Effect of Acute Paracetamol Overdose on Changes in Serum Electrolytes

Bacteraemia in Haemodialysis Patients – Incidence, Aetiology and Outcome C Stirling, E Mazonakis, KL Booth, S Morris, CC Geddes Glasgow Royal Infirmary and Western Infirmary.

Bacteraemia is known to be an important cause of morbidity and mortality. Patients on haemodialysis are at increased risk of bacteraemia because they require repeated vascular access (via AVF or dialysis line). The aim of this study was to determine the incidence and aetiology of bacteraemia and examine patient survival following an episode of bacteraemia.

We searched the renal unit database and bacteriology database for all positive blood cultures between Jan 2003 until December 2003 in any patient attending the Glasgow Renal Units. This included patients attending the renal units at Glasgow Royal Infirmary, Stobhill, Western Infirmary, Falkirk and Inverclyde Royal Infirmary. There were 503 positive blood cultures. Four hundred and eighteen of these positive cultures occurred in haemodialysis patients. A single bacteraemic episode was defined as any positive blood culture or subsequently positive blood culture with the same organism in the next 7 days. There were 288 such episodes in 186 patients during 2003. At the time of the bacteraemic episode, 225 (78%) occurred when a dialysis line was the mode of vascular access. Of this group, the dialysis line was identified as the source of the sepsis in 167 cases (74%). The organisms identified included coagulase –ve staph (36%), staph aureus (26%), MRSA (15%), gram –ve (7%), streptococcus (5%) and others (11%). Nine patients developed endocarditis all of whom were dialysing via a line at the time.

64 patients (34%) had more than 1 bacteraemic episode during the year and 11 patients had more than 3 episodes. Eighty eight patients died during follow up and 1 year survival after the first bacteraemia episode was 55%.

These data confirm that bacteraemia is common in haemodialysis patients and that line sepsis is the most common source. Bacteraemia is also associated with a high risk of subsequent mortality. A number of strategies may be required to tackle this problem including improving the number of patients with permanent access, evaluating the use of temporary lines and permcaths and reviewing antibiotic policy. Line related sepsis in haemodialysis patients – incidence, organisms and subsequent mortality. E Mazonakis, C Stirling, D Wright, K Booth, N Heron, C C Geddes Renal Unit, Western Infirmary, Glasgow

Background. Line related sepsis (LRS) is an important cause of morbidity and mortality in haemodialysis (HD) patients. The prevalence of central lines for HD access is increasing. The aim of this study was to determine the incidence of LRS, the organisms involved and the associated patient survival following LRS.

Methods. We searched the renal unit and bacteriology databases for all episodes of LRS that occurred between Jan 2003 until December 2003 in any patient attending the three HD units associated with our centre for chronic haemodialysis. Number of days exposure to temporary lines and tunnelled lines in the same time period were calculated for the whole HD population using the electronic patient records. Patient survival after the first episode of LRS in the year was analysed by Kaplan Meier plot.

Results. There were 80 episodes of LRS in 61 patients out of a total of 199 patients exposed to lines for HD in the year 2003. 43 occurred in association with temporary lines and 37 with tunnelled lines. 33 episodes were line tip culture + blood culture positive; 41 blood culture positive only; 3 line tip culture positive only; and 3 were diagnosed on clinical features only. The maximum number of episodes in a single patient was 4. The organisms identified included staph aureus (33%), coag –ve staph (35%), MRSA (23%), and there were no differences between temporary and tunnelled lines. The incidence of LRS was 12.0 per 1000 patient days in patients dialysing with temporary lines and 2.0 per 1000 patient days in patients dialysing with tunnelled lines. For those patients experiencing LRS the median time to LRS was 20.2(0-65) days in temporary lines and 112.7(1-609) days in tunnelled lines. Median patient survival after the first episode of LRS in the year was 417 days. The infecting organism was not predictive of subsequent survival.

Conclusions. These data confirm that LRS is common and is associated with a high risk of subsequent mortality. The risk of related sepsis is higher with temporary than tunnelled lines. Calculating incidence in the context of total number of days exposure will allow meaningful assessment of future preventative interventions. Nephrogenic Fibrosing Dermopathy- Case report

Neary J1, Smith M2, Winney R1, Benton C2. Departments of Nephrology1 and Dermatology2, Royal Infirmary of Edinburgh.

Nephrogenic Fibrosing Dermopathy (NFD) is a recently recognised scleroderma-like skin condition that develops in patients with End Stage Renal Disease. We describe a case in a 38 yo peritoneal dialysis patient from our unit. The patient presented with a four-month history of painful, swollen, erythematous and restricted ankles bilaterally. He had a background of Alport’s syndrome and had commenced CAPD eleven months previously when his renal transplant failed. He had also recently been commenced on an Icodextrin exchange as part of his CAPD regime. Investigations were unremarkable except for a mild eosinophilia. Skin biopsy showed hyalinisation of dermal collagen consistent with sclerodermatous change. He was treated with physiotherapy and corticosteroids and was also changed to haemodialysis using high-flux membranes with mild improvement only. A trail of PUVA therapy was unsuccessful. In addition to the case presentation, we will discuss an approach to the diagnosis and treatment of patients presenting with NFD. Serum Brain Natriuretic Peptide, Myocardial Fibrosis and Left Ventricular Function in End Stage Renal Failure

Patrick B. Mark1, Colin J. Petrie2, Nicola Johnston2, Kevin G. Blyth2, John E. Foster2, Henry J. Dargie2, Alan G. Jardine1. 1. Renal Unit, Western Infirmary, Glasgow and 2. Department of Cardiology, Western Infirmary, Glasgow

Background. Patients with end stage renal failure (ESRF) have an increased cardiovascular mortality with left ventricular (LV) disorders being a marker of poor outcome. Cardiac magnetic resonance imaging (CMR) assesses LV dimensions and non- invasively identifies myocardial fibrosis. Serum brain natriuretic peptide (BNP) has been shown to correlate with patient survival in ESRF. We studied the relationship between BNP, LV dimensions and the presence of myocardial fibrosis as assessed by CMR. Methods 84 ESRF patients from the renal transplant list (54 men, median age 54, range 27-72) underwent CMR (1.5T scanner, Siemens Sonata) with LV dimensions assessed by cine stack. Further images were acquired following i.v. gadolinium-DTPA, with images assessed for the presence and extent of late gadolinium enhancement (LGE) indicating myocardial fibrosis. Serum was taken for BNP (Shionoria) pre-scan. Results There was an overall correlation between serum BNP and LV mass index (r=0.24, p<0.05), and end systolic volume/Body Surface Area (r=0.35, p<0.01) but not ejection fraction (r=-0.19, p=0.09). 25 (29.8%) of patients had evidence of myocardial fibrosis indicated by positive LGE. Serum BNP correlated with mass of myocardial fibrosis indicated by LGE (r=0.33, p<0.01). In the sub group of patients with LGE there was stronger correlation between serum BNP and LV mass index (r=0.56, p<0.01), end systolic volume/Body Surface Area (r=0.41, p<0.05) and negative correlation with ejection fraction (r=-0.42, p<0.05). There was no relationship between BNP and LV dimensions in the sub group of patients without LGE. The range for BNP in ESRF was wide (LGE positive - 0-1089pg/ml; negative - 0-2085pg/ml) . Conclusions Myocardial damage indicated by LGE is common in ESRF. The relationship between BNP and myocardial dimensions in ESRF is dependant on the presence of myocardial damage and suggests that BNP may be raised either in response to, or as a marker of myocardial fibrosis in ESRF. The wide range of serum BNP also suggests impaired BNP clearance in ESRF.

Conflict of interest. None Funding. British Heart Foundation Long overnight haemodialysis in a satellite unit – a case control study. Nicola Clark, Marion Houston, R Stuart Rodger, Colin C Geddes. Renal Unit, Inverclyde Royal Hospital, Greenock

Background. Published studies suggest longer haemodialysis (HD) is associated with improved outcomes compared with conventional HD.

Methods. We conducted a retrospective case controlled study to compare selected variables in 11 patients attending our satellite HD unit for long overnight HD (7 hours thrice weekly) compared with 11 age and sex matched patients attending for conventional HD (4-5 hours thrice weekly). Patients were on this mode of HD continuously for a minimum of 9 months and data were averaged from the 6 months before this study.

Results. Patients on long HD had a higher urea reduction ratio (84.8% v 78.0%; p=0.002). Patients on long HD required a significantly lower dose of erythropoietin to achieve target haemoglobin levels (4652 units per week v 9485 units per week; p=0.03) despite similar intravenous iron doses and serum ferritin. 1 patient in the long HD group was prescribed dietary potassium restriction compared with 10 patients in the conventional HD group and 1 patient in the long HD group was prescribed dietary phosphate compared with 10 patients in the conventional HD group. Despite this there was a trend to lower pre-dialysis serum potassium (4.44mmol/L v 4.79mmol/L; p=0.05) and phosphate (1.48mmol/L v 1.75mmol/L; p=0.12) in the long HD group.

Conclusion. The availability of long overnight HD in a satellite unit increases patient choice and is associated with increased small solute clearance, lower erythropoietin requirements and a substantially reduced requirement for dietary potassium and phosphate restriction. Haemoglobin Target for Haemodialysis Patients – Is It Achievable?

C Stirling, RK Patel, K Simpson. Renal Unit, Glasgow Royal Infirmary

The most recent UK Renal Association Standards Document (2002) recommends that patients with chronic renal failure (including haemodialysis patients) should achieve a haemoglobin (Hb) of 10g/dl within 6 months of being seen by a nephrologist. This is an ambitious target when you consider the results of the NHS QIS review of renal services in 2003. Only 3/10 units in Scotland achieved the standard of >10g/dl in >85% of haemodialysis patients after 3 months on dialysis. We have reviewed haemoglobin results in our dialysis patients over the last 5 years. They show that although there was an initial improvement in the proportion of patients reaching a haemoglobin of 10g/dl, there has not been ongoing improvement and the results still fall short of the new standard that all haemodialysis patients should have a Hb >10g/dl. We have looked at results in individual patients to identify reasons why we consistently fail to achieve a Hb>10g/dl in 20-25% of these patients. We suspect that it is partly due to the way in which we currently collect the data (ie point prevalence) and partly due to variation in patients’ clinical status. Using the electronic patient record (EPR), we selected the first haemoglobin result of the month in all haemodialysis patient (n=227) over a 6-month period (n=1332). The mean haemoglobin was 11.5g/dl (+/- 1.7 SD) and 20% of results were <10g/dl. We also looked at the variation in Hb results in each patient over the 6 month period using the standard deviation as a measure of intrapatient variability. We noted that although patients with the higher standard deviation (>1.5) had similar mean haemoglobin (11.33 v 11.58g/dl), they missed the target more often (30% v 14%) than those with a lower standard deviation. This group with a highly variable haemoglobin represented 22% of the haemodialysis population. We have looked at reasons for this intrapatient variability and believe this group illustrates why it is difficult to achieving this standard in a haemodialysis population. Patient opinion regarding the UK Transplant cadaveric kidney allocation scheme Chris Smith, Anita Ganai, R Stuart Rodger, Colin C Geddes. Renal Unit, Western Infirmary, Glasgow

Background. UK Transplant (UKT) has developed a national cadaveric kidney allocation scheme in an attempt to balance optimisation of graft survival and equity of access. Priority is given to minimising HLA mismatches. A points scoring system that includes 6 criteria is used if there are two or more equally matched recipients. The aim of this study was to analyse patient opinion with respect to the UKT allocation scheme. Methods: Patients attending three out-patient haemodialysis (HD) centres and patients attending transplant (Tx) follow up clinics were invited to complete a questionnaire. 8 scenarios were presented in which 2 potential recipients (PR) differed in 1 or 2 factors and were suitable for the same donor kidney. Participants were invited to indicate which of the two patients should receive the donor kidney assuming that all other factors were equal. Results: 232/295 (78.6%) patients completed questionnaires (104 HD, 128 Tx). In the following scenarios the potential recipient who would receive the kidney under the current UKT allocation scheme is shown in italics and the percentage of study participants agreeing with this allocation is shown in brackets: PR with 75% probability of 3 year transplant survival (equivalent to complete HLA mismatch) on waiting list for 7 years v PR with 85% probability of 3 year transplant survival (equivalent to complete HLA match) on waiting list for 2 years (24.6%); PR not yet on dialysis on waiting list for 5 months v. PR on dialysis for 1 year on waiting list for 3 months (6.0%); paediatric PR v adult PR (39.7%); 7 year waiting time v 2 year waiting time (66.4%); 2 years of dialysis, 1 year on waiting list v 1.5 years of dialysis, 1.5 years on waiting list (21.1%); 20 year old PR v 60 year old PR (34.9%); PR from city with 20 donations this year v PR from city with 10 donations (4.3%). 91.4% respondents agreed that recipient gender should not be used as a criterion. The average percentage of ‘don’t know’ responses was 14.9% per scenario (range 4.5-31.0%). Responses were broadly similar between HD and Tx patients, between age groups and between males and females. Conclusions: These data show that patients have opinions about cadaveric organ allocation, disagree with many aspects of current allocation policy and regard time on dialysis as a more important criterion for organ allocation than HLA matching or time on the waiting list. The UKT allocation scheme should be refined to take account of patient opinion. The changing presentation of acute rejection in low risk patients treated with anti-CD25 antibody and rapid steroid elimination YM Woo1, JS Gill1,2, DN Landsberg1,3, PA Keown3,4, AB Magil5 1Nephrology, St. Paul’s Hospital, University of British Columbia, 2 Nephrology, Tufts- New England Medical Center, Boston, 3 British Columbia Transplant Society, Canada, 4Nephrology, Vancouver General Hospital, University of British Columbia, 5Pathology, St. Paul’s Hospital, University of British Columbia

In the renal transplant centre of British Columbia, immunosuppressive protocol for adult, low risk, primary kidney transplant recipients has changed over time from triple therapy with steroids, MMF and calcineurin inhibition (pre-Aug 2001) to the addition of anti-CD25 antibody induction (Aug 2001-Feb 2003) and subsequently, to a programme of anti-CD25 antibody induction with steroid elimination within the first 36 hours after transplantation (March 2003 onwards). The purpose of this study was to compare the clinical and pathological presentation of biopsy-proven acute rejection (AR) in patients on the different immunosuppressive regimens. Analysis included only AR episodes in the first six months.

One hundred and eighty two patients received triple therapy, 167 received additional treatment with anti-CD25 Ab induction and 58 patients received the rapid steroid elimination (RSE) programme. Baseline characteristics in the 3 patient groups were similar apart from an increase in HLA-DR mismatch in the latter two groups, which was driven by a change in allocation policy in British Columbia. The incidence of AR was 26% in the triple therapy group, 19% with the introduction of antiCD25 Ab induction and 17% in the RSE group. There was a striking reduction in interstitial forms of AR (Banff I) since the introduction of anti-CD25 Ab induction and an increased proportion of vascular AR (Banff II). There was no difference in the presence of peritubular C4d staining in the three different immunosuppressive regimens. Clinically, the Banff II AR episodes were heterogeneous in their presentation and on further examination, their diversity appeared to be related to the degree of interstitial inflammation present on biopsy. In vascular rejection where interstitial involvement was minimal (<25%), clinical presentation was more subtle and the vast majority of cases returned to baseline renal function despite some patients not receiving treatment. Short term graft survival was not different in vascular AR with <25% interstitial involvement vs. >25% interstitial involvement. In patients with AR, those who had vascular AR with minimal interstitial involvement were 6.4 times more likely to have received treatment with anti-CD25 Ab.

The updated Banff ‘97 classification of renal allograft rejection does not differential acute vascular rejection on the basis of interstitial involvement. Based on our preliminary findings, we wonder if the degree of interstitial inflammation needs to be considered in this era of newer immunosuppressive drugs.

In summary, we have found an increased incidence of Banff II vascular AR with minimal interstitial involvement, since the introduction of anti-CD25 Ab induction protocols. This form of AR appears to have a different clinical presentation in the short-term; long-term follow up in needed to determine outcomes in these patients. This form of AR merits further study. Abstract:

Late tissue invasive Herpes Simplex Virus in a renal transplant recipient

Andrew Henderson, Mark Andrews, Abeed Pall, Paul McIntyre, Shaun Walsh, Stewart Fleming. Departments of Renal Medicine, Virology and Pathology Ninewells Hospital Dundee.

Viral infections are common in transplant recipients with Cytomegalovirus infection being the most well recognised. Systemic Herpes Simplex Virus infection is rare but has been reported in the early transplant period and has a poor outcome. We describe a 35 year old lady, two years post renal transplant on tacrolimus and azathioprine who developed HSV hepatitis at the time of a genital infection. Subsequently she suffered a probable HSV pancreatitis and allograft interstitial nephritis. Diagnosis was made by viral culture from a cutaneous lesion, liver biopsy and later renal biopsy. Initial treatment was intravenous aciclovir in conjunction with a reduction of immunosuppression followed by prophylaxis with oral valaciclovir. Despite this she had ongoing tissue invasive disease and underwent transplant nephrectomy to allow the withdrawal of immunosuppression. Prediction of survival in non-diabetic renal transplant recipients by random blood sugar.

Revanur K, Tutone V, Mark P, Traynor J, Buist L, Geddes C, Deardon D, Jardine A,

Abstract Immunosuppression induced new onset diabetes after renal transplant (NODAT) is associated with reduced patient survival. Less is known about more subtle changes in glucose homeostasis. We have retrospectively analysed random blood glucose levels at the end of month 1, 2 and 3 following transplantation in 1186 cadaveric and live related renal transplant recipients who received their grafts in our center between 1984 and 2002. Patients were grouped into those having end stage renal failure secondary to diabetic nephropathy, those developing NODAT and those without diabetes. Our data confirmed that survival of patients with NODAT was compromised and that long term survival in this group was similar to patient with diabetic nephropahthy and ESRD. Furthermore, our data has shown that in patients without diabetes, random blood glucose was a strong determinant of outcome even in the low – normal range.

NODAT is an important, modifiable risk factor for cardiovascular disease in tranplant recipients. Our data confirms a continuum of increasing risk in non diabetic transplant recipients who have impaired glycaemic control . These data advocate more detailed screening for impaired glucose tolerance in this population. . Minimal change disease in the elderly-Case series

Simpson K1, Neary J1, Bellamy C2, Goddard J1 Dept of Renal Medicine1 and Pathology2, Royal Infirmary of Edinburgh.

Minimal change disease (MCD) is the most common form of Nephrotic syndrome seen in children and when it occurs in adults, the mean age for presentation is 40 years. We present a study looking at presentation, clinical course, treatment responsiveness and outcomes in a group of patients aged >65 yo with MCD diagnosed on renal biopsy. It is a small retrospective study (n=7) looking at confirmed cases in this age group over a 6-year period. The mean age of patients is 78 years, with a mean albumin at presentation of 24.1 g/L and a mean 24-hour urinary protein of 11.4 g/collection. Renal impairment at presentation occurred in 3/7 cases but acute renal failure was present in one case. There was a high incidence of malignancy in this age group (4/7 patients) and one case was possibly associated with NSAID use. Our unit has standard protocol of steroid therapy for first line treatment of MCD. Complete remission was seen in only 3/6 treated patients with one steroid resistant case and two deaths on treatment. Relapse rate data is limited. In addition to the case series, we present data on the limitations of current definitions of response in MCD and suggest an alternative regime steroid therapy in elderly patient. We are also seeking further cases to develop a collaborative study of MCD in this age group. The prevalence of moderate and severe renal impairment in patients with type 2 diabetes Alison Severn1, Peter T Donnan2, Peter James2, Philip Thompson2, Anne Davidson1 and Andrew D Morris3 1Renal Unit, Ninewells Hospital, Dundee, 2Health Informatics Centre, University of Dundee and 3Department of Clinical Pharmacology, University of Dundee

Diabetic nephropathy is a common cause of end-stage renal failure (ESRF); it was the primary renal diagnosis in 18% of patients starting dialysis in Scotland in 1997-2001. Little information is available on the prevalence of milder degrees of renal impairment in patients with type 2 diabetes. The DARTS data set contains clinical data on all patients in Tayside in whom diabetes has been diagnosed since 1993. For this study, anonymised data from patients with type 2 diabetes on the database in 2001 were analysed. For each patient, calculated creatinine clearance was derived, using the Cockcroft-Gault equation. For patients with more than one creatinine measurement during 2001, creatinine clearance was calculated for each measurement, and the mean creatinine clearance determined. There were 9148 patients with type 2 diabetes in Tayside, giving a prevalence of 2.35%. Complete data were available for 7681 patients (84%). Of these, 6415 (83.5%) were over 55 years old, and 4078 (53.1%) were male. In 224 patients (2.9%; 95% CI 2.5-3.3%), calculated creatinine clearance was less than 30ml/min and in 2140 (27.9%; 95% CI 26.9- 28.9%), it was 30-60ml/min. Significant renal impairment is extremely common in patients with type 2 diabetes; over 30% of patients have a calculated creatinine clearance of less than 60ml/min. Renal impairment increases the risk of cardiovascular events, which is already high in this population. Although many of these middle-aged and elderly patients with diabetes will die before reaching ESRF, a significant number will require dialysis over the next few years. Contrast nephropathy following angiography: Women are at much higher risk

I MacLeod, A Barclay, S Chakraverty, S Edie, J Kerr, M Moffat, V Wood and A Severn

Patients undergoing angiographic procedures are at high risk of post contrast nephropathy (PCN). The risk of PCN is said to be higher in patients with pre- existing renal impairment, but frequently renal function is not adequately assessed before angiography. We performed a retrospective analysis of patients undergoing peripheral or renal angiography, angioplasty or stent insertion. We used the MDRD formula to estimate GFR before and after each procedure.

Data were available for 50 patients (30 men and 20 women), who had undergone 52 procedures. (2 patients had each undergone 2 procedures.) Mean age was 71.1 years, and age range was 40-92 years; 35 patients (70%) were over 70 years of age. 12 patients (24%) had diabetes. The mean pre-procedure GFR was 53.3ml/min. 23 patients had stage 3 renal impairment (estimated GFR 30-60ml/min) and 9 patients stage 4-5 (estimated GFR <30ml/min). GFR fell by at least 20% following angiography in only 7 patients (14%). Neither pre-contrast GFR nor age predicted PCN. Patients with diabetes were no more likely to suffer a fall in GFR than those without diabetes. However, 6 of the 7 patients who suffered a serious decline were women (relative risk 9; p< 0.01).

Renal impairment, of at least moderate severity, was present in 64% of these patients with vascular disease. It is more common in these patients than in the general population, or in the elderly (5% and 16% respectively) or in type 2 diabetics in Tayside (31%). Its prevalence is probably under-estimated; many of our patients with low GFRs had serum creatinine levels in the ‘normal range’. The ‘traditional risk factors’ for contrast nephropathy, renal impairment and old age, are of limited value in predicting deterioration in renal function after angiography, as they are present in most patients. Our data suggest that women are at much higher risk than men; this has not previously been reported. Further narrowing of the candidate gene interval for Familial Mesangiocapillary Glomerulonephritis type III.

Stephens G 1, Neary J2,3,4, Conlon P3, Winn M4. 1Department of Genetics, Trinity College, Dublin, Ireland. 2Department of Renal Medicine, Royal Infirmary of Edinburgh. 3Department of Nephrology, Beaumont Hospital, Dublin, Ireland 4Center of Human Genetics, Duke University Medical Center, NC, USA

A familial form of Mesangiocapillary Glomerulonephritis (MCGN) type III was previously described by this group*. In this study, the condition was linked to a 22 Centimorgan (Cm) region on Chromosome 1q31-32 between the microsatellite markers D1S3470 and GATA124f08. In a revision of the human genome, the marker GATA124f08 was relocated and thus a further fine mapping study was carried out in Duke University. Primers pairs for 5 new microsatellites were amplified using standard conditions and the PCR products run on acrylamide gels stained with Sybergold and scanned on a Hitachi FMB102 scanner. The images were analyzed with Bioimage software. Haplotype analysis was carried in order to identify recombination events. The most likely linkage phase was assigned by minimising the number of recombinations with in the pedigree. Haplotypes constructed using data from the previous study* and the 4 successfully genotyped markers narrowed the minimal candidate region from 22 Cm to 11.84 Cm, between the markers D1S3470 and D1S1647. This revised candidate gene region encompasses a group of proteins involved in the regulation of complement activation (RCA) which control the activity of C3-convertase. Mutations in these regulatory proteins may give rise to hypocomplementaemia and the formation of deposits characteristic of MCGN type III.

* Linkage of a Gene Causing Familial Membranoproliferative Glomerulonephritis Type III to Chromosome 1. Neary J et al. J Am Soc Nephrol. 2002: Aug;13(8):2052-7 Proteinuria: measurement, implications and treatment options

Gayle McKellar, Heather Barrington, Sue Robertson, Chris Isles Renal Unit and Department of Biochemistry, Dumfries and Galloway Royal Infirmary, Dumfries, DG1 4AP

An accurate measurement of urine protein is important partly because it informs the decision on renal biopsy and partly because it predicts both renal and cardiovascular outcomes. The gold standard for urine protein measurement has always been the 24 hour urine collection. This is accurate if the patient remembers to include all urine passed during the 24 hours of collection, but is clearly inconvenient to collect. Some idea of the completeness of a 24 hour urine collection can be gained by measuring urine creatinine. 24 hour urine collections in which the ratio of measured creatinine to estimated creatinine is between 0.75 and 1.25 are likely to be accurate whereas 24 hour urines with ratios that lie outside these limits are not.

The purpose of our study was two-fold. First, to survey the 41 consultant nephrologists in Scotland for their views on the measurement of proteinuria, the level of proteinuria at which they would recommend a renal biopsy and the level of proteinuria at which they might recommend a statin. We did not poll physicians’ views on renin angiotensin system blockade in the belief that most would recommend an ACE inhibitor or angiotensin receptor blocker for patients with proteinuria exceeding 0.5 to 1.0 g/24 hours. Second, we conducted a small study in which we compared different measures of protein output at different times of day with 24 hour urine protein. The different measures of protein output were protein:creatinine ratio in mg/mmol and in g/g, also estimated protein output corrected for ideal body weight in g/24 hours. Each patient was asked to provide accurate timed urine collections for 2400 to 0800 hours, 0800 to 1600 hours and 1600 to 2400 hours.

Our survey showed considerable variation in clinical practice, not only when measuring proteinuria but also when recommending a biopsy and prescribing a statin. The results of our study of protein output confirm a greater diurnal variation in protein than creatinine excretion, and support the view that estimated protein output based on urine collected between 0800 and 1600 hours is an acceptable and more convenient alternative to a 24 hour urine collection. VASP, iNOS and epithelial cell shedding : a role in acute tubular necrosis? Susan M Crail and Thomas J. Evans. Division of Immunology, Infection and Inflammation, Glasgow University

Acute renal failure (ARF) complicating sepsis is common and carries an adverse prognosis (Neveu et al 1996). The major pathological change seen in the kidneys is shedding of proximal tubule cells into the tubule lumen leading to obstruction and decline in GFR. We have shown that such changes may be induced by sepsis-associated, pro-inflammatory cytokines via the induction of inducible nitric oxide synthesis (iNOS) (Glynne& Evans 1999). The mechanism by which this occurs is unclear. A possible target of nitric oxide (NO) is vasodilator-stimulated phosphoprotein (VASP). VASP is a widely distributed protein located in particular at regions of cell: cell and cell: matrix adhesions. It nucleates F-actin polymerisation and is found at sites of cytoskeletal turnover. VASP contains three phosphorylation sites - Ser157, Ser239 and Thr278. The Ser239 site is preferentially phosphorylated by cGMP-dependent kinase and is therefore sensitive to alterations in NO. Phosphorylation at the Ser157 is predominantly by cAMP- dependent protein kinase and is associated with an apparent mass shift from 46 to 50kDa on SDS- Page electrophoresis. The Ser239 site is close to areas of the protein associated with G-actin binding and F-actin nucleation. We proposed that iNOS induction could lead to an increase in Ser239 phosphorylation, altering the ability of VASP to associate with the actin cytoskeleton and cell:cell and cell:matrix complexes. iNOS was transfected into human proximal epithelial tubule cells (HPTEC). 24 hours following transfection the cells were fixed and stained for iNOS and VASP. Immunofluorescence microscopy showed an alteration in the distribution of VASP in cells expressing iNOS. In these cells the normal pattern of VASP localisation at focal adhesions was significantly reduced and the cells showed a more rounded morphology. iNOS was also transfected into the 16HBE epithelial cell line. Samples were lysed and used for Western blot analysis at various timepoints following transfection, using a monoclonal antibody that only recognises the Ser239 phosphorylated form of VASP and a polyclonal antibody that recognises all forms of VASP. Blotting for Ser239 phosphorylated VASP showed this form appeared between 4-6 hours following transfection and disappeared by 8 hours. Interestingly, this form of VASP was only seen at the 50kDa position indicating that it must also have undergone Ser157 phosphorylation to cause this apparent mass shift. We therefore also investigated the effects of adding a cAMP analog to iNOS-transfected cells. Following the addition of 8-BrcAMP, the Ser239 form was maintained for a much longer period of time and was still present at high levels 8 hours following iNOS transfection. This was not due to 8- BrcAMP as addition of this alone did not cause any Ser239 phosphorylation. We conclude that, in these cells, NO-mediated phosphorylation of Ser239 is only possible following Ser157 phosphorylation, possibly due to an alteration in protein conformation. This indicates that NO mediated effects on VASP phosphorylation are also critically dependent on changes in cAMP levels. If this is the mechanism by which tubule cells are shed in sepsis, it offers two potential routes for intervention – by modulation of the cAMP or the cGMP dependent pathways. This will be investigated further using VASP mutants that cannot be phosphorylated at these sites.

References Glynne PA & Evans TJ. Inflammatory cytokines induce apoptotic and necrotic cell shedding from human proximal tubule epithelial cell monolayers. Kidney Int. 1999 55 2573 – 97 Neveu H, Kleinknecht D, Brivet F, Loirat P & Landais P. Prognostic factors in acute renal failure due to sepsis. Results of a prospective multi-centre trial. Nephrol.Dial.Transplant. 1996 11 293-299 Severe Coagulopathy after Routine Heparin Lock of Dialysis Lines

S. McLeod, M. Gill, C.S. Macmillan

Department of Anaesthesia and Intensive Care, Ninewells Hospital, Dundee DD1 9SY

Background: After haemodialysis some intensive care patients were noted to have a bleeding diathesis and deranged coagulation - isolated elevation of the Activated Partial Thromboplastin Time (APTT) which reversed with the addition of Protamine. Heparin was not used during dialysis in many cases, and there was no obvious clinical explanation for these observations. The most likely source was Heparin administered as a ‘hep-lock’. This was directed by the dialysis line manufacturers to prevent intra-catheter blood clots after each renal replacement therapy (RRT), the concentration of heparin being 5000 i.u/ml and the volume dependent on the length of the line in-situ. We were concerned that a coagulopathy could result from the Hep-lock procedure, and that in intensive care patients with multiple co-morbidities the consequences could be serious. In the interests of patient safety we monitored coagulation after RRT to ascertain if there was indeed a clinically relevant problem.

Methods: A period of monitoring was planned for 4 months. The RRT lines were 20cm or 25cm Gamcath (Gambro, Hechingen, Germany). Both nursing and medical staff hep- locked the lines. After RRT patients had venous blood, for APTT and its ratio (APTTr), taken from a ‘virgin’ peripheral vein immediately before hep-lock and a second sample taken 30-120 minutes later.

Results: Clinical practice was modified after only 2 months monitoring. During this time 73 patients were admitted to ICU with 20 requiring RRT (27%). 13 RRT patients had 32 (24%) paired samples analysed out of a potential 132 samples from all 20 patients. Of the pre-hep-lock samples 25 (78%) had APTTr <1.5. Only one of the pre-hep-lock samples had a grossly elevated APTTr at 3.1. Of the post-hep-lock samples 28 (88%) had APTT >1.5 with 17 (53%) of these >7 (the laboratory ceiling for APTTr measurement was 7). A non-parametric sign test found this to be significant with p<0.0001. None of the patients suffered clinically obvious morbidity relating to coagulation derangement. There was no obvious difference between the length of line or staff member inserting ‘heplock’. There was no correlation with timing of samples.

Conclusion: 88% of all post-hep-lock samples had an increased APTTr and in 53% this was grossly abnormal (APTTr >7). Only one of the pre-hep-lock samples had a grossly elevated APTTr at 3.1, indeed most (78%) had normal APTTr (<1.5). The grossly elevated pre-heplock sample had Heparin used in the circuit during dialysis and probably was related to this. These data support the conclusion that hep-lock, using 5000 i.u./ml, causes deranged APTTr. Despite the low overall sample rate (24% of possible opportunities) the findings are both clinically relevant and significant. As such the clinical practice in the ICU is now to use 1000 i.u./ml heparin for hep-lock. Aorto-caval fistula, a most unusual cause of acute renal failure!

M.R.G.King, C.McCulloch, & R.J.Winney

We present a case of a 63-year man with no significant past medical history who presented with chest pain, gross fluid overload, dusky peripheries, frank haematuria and acute anuric renal failure. A continuous flow murmur was present in the abdomen and diagnosis of aorto-caval fistula was confirmed by CT angiogram. Renal biopsy was essentially normal. Surgical correction of the fistula resulted in near instant production of urine and renal function recovered within the next few days.

Aorto-caval fistula is a rare but previously described cause of acute renal failure. A review of the literature revealed five previously described cases. The characteristics of this condition will be discussed as will the likely aetiology of the renal failure in such cases.

(No conflicts of interest) E.Coli 0157 related Haemolytic Uraemic Syndrome in a Jehovah’s Witness treated by apherisis using non blood derived replacement fluid.

Andrew Henderson, Abeed Pall and Sam Rawlinson Departments of Renal Medicine and Blood Transfusion Ninewells Hospital, Dundee

Haemolytic uraemic syndrome (HUS) is a well recognised complication of enterohaemorrhagic E.Coli 0157 infection. In adults the prognosis is poor with reported mortality rates of between 50 and 90%.

No therapy has been proven to be beneficial in Adult HUS although both plasma infusion and therapeutic plasma exchange (TPE) can be used and have case series data to support treatment. The rational for using TPE was supported after the West of Scotland outbreak where the expected mortality was 90% while actual mortality was 50%.

We describe a 44 year old Jehovah’s Witness who was receiving treatment for ovarian carcinoma with Paclitaxel and Carboplatin who developed haemorrhagic colitis and went on to develop HUS. Stool cultures confirmed verotoxin producing E.Coli 0157 infection. She had oliguric ARF and severe anaemia. Supportive treatment with haemodialysis and high dose erythropoietin was commenced. Due to her religious beliefs conventional TPE was not an option nor was blood transfusion. It was felt however that an attempt at TPE using Gelofusine as a replacement fluid was warranted in view of the degree of anaemia and ongoing haemolysis. TPE with gelofusine was therefore carried out on an alternate day basis. The problems associated with gelofusine replacement included profound hypoalbuminaemia and a degree of coagulopathy With TPE and continued supportive care there was evidence of improvement in her haemolysis markers and her renal function and she went on to make a full recovery.

Although she may have recovered without TPE this case shows that TPE with gelofusine is a feasible technique in patients with HUS and if patients are unable to receive standard supportive care including blood transfusion it should be considered to try and prevent ongoing haemolysis.

TITLE: EFFECT OF ACUTE PARACETAMOL OVERDOSE ON CHANGES IN SERUM ELECTROLYTES N Pakravan, J Goddard*, DN Bateman. NPIS Edinburgh, Scottish Poisons Information Bureau and Department of Renal Medicine*, Royal Infirmary of Edinburgh, Edinburgh

Introduction: Paracetamol is a widely available over-the-counter analgesic, which is frequently taken in overdose. It has some prostaglandin synthesis inhibitory actions (Rang et al, 2003). In overdose NSAIDs, which also inhibit prostaglandin synthesis, can cause dose-dependent hypokalemia, increase fractional excretion of potassium and cause sodium retention due to renal vasoconstriction (Goddard et al, 2003). Therapeutic doses of paracetamol have no effect on potassium levels or excretion (Prescott, 1996).

Aim: To study electrolyte changes in patients with paracetamol overdose

Method: A retrospective study was conducted on 30 patients with paracetamol overdose aged 16-65y admitted to the toxicology ward of the Royal Infirmary of Edinburgh from 2000-2003. We excluded the effect of other drugs known to be nephrotoxic by history. Information regarding tablets taken, time and date of ingestion, NAC treatment and biochemistry results at the time of admission (4-6 h post-ingestion) and approximately 18-20 hours post-ingestion were obtained from patient’s note.

Results: The data shows a significant correlation between 4 h paracetamol level and serum potassium changes (R2 = 0.22, p<0.01) (Fig-1). There was no significant change in serum sodium or creatinine. The mean potassium fall per hour in the tertile with the highest 4 h paracetamol concentration (mean paracetamol level = 198 mg/l) was 0.03 ± 0.01 mmol/l/h (Fig-2). Administration of NAC did not alter this effect on potassium.

Fig-1:4 h paracetamol vs potassium change Fig-2: K+ change per h compared with 4 h paracetamol 1 0.06 l / l 2 o R = 0.22

m 0.5 0.04

m P < 0.01

e 0.02 g 0 n a

m -0.02 u i

s -1 s

a -0.04 t o p -1.5 -0.06 0 100 200 300 < 1 1 0 1 1 0 - 1 7 0 > 1 7 0 4 h paracetamol mg/l G R O U P S ( 4 h p a r a c e t a m o l l e v e l m g / l )

Conclusion: Paracetamol overdose is associated with hypokalemia in proportion to the dose ingested, suggesting a specific renal effect of paracetamol in overdose. These findings could be consistent with increasing aldosterone action on the distal tubules as renal perfusion falls due to paracetamol-induced renal vasoconstriction.

References: Goddard J et al. J Toxicol Clin Toxicol 2003; 41:747. Prescott LF. Taylor& Francis Ltd, 1996. Rang HP et al. Churchill Livingstone, 2003.