The Link Between Endothelial Function and Proteinuria in Patients with Primary Glomerulonephritis.
Bruce Mackinnon1, Christopher J Deighan, 1 Naveed Sattar 2,
Michael Boulton-Jones 1 Jonathan G Fox 1
1 Renal Unit, Glasgow Royal Infirmary. 2 Department of Pathological Biochemistry, Glasgow Royal Infirmary
Introduction. The increased incidence of cardiovascular mortality is well established in patients with end stage renal disease (ESRD). The magnitude of the increase in risk is unlikely to be explained by traditional risk factors for cardiovascular disease alone. Proteinuria itself may constitute an additional risk factor, and proteinuric patients are known to have a degree of endothelial dysfunction. Whether proteinuria directly influences endothelial function, or whether there is an intermediate pathogenetic factor, is the subject of intense investigation.
Aim. The aim of this study was to examine the relationship between proteinuria and endothelial dysfunction, as reflected by serum von Willebrand factor (vWF), and the soluble cell adhesion molecules VCAM and ICAM, in patients with primary glomerulonephritis (GN). A secondary aim was to discern whether any relationship could be explained on the basis of differences in renal function, lipid profile, inflammation or blood pressure.
Methods A cross-sectional study was undertaken in consecutive patients attending a general nephrology clinic with biopsy proven primary GN. Patients with ESRD, those on immunosuppressive drugs, or with intercurrent infective illnesses were excluded. Blood pressure, and body mass index were recorded. Routine lab assays were undertaken for serum creatinine, lipid profile, and 24-hour urinary protein (QP). Extra serum samples were stored at –80oC, to be thawed in batches for measurement of vWF, VCAM, ICAM, and sensitive C reactive protein (sCRP).
Results. Data were collected from 129 (86 male) patients. Mean ( SD) estimated creatinine clearance was 64 ( 32) ml/min, and median (IQ range) 24 hour proteinuria was 1.1g (0.22g-2.9g). Mean vWF, VCAM and ICAM were 173 ( 68) IU/dl, 594 ( 262) ng/ml and 262 ( 101) ng/ml respectively and median sCRP was 2.33 (0.83-5.68) mg/l. There was a significant positive correlation between vWF and QP (R = 0.41, p<0.001). When split into 4 groups, according to QP (0-300mg, 300-1000mg, 1000-3000mg, and >3000mg), there was a significant, stepwise increase in mean vWF (F=31, p<0.001), VCAM (F=21, p<0.001), and ICAM (F=9, p=0.004). On multivariate analysis with vWF as the continuous dependent variable, QP, age, and total cholesterol were the only significant independent correlates (model adjusted R2 = 0.33, p < 0.001).
Discussion. In patients with primary GN, there is a significant linear trend towards worse endothelial function as reflected by either vWF, VCAM, or ICAM as proteinuria increases. Endothelial function, as reflected by serum vWF, is independently correlated with total proteinuria, age, and total cholesterol. This relationship is independent of differences in renal function, inflammation, or blood pressure.
Improvement of the haemodynamic derangement in hepatorenal syndrome with albumin dialysis
S.H.Lambie1,3, J.G.Freeman2, T Bennett3, and C.W.McIntyre1,3, Department of Renal Medicine1 and Dept. of Gastroenterology2, Derby City General Hospital, and Centre for Integrated Systems Biology and Medicine3 (Nottingham University)
The systemic haemodynamic changes observed in hepatorenal syndrome are dominated by arteriolar dilatation, presumed to be a consequence of translocation of endotoxins across the intestinal membrane. This results in low systemic vascular resistance, high cardiac output and consequent systemic hypotension.
Therapy for hepatorenal syndrome using the Molecular Adsorbents Recirculating System (MARS) is becoming an increasingly well recognised and effective treatment. In this system blood is circulated through a hollow fibre dialyser (MARS flux) that allows water-soluble solutes to diffuse across the membrane, or lipophilic and protein bound solutes to be adsorbed onto it. A washing solution of 20% albumin is circulated through the dialysate compartment. This exploits the kinetics of protein binding and provides the driving force for the removal of ‘hepatic toxins’. The albumin is then recirculated in a closed circuit, where it is regenerated on-line by deligandisation. This is achieved by passing the albumin through two adsorption columns (diaMARS) and a standard kidney dialyser.
The aim of this study was to assess whether systemic detoxifixation using MARS therapy resulted in improvement in systemic haemodynamics. We used the Finometer to study the haemodynamic response to MARS therapy for acute hepatorenal syndrome over 3 sessions. The Finometer uses a system of continuous non-invasive pulse-wave analysis. This technology employs the finger-clamp method, in which changes in digital arterial diameter are detected by means of an infrared photoplethysmograph and opposed by an ultra-fast pressure servo controller that changes pressure in an inflatable air bladder, with both mounted in a finger cuff. Pulse wave analysis of the resultant arterial waveform allows calculation of a wide variety of haemodynamic variables. The Finometer was applied for 10 minutes prior to MARS therapy, 8 hours of therapy and 1 hour post therapy
In these three sessions Cardiac Output fell to a nadir of 78% of the initial value, while Total Peripheral Resistance rose to maximum of 146 % of the initial value. Systolic and diastolic BP improved slightly with therapy (by 8% and 13% respectively). In contrast with HD there was no significant rebound in CO and TPR in the hour following therapy. The Bilirubin Reduction Ratio was 29% (range 22-42%).
In conclusion MARS therapy for acute hepatorenal syndrome is associated with a significant and sustained improvement in the systemic haemodynamic disturbance associated with this condition, and the Finometer is a useful tool with which to study these changes.
BK virus nephropathy in a renal transplant recipient on sirolimus, tacrolimus and prednisolone.
Andrew Henderson1, Abeed Pall1, Paul McIntyre2, Steve Lang3, Stewart Fleming3
1-Renal Unit, Ninewells Hospital, Dundee 2- Department of Virology, Ninewells Hospital, Dundee 3-Department of Pathology ,Ninewells Hospital, Dundee
Polyoma BK virus is now recognised as a significant cause of transplant dysfunction. The prevalence of BK nephropathy (BKN) has increased in the last several years and is reported in up to 5 % of allograft biopsies. The exact reason for this increase is not clear but is thought to be related to the use of more potent immunosuppressive regimens.
We describe a patient who developed BKN while on sirolimus, tacrolimus and prednisolone. The diagnosis was based on seropositivity, detection of BK virus DNA in urine and plasma and typical viral inclusions on histology. Management was aimed at reducing the total immunosuppression with the initial discontinuation of sirolimus and reduction of tacrolimus dose. With the continued decline in allograft function and histological evidence of progressive BKN along with persistently high viral load, the regimen was switched to a cyclosporin and prednisolone.
This is the second report of a patient developing BKN on treatment with sirolimus and as far as we are aware the first in a patient on sirolimus and tacrolimus combination.
ENHANCEDBETA-2-MICROGLOBULIN (ß2-m) ELIMINATION AND RESTRICTED ALBUMIN LOSS BY THE NEW FX-CLASS OF DIALYSERS DIFFERENT DIALYSER DURING ON-LINE HAEMODIAFILTRATIONSudhir K. Bowry 1 Peter Ahrenholz 3, Roland E. Winkler 2, Ann Michelsen 2 3 BioArtProducts GmbH, Rostock, Germany ; 2 Dialyse-Gemeinschaft Nord e.V., Rostock, Germany and 1 Fresenius Medical Care, Bad Homburg, Germany .
Contemporary haemodialysis therapy modalities such as on-line haemodiafiltration (HDF) strive to enhance the removal of large-molecular weight uraemic solutes from the blood of patients with end-stage renal disease (ESRD). The recent proliferation of synthetic high-flux membranes, having highly variable structural and performance characteristics, necessitates an assessment of the precise sieving properties of the different high-flux dialysers with respect to their elimination of large-molecular weight uraemic solutes (such as ß2-m) as well as to their leakage of essential proteins such as albumin.
In a prospective, cross-over study 3 ESRD patients were treated with 8 different high-flux membrane / dialyser types at different fluid substitution flow rates (i.e. Qs of 0, 30, 60, 90 ml/min; total of 96 treatments): FX60 (Fresenius Medical Care), BS-1.3U (Toray), BLS814G (Bellco), FLX15GW (Nikkiso), APS-650 (Asahi), Polyflux14S (Gambro), H4 (Cobe/Hospal), Tricea CT150G (Baxter/Nipro). Albumin loss (Malb) and ß2-m removal were measured from the total dialysate collected as well as from samples collected continuously during the treatment. ß2-m removal rates (RRß2M) were measured from plasma samples taken pre- and post-treatment. ß2m whole-blood clearance data were calculated from arterial and venous concentrations obtained under HDF mode conditions (blood flow 300 ml/min, total UFR = weight loss UFR + Qs).
Albumin loss and RR-ß2-m at UFR = 90 ml/min (calculated from regression curves):
Dialyser: BS-1.3U
APS650S
FX60
BLS814GH4
PF14S
TCA150G
FLX15GWS
RR ß2-m [%] 76
73
73
70
67
67
50
50
Malb[mg/4h] 7054
3718
1992
6873
1710
975
3275
382
The albumin loss was strongly dependent on UFR and time; the ß2-m clearance increased linearly with increasing UFR.
Only four dialyser types provided ß2-m removal above the 70 % threshold value (deemed as high ß2-m RR). However, of these, three dialyser types caused an albumin leakage well above the 2g / treatment threshold value; only the FX60 dialyser type caused lower albumin leakage (1992 mg/4h), thereby providing the optimal ß2-m removal / albumin loss balance. Other dialyser types showing albumin leakage < 2 g/4h, were nevertheless considerably less efficient in their ß2-m removal characteristics.
Thus, modern dialyser membranes intended for high-flux / convective treatment modalities (e.g. HDF) vary markedly in terms of their efficiency to remove uraemic toxins such as ß2-m while simultaneously restricting the inadvertent loss of useful proteins such as albumin. Only the FX-class of dialysers provided the controlled balance between high elimination rates of large solutes and low albumin leakage. This balance is attributed to the unique, nano-controlled fine structure of the Helixone® membrane within the FX-class of dialysers.
Pure red cell aplasia associated with erythropoietin therapy in the UK
Anna Thompson1, Iain Macdougall2, Judith Marsh3, and A. Neil Turner1
1 Renal Medicine, Royal Infirmary of Edinburgh, and the Renal and Autoimmunity Group, Centre for Inflammation, University of Edinburgh
2 Renal Unit, King’s College Hospital, London
3 Dept Haematology, St George’s Hospital, London.
A cluster of cases of pure red cell aplasia (PRCA) has been noted in patients with chronic renal failure treated by erythropoietin (EPO) in Europe since 1998. Investigation showed it to be due to autoantibody formation that neutralised endogenous EPO as well as the recombinant therapeutic product.
We obtained extensive clinical data on 20 strictly-defined cases occurring in Scotland, England and Wales by visiting host units and scrutinising case records. 19 were male and their median age was 76.5 years (range 29-80). Eleven were receiving haemodialysis, 6 peritoneal dialysis, and 3 were pre-dialysis. All had received erythropoietin alfa by the subcutaneous route. Most were elderly men and most had other significant diseases. There was no discernible association with renal or other diagnosis, other drugs received, or other factors. In 5 patients, PRCA had recovered by the beginning of 2003. Three patients had died. 12 remained transfusion-dependent. Various immunusuppressive agents were administered. There was no clear association between any particular treatment and rapid or slow recovery.
The cause of the outbreak remains unproven but it was temporally associated with a formulation change for erythropoietin alfa. Our survey supports the continued safety of intravenous administration of erythropoietin alfa and does not suggest that other types of recombinant erythropoietin have experienced any recent change in the incidence of this rare complication.
Similar experiences have been recorded with other recombinant products, but generally recombinant erythropoietin has been associated with a very low rate of antibody formation. These experiences reduce the likelihood that generic preparations of recombinant products will lead to rapid cost-savings after the expiry of relevant patents.
Living donor kidney transplantation – variation in practice throughout the United Kingdom
J A Lumsdaine, S J Wigmore, M Akyol, J L R Forsythe
Transplant Unit, Royal Infirmary of Edinburgh
The development of guidelines by the British Transplantation Society/Renal Association in 2000 should assist clinicians in designing boundaries of acceptable practice in living donor kidney transplantation. Eighteen months after the publication of these guidelines, this study examined the donor assessment protocols, acceptability criteria and follow-up procedures throughout the UK.
Method: The 25 transplant centres performing living donor kidney transplantation were sent a structured questionnaire. All 25 centres responded.
Results: An independent medical assessor reviews potential live related donors in nine of the 25 centres, with three centres routinely referring both living related and unrelated donors to a psychologist. Twenty centres would consider paired exchange, and fifteen non-directed donation in the future, pending legal agreement. Eleven centres routinely perform differential renal function scans. Ten centres always perform the donor and recipient operations simultaneously, five when theatres available and nine sequentially. Nine offer laparoscopic donor nephrectomy. Sixteen centres obtain reimbursement of expenses from the recipient health boards.
Thirteen centres would proceed and nine adult centres would not proceed to donation with a 45 year old woman who has an isotope GFR 68mls/min, creatinine clearance 80mls/min who wished to donate to her 15 year old son. Only six would proceed and 17 adult centres would not proceed with the same donor wishing to donate to her friend. Two centres were undecided. Twelve centres would proceed and 10 adult centres would not proceed with a 60yr old man on one anti-hypertensive with mild left ventricular hypertrophy and retinopathy who wished to donate to his son. Seventeen centres would accept a 24yr old woman as a donor for her 55yr old diabetic father, six centres would not proceed and two centres were undecided. Twenty-two centres offer life-long follow-up.
Discussion: These results display differences in the assessment methods and acceptance criteria of donors throughout the UK. An independent doctor reviews all unrelated donors for independent review for the purposes of ULTRA. However less than a half of centres review related donors by someone outside the transplant team. Paired exchange and non-directed donation appear to be an acceptable consideration for the future in over half the centres. Criteria for accepting potential candidates for donation appear to be interpreted variably, depending on the relationship between the donor and the recipient. Significant variation in the practices of different units may lead to inequitable access throughout the UK. With the majority of centres now providing life follow-up, comprehensive data about safety of kidney donation in the UK will be available in the long term.
Deprivation, Dialysis and Death in Scotland.
The Scottish Renal Registry (presented by BJR Junor)
The Scottish Renal Registry database includes the Postal Code for all patients starting renal replacement therapy (RRT) in Scotland for more than 20 years. Using the Carstairs Deprivation Index (based on overcrowding, male unemployment, social class and car ownership) this allows the allocation of a deprivation category from Depcat 1 (most affluent) to 7 (most deprived) to all patients. Although there is little difference in the deprivation distribution between the prevalent RRT patients and the general population, the new patients in both the decades 1980-89 and 1990-99 show an increased take-on rate per million in the more deprived groups. This was not due to there being more older patients but there was a higher proportion of patients with an unknown diagnosis in the most deprived groups.
The median survival of new patients by deprivation category was not different for those over the age of 55 years but there was a progressive shortening of median survival from more than 20 years in the least deprived to 12 years in the most deprived under the age of 55 years.
In the general population the Standardised Mortality Rate increases from 83 in Depcat 1 to 125 in Depcat 7 overall but the difference is much higher for young men (58 for Depcat 1 and 171 for Depcat 7 for those aged between 35 and 44 years) and for deaths from ischaemic heart disease in those under 65 years (63 for Depcat 1 and 123 for Depcat 7).
Previous studies in Europe (ERA/EDTA Report on Management of Renal Failure in Europe 1991) have shown an increased death rate from myocardial ischaemia/infarction in RRT patients approximately 20 times that in the general population in different countries. This would have the effect of exaggerating the already very high mortality rate in Scotland from ischaemic heart disease and also the pre-existing difference related to deprivation.
The data demonstrate that a similar pattern of distribution of deprivation in the prevalent RRT patients and the general population of Scotland disguises an increased incidence of chronic renal failure in more deprived groups. This increased incidence is balanced by an increased death rate in younger, more deprived patients, most likely due to ischaemic heart disease.
Epidemiology of Acute renal failure treated with renal replacement therapy in Scotland – The ARFS study.
Jyoti Baharani 1*, Lawson Loraine 1,Heather Martin 1, Wendy Metcalfe 3, Gordon Prescott 2, W Cairns Smith 2, Keith Simpson 3, Alison MacLeod 1 and Izhar Khan 1.
1 Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom; 2 Public Health Medicine, University of Aberdeen, Aberdeen, United Kingdom and 3 Scottish Renal Registry, Glasgow, United Kingdom
The Acute renal failure Scotland study (ARFS) is the first comprehensive, prospective national study of the incidence of ARF receiving RRT in Scotland. We have registered adult patients in Scotland (population 5 064 200) with ARF, acute on chronic renal failure (ACRF) and CRF receiving their first RRT over a 9-month period.
All adult patients in Scotland receiving their first RRT were identified by regular phone calls and visits to all 20 Scottish hospitals offering this treatment. In addition to this, some Scottish patients may occasionally receive RRT in the north of England and these hospitals were included in our study. We completed a standard data collection form for each patient registered into the study.
Over the recruitment period of 36 weeks, 878 patients fulfilling study criteria for ARF and ACRF were identified (mean age 62.1 years, 60.1% male).
The results are shown in the table below.
NORTH / SOUTH-EAST / WESTNumber of patients / 254 / 234 / 390
Number of Hospitals offering RRT for ARF in this region / 3 / 6 / 11
Population of region / 1 164 700 / 1 235 640 / 2 663 860
Incidence of ARF treated with
RRT in this region (p.m.p/year) / 218 / 189 / 146
We found an incidence of 223 p.m.p/year for ARF and ACRF receiving RRT; a third of these cases occur in patients with a degree of pre-existing renal impairment (ACRF).