, HK-2. Incubation of HK-2 cells with heparin led to a dose- and time-dependent increase in FGF-2 concentration in the culture supernatant that was not accompanied by alterations in FGF-2 messenger RNA expression, assessed by reverse-transcriptase polymerase chain reaction and Northern analysis. The heparin-induced increase in FGF-2 concentration was accompanied by a decrease in the amount of FGF-2 bound to the extracellular matrix, although this accounted for only a small proportion of the total FGF-2 generated. Induction of FGF-2 by 2-O-desulfated heparin, together with a reduction in total cell-associated FGF-2 and anti-FGF-2 antibody binding to fixed permeabilized cells after the addition of heparin, suggested that the FGF-2 released was mainly derived from a preformed intracellular source. That FGF-2 was predominantly derived from an intracellular pool was also confirmed by pulse chase experiments. The addition of heparin resulted in the generation of bioinactive FGF-2, judged by in vitro fibroblast proliferation. Conversely, heparitinase treatment of supernatant samples from heparin-treated cells and the addition of 2-O-desulfated heparin resulted in the generation of active FGF-2, suggesting that the generation of bioinactive FGF-2 was related to binding of FGF-2 by extracellular heparin after its release from cells. These data show that heparin depletes both the cell and surrounding matrix of FGF-2 and suggest that FGF-2 released from cells was mainly derived from a preformed intracellular source. Furthermore, FGF-2 released from epithelial PTCs after the application of heparin was bioinactive. This likely resulted from released FGF-2 binding to an excess of extracellular heparin. Results presented here therefore suggest a mechanism by which heparin, through its effect on depletion of matrix and cells of FGF-2 and its generation in an inactive form, may influence progressive renal interstitial fibrosis.

Association of prolonged hyperglycemia with glomerular hypertrophy and renal basement membrane thickening in the Goto Kakizaki model of non-insulin-dependent diabetes mellitus.

The aim of the current study was to characterize the effects of prolonged hyperglycemia on renal structure and function using a model of non-insulin-dependent diabetes mellitus: the Goto Kakizaki (GK) rat, which does not have confounding variables, such as hyperlipidemia, obesity, or elevated blood pressure. The data show that hyperglycemia in this model was not associated with the development of significant proteinuria, but it was associated with the development of definitive age-dependent renal structural changes. These changes consisted of thickening of glomerular basement membrane at 35 weeks and tubular basement membrane. This thickening was accompanied by marked glomerular hypertrophy resulting from a parallel increase in total capillary luminal volume and mesangial volume, but fractional capillary and mesangial volumes remained unchanged. There was evidence of podocyte injury, as assessed by de novo expression of desmin. In contrast, there was no evidence of mesangial cell activation, as assessed by their de novo expression of alpha-SMA. Interstitial monocyte/macrophage influx increased significantly in GK rats at 12 weeks compared with Wistar controls. Glomerular macrophage infiltration was elevated significantly in 35-week GK rats. The structural changes described in the GK rat are similar to those described in prolonged non-insulin-dependent diabetes mellitus patients who have not developed overt renal disease. This model allows us to investigate further the mechanisms involved in the pathogenesis of the consequences of prolonged hyperglycemia.

Diabetic nephropathy: the modulating influence of glucose on transforming factor beta production.

Diabetes in now the commonest cause of renal failure in the western world. Furthermore the survival of diabetic patients requiring dialysis treatment for renal failure is far less than patients with renal failure secondary to all other diseases. It is therefore important to identify the factors that control the development of progressive renal disease to allow targeted therapeutic interventions which would have major implications both to patient well-being and also to the provision of health care world wide. In this review we discuss possible metabolic consequences of hyperglycemia and their role in the pathogenesis of diabetic nephropathy. We also focus on the involvement of the pro-fibrotic cytokine Transforming Growth Factor beta, and contrast its role in the pathogenesis of glomerular and tubulo-interstitial changes seen in diabetic nephropathy.

Diabetic nephropathy: the central role of renal proximal tubular cells in tubulointerstitial injury.

Diabetic nephropathy is now the commonest cause of end stage renal disease and accounts for 30-40% of all patients requiring renal replacement therapy. Furthermore, the incidence of diabetic nephropathy continues to increase, in part due to the improved survival of type 2 diabetic patients as the cardiovascular mortality in this group declines (Ritz and Stefanski, 1996). Clinically incipient nephropathy is first manifest by the onset of persistent microalbuminuria, after which, overt diabetic nephropathy is heralded by the appearance of persistent proteinuria. Subsequently, there is a progressive decline in glomerular filtration rate (GFR) resulting, within 5 years, in end stage renal disease in 50% of patients (Hasslacher et al., 1989). The pathology of the renal lesions are similar in type I and II diabetes (Taft et al., 1994), although it has been suggested that there is more heterogeneity in type II diabetes (Chihara et al., 1986). Studies analysing structural-functional relationships have demonstrated that the development of proteinuria correlates with the degree of mesangial expansion (Mauer et al., 1984; White and Bilous, 2000). Although diabetic nephropathy was traditionally considered a primarily glomerular disease, it is now widely accepted that the rate of deterioration of function correlates best with the degree of renal tubulointerstitial fibrosis (Mauer et al., 1984, Bohle et al., 1991). This suggests that although in the majority of patients the primary event is a condition manifest by glomerular changes resulting in proteinuria, the long-term outcome is determined by events in the renal interstitium. With the increasing awareness of the importance of these pathological interstitial changes, interest has focused on the role of cells, such as the epithelial cells of the proximal tubule (PTC) or the interstitial myofibroblast, in the initiation of fibrosis. The aim of the present review is to analyse the available data supporting the role for the PTC in orchestrating renal interstitial fibrosis in diabetic nephropathy as a result of glucose-dependent alterations in PTC function. The potential for subsequent effects on PTC-fibroblast cross-talk will also be considered.

Rodent models of nephropathy associated with type II diabetes.

End-stage renal disease from diabetic nephropathy, mainly due to type II diabetes, is an increasing problem in Western countries. The pathogenesis of diabetic nephropathy is still incompletely understood and much of the experimental insight has been obtained from insulinopenic animal models, resembling type I diabetes. This review therefore aims to describe available rodent models of nephropathy associated with type II diabetes. The review focusses on the metabolic as well as renal functional and structural changes. The usefulness of these rodent models to study renal involvement in type II diabetes is discussed with particular emphasis on confounding factors such as hyperlipidemia, hypertension, immunologic abnormalities, urogenital structural abnormalities and other associated pathological conditions. In addition recent observations on two rat strains, the obese Zucker (fatty) and Goto Kakizaki (GK) rat, are discussed in detail.

Acute renal failure associated with non-fulminant hepatitis A.

A 49-year-old man developed acute renal failure as a complication of non-fulminant hepatitis A. This is a rare association of uncertain etiology.

The influence of recipient and donor age on the outcome of renal transplantation.

This paper assesses the impact of age on the outcome of cadaveric renal transplantation. Data are presented on 99 consecutive patients undergoing first renal allografts at one unit. Patients are divided into those aged less than 50 (n = 53), patients between 50 and 60 (n = 16), and those aged 60 years and over (n = 30). There was no significant difference in graft survival at one year between the three groups. There was however an increased mortality with increasing recipient age (1.9%, 12.5% and 20.0% respectively for each age group). The effect of increasing donor age on graft survival was also studied. Graft survival at two years for first grafts was not influenced by donor age. We conclude that age alone is not a criterion for exclusion of patients from transplant programs. In addition we provide data to support the use of elderly donors as a potential source of cadaveric renal grafts for certain patients.

The long-term impact of eGFR reporting on referral patterns.

BACKGROUND: The prognostic significance of CKD has driven the widespread introduction of automated estimated glomerular filtration rate (eGFR) reporting, and the incorporation of CKD in the revised Quality Outcomes Framework (QOF) of the General Medical Services (GMS) contract in the U.K. AIMS: To assess the long-term impact of the introduction of these two initiatives, on patient referral numbers to a nephrology service. METHODS: Data was collected on the numbers and basic characteristics of all new patients referred from April 2005 to March 2011, to one NHS Health Board. RESULTS: Introduction of eGFR reporting and CKD QOF domains was associated with a significant increase in the number of referrals, which was sustained. The initiatives also led to a sustained increase in the mean age of the patients at referral, predominantly due to an increase in the age of female patients referred. There was also an increase in the proportion of female patients referred. In the immediate aftermath of the introduction of change there was a transient decrease in the average eGFR at referral, a decrease in age of patients referred with an eGFR <15ml/min and an increase in the eGFR of patients >70yrs of age. CONCLUSIONS: The data demonstrates significant and sustained increase in numbers of referrals. In the short term this was associated with a reduction in referral of elderly patients with stage 5 CKD and an increase in elderly patients with mild renal impairment. In the longer term we saw an increase in referral of an older female population.

Severe hyperkalaemia: demographics and outcome.

BACKGROUND: Few studies have evaluated the prevalence of severe hyperkalaemia in unselected patient populations. We identified all episodes of severe hyperkalaemia occurring in 1 year, and described patient demographics, clinical response and outcome. We also assessed junior doctor knowledge of its causes and significance. MATERIALS AND METHODS: A retrospective interrogation of the database of the regional biochemical laboratory identified all episodes of severe hyperkalaemia (K≥ 6.5 mmol/L) occurring in 2011. The understanding of trainee doctors of the importance, causes and treatment of severe hyperkalaemia was assessed by structured questionnaire. RESULTS: Severe hyperkalaemia was recorded in 433 samples (365 patients) giving a prevalence of 0.11%. Thirty-six per cent of episodes occurred in patients under the care of a nephrologist, who were significantly younger than those not under the care of a nephrologist. In the nephrology cohort, 86% occurred in patients with chronic kidney disease (CKD), the majority of which had CKD Stage 5. In the non-nephrology cohort, only 65% occurred in the context of CKD, which was equally distributed between Stages 3 and 5 CKD. In both patient groups, roughly 50% of episodes occurred in association with acute kidney injury (AKI). Acute mortality (death within 48 h of documented severe hyperkalaemia) was higher in the non-nephrology compared with the nephrology cohort. Time to repeat serum potassium was influenced by the clinical setting with shorter time to repeat for acute care compared with ward settings. Assessment of trainee doctor's knowledge suggested significant deficiencies in relation to severe hyperkalaemia. CONCLUSIONS: The prevalence of severe hyperkalaemia was low and occurred predominantly in the context of CKD and/or AKI. The majority of episodes occurred in patients not under the care of a nephrologist. Variability in time to repeat serum potassium levels suggested deficiencies in care, and assessment of trainee doctor's knowledge suggests the need for further educational initiatives to highlight its importance.

Applying estimated glomerular filtration rate to an ageing population: are we in danger of becoming ageist?

BACKGROUND: Management of CKD is a major public health concern. The introduction of automated eGFR reporting has seen an increase in labelling of elderly patients with CKD. The prognostic significance of the CKD label in this population remains controversial. AIM: To investigate rates of specialist intervention in the over 75's to determine whether these patients may be more appropriately managed in primary care, relieving the burden of excessive outpatient visits in this population. METHODS: Retrospective review of patient notes and laboratory reports over 25 consecutive renal outpatient clinics within a single NHS trust. RESULTS: 546 patients were studied. The mean age of patient was 68.7 years (SD+/-14.9). The over 75's had more advanced renal disease compared to under 75's (mean eGFR 28.2 vs. 41.3 ml/min/1.73 m(2)), but there was no significant difference in eGFR stability between the older and younger cohort or in the overall rate of intervention (32.5% vs. 30.7% p=0.86). The over 75's had a lower mean haemoglobin (11.8 vs. 12.6, p=<0.001) necessitating greater EPO requirements (25.2% vs. 10.5%, p=<0.001). The greatest intervention was seen in the more advanced CKD patients (29% of CKD 3 vs. 55% of CKD 5), and in those with diagnoses requiring immunosuppression. CONCLUSION: Intervention to management may be predictable on the basis of specific diagnoses and advancing CKD stage but not by patient age. We can provide no evidence to suggest that elderly CKD patients are managed any differently to younger patients and in fact have a higher need for attention to and treatment of renal anaemia, validating their attendance in nephrology clinic.

Impact of chronic kidney disease management in primary care.

BACKGROUND: The introduction of eGFR reporting and publication of national CKD guidelines has led to major challenges in primary and secondary care, leading to an increase in the number of referrals to nephrology clinics. We have shown that introduction of a renal patient care pathway reduces nephrology referrals and enables managed discharges of CKD patients to primary care. The aim of this article is to examine the outcome of patients discharged to primary care to find out if there is an associated risk with increased discharge supported by the patient pathway. METHODS: The study was carried out within a single NHS Trust covering a population of 560,000. All patients discharged from the trust's renal outpatient clinic between June 2007 and July 2008 were identified. Patient notes and the local laboratory database systems were used to determine the source and timing of tests. RESULTS: A total of 31 new referrals and 57 regular follow-ups were discharged during this period. The median age of discharge was 67.5 years. Most subjects (60%) had CKD stage 3 at the time of discharge. A total of 23% of discharges were categorized as CKD stages 1, 2 or normal and 17% of patients had CKD stage 4. Overall, 93% had stable eGFRs prior to discharge, 77.5% of patients had blood pressure within threshold (140/90 according to UK CKD guidelines) and 97.7% of patients had haemoglobins >10 g/dl. Post-discharge 83% of patients had eGFRs recorded by their general practitioner and 92.6% of these were measured within appropriate time frames as per CKD guidelines. The majority of patients (82%) had either improved or stable eGFR post-discharge and only three patients had a significant decline in their eGFR. CONCLUSION: These data indicate that selected CKD patients can be appropriately discharged from secondary care and adequately monitored in primary care. Furthermore, we have shown that this was a safe practice for patients.