Patients with diabetic nephropathy on renal replacement therapy in England and Wales.

BACKGROUND: The incidence of patients with diabetic nephropathy (DN) who start renal replacement therapy (RRT) is increasing. AIM: To describe the characteristics and survival of patients with DN starting RRT in the UK. DESIGN: Retrospective cohort study. METHODS: We analysed data for incident patients on RRT in centres participating in the Renal Association UK Renal Registry (UKRR), 1997 -2004, comparing DN vs. non-DN patients with regard to survival, social deprivation, ethnicity, gender, and age, using Cox regression models. RESULTS: DN was the most common renal disease (19%) in the 20 532 patients starting RRT. The majority of patients with DN (77%) were Caucasian. Within the Caucasian population, DN patients were more likely to be from a socially deprived area (p < 0.0001). About 20% were referred <3 months before starting RRT. The difference in crude survival was greatest in younger patients (5-year survival was 56% (DN) vs. 85% (non-DN) in patients aged 18-54 years, and 17% (DN) vs. 28% (non-DN) in patients aged >or=65 years). Despite adjusting for gender, age, treatment modality, social deprivation, referral and co-morbidities, the long-term prognosis for DN patients aged 18-54 years was worse (adjusted hazard ratio 2.13, 95%CI 1.23-3.67) than for older age groups. DISCUSSION: Patients with DN starting RRT are more likely to come from socially deprived areas. Relative risk of death is greatest in working-age DN patients and is not fully explained by recorded co-morbidity. This emphasizes the need for focused diabetes care in poorer areas, and assessment of quality of care of diabetic patients on RRT.

Social deprivation and survival on renal replacement therapy in England and Wales.

This study examines the association between social deprivation and patient characteristics and outcomes in a nationally representative cohort of incident renal replacement therapy (RRT) patients. All Caucasian patients reported to the UK Renal Registry between 1997 and 2004 by centers in England and Wales with high data completeness were included. Social deprivation was assessed using the Townsend index. Socially deprived patients were more likely to be referred late. They were less likely to receive peritoneal dialysis (25.1 vs 34.8% on day 1, P trend <0.0001) or a renal transplant (5.3 vs 12.4% at 1 year, P trend <0.0001), and were less likely to attain UK Renal Association standards for hemoglobin and phosphate at 1 year. Crude survival decreased significantly with increasing deprivation for patients under the age of 65 years, but not for those aged 65 years and above (likelihood ratio for age-social deprivation interaction P<0.0001). Social deprivation was significantly associated with poorer survival after adjustment for age, gender, and cause of renal failure. After adjusting for baseline co-morbidity, social deprivation was no longer associated with poorer survival. Baseline differences in co-morbidity seem to explain poorer crude survival in incident Caucasian RRT patients from socially deprived areas in England and Wales. Differences also exist in some processes of care and intermediate outcomes, which may be amenable to intervention.

Current chronic kidney disease practice patterns in the UK: a national survey.

BACKGROUND: There is an increasing focus on improving the detection and management of patients with chronic kidney disease (CKD). Data on CKD prevalence based on population sampling are now available, but there are few data about CKD patients attending nephrology services or how such services are organized. AIM: To survey services for CKD patients nationally. METHODS: A pre-piloted questionnaire was sent to all 72 renal units in the UK, referring to the situation in June 2004. RESULTS: Seventy units (97%) responded. The median ratio of prevalent CKD patients/prevalent renal replacement therapy (RRT) patients in the 25 units with data was 3.7 (IQR 2.7-5.7) and the median ratio of CKD stage 4 and 5 patients/prevalent RRT patients was 0.6 (IQR 0.4-1.1). This gives an estimated 140 000 CKD patients under the care of UK nephrologists, with 23 000 at CKD stage 4 or 5 (excluding those on RRT). Very few units had a full complement of the recommended multi-skilled renal team. Counsellors and psychologist were the most common perceived shortages. Of 70 responding units, 50 (74%) were using low clearance clinics for management of advanced CKD patients. Elective dialysis access services often had long delays, with median waiting time for vascular access ranging between 1 and 36 weeks, and for Tenchkoff catheter, between 0 and 12 weeks. DISCUSSION: CKD patients are a significant workload for UK nephrologists. Current provision of service is variable, and services need to be re-designed to cope with the expected future increase of referral of CKD patients.

An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.

OBJECTIVES: To survey of the structure, processes and organisation of renal satellite units (RSUs) in England and Wales (Phase 1), and to compare the effectiveness, acceptability, accessibility and economic impact of chronic haemodialysis performed in RSUs compared to main renal units (MRUs) (Phase 2). DATA SOURCES: Phase 1: all renal satellite units in England and Wales. Phase 2: haemodialysis patients in a representative sample (based on geography, site, private--public ownership, medical input) of 12 RSUs and their MRUs. REVIEW METHODS: Phase 1 consisted of a questionnaire survey. Semi-structured interviews were held in a representative sample of 24 RSUs with the senior clinician, senior nurse and manager. Phase 2 consisted of a cross-sectional comparison of patients in these RSUs and patients in the parent MRUs deemed suitable for satellite care by senior staff. Clinical information was obtained from medical notes and unit computer systems. Generic and disease specific health-related quality of life (HRQoL) measures were used. Co-morbidity was assessed by the Wright/Khan Index, the Lister/Chandna score, the Modified Charlson Index, and the Karnofsky Performance Score. Statistical analyses compared RSU versus MRU patients and took account of the paired and clustered nature of the data. RESULTS: In Phase 1, responses were received from 74/80 (93%) of RSUs; 2600 patients were being treated in these RSUs. The interviews were generally positive about the impact of RSUs in terms of improved accessibility and a better environment for chronic haemodialysis (HD) patients, and in expanding renal replacement therapy patients (RRT) capacity. In Phase 2, some 82% of eligible patients took part, 394 patients in the 12 RSUs and 342 in the parent MRUs. The response rate was similar in both groups. There were no significant differences in clinical processes of care. Most clinical outcomes were similar, especially after pooled analysis, although a few parameters were statistically significantly different -- notably the proportion achieving Renal Association Standards for adequacy of dialysis as measured by the urea reduction ratio (URR) was higher in the RSU patients. Patient-specific quality of life did not differ except on the patient satisfaction questions from the KDQOL, which were scored higher by the RSU sample. Strength of preference for health status on and off dialysis was very similar between the groups, as were EQ-5D utilities. Major adverse events were not common in the RSU patients, although there were many hypotensive episodes on HD, a proportion of which affected the duration of the HD session. Of the costs measured, the only difference that was statistically significant was for District Nurse visits. Of particular note was that despite the MRU group having a higher proportion of patients hospitalised, this did not translate into a statistically significant budgetary impact in terms of the total cost per patient of hospitalisations or mean cost per patient per hospitalisation. CONCLUSIONS: This study has shown that RSUs are an effective alternative to MRU HD for a wide spectrum of patients. They improve geographic access for more dispersed areas and reduce patients' travel time, and are generally more acceptable to patients on several criteria. There does not seem to be an adverse impact of care in the RSUs although comparative long-term prospective data are lacking. The evidence suggests that satellite development could be successfully expanded; not all MRUs have any satellites and many have only a few. No single RSU model can be recommended but key factors would include local geography, the likely catchment population and the type of patients to be treated. There is a need for more basic budgetary information linking activity and expenditure to be available and more transparent, to perform at least an insightful top-down costing of the two care settings. Other areas suggested for further research include: a comparison of adverse events occurring in MRUs and RSUs with longer duration and larger numbers to identify more severe events, along with the more research into the scope for preventing such events, and a study into the patients deemed ineligible for satellite care. International comparisons of satellite care would also be useful.

Regional differences in the provision of adult renal dialysis services in the UK.

BACKGROUND: Provision of renal dialysis varies between UK regions. AIM: To analyse these differences in provision and investigate their causes. DESIGN: Questionnaire-based survey. METHODS: A questionnaire was posted to all renal provider units and renal commissioning groups in the UK. Questions covered issues such as dialysis modalities and patient choice. Data were collected by telephone interview (or post in some cases) and analysed using SPSS. RESULTS: All renal provider units in the UK responded. A full range of modalities was provided by the majority of units. Clear variations in the level and quality of dialysis provision were seen between the UK regions. These included variation in choice of dialysis modality, provision of high-cost drugs, vascular access waiting times, number of support staff and availability of spare dialysis slots. DISCUSSION: The considerable variation between UK regions in the provision of adult renal dialysis services cannot be entirely explained by age or ethnic variation, and is in part due to limited bed space, dialysis machines and support staff, as well as changes in commissioning arrangements. To meet the requirements of the renal national service framework in most regions, changes to policy and funding will be required, such that the relatively new commissioning groups implement more appropriate funding structures in closer dialogue with their provider units.

Trends in adult renal replacement therapy in the UK: 1982-2002.

BACKGROUND: Following the introduction of dialysis and transplantation for the treatment of established renal failure (ERF) 40 years ago, the UK failed to match the achievements of many other countries. AIM: To review progress with treatment for ERF in the UK in the past 20 years. DESIGN: Review of four cross-sectional national studies, and 1997-2002 annual UK Renal Registry data. METHODS: Data on UK patients on renal replacement treatment (RRT) were collated from three sources: European Registry reports for 1982-1990, surveys carried out within the UK in 1993, 1996, 1998 and 2002, and the UK Renal Registry database (1997-2002). Trends in acceptance and prevalence rates, median age, cause of ERF, and treatment modality were analysed and compared with current data from other countries. RESULTS: The UK annual acceptance rate for RRT increased from 20 per million population (pmp) in 1982 to 101 pmp in 2002. This growth was largely in those aged over 65 years, and in those with co-morbidity. Annual acceptance rates for ERF due to diabetes rose from 1.6 to 18 pmp. The prevalence of RRT increased from 157 pmp in 1982 to 626 pmp in 2002. Hospital haemodialysis has become the main modality, and is increasingly being provided in satellite units. Although rising, UK acceptance and prevalence rates are still lower than in many developed countries. DISCUSSION: Despite significant expansion in RRT services for adults in the UK over the last 20 years, there is evidence of unmet need, and need is expected to rise, due to demographic changes and trends in type 2 diabetes. Continuing growth in the already substantial investment in RRT will be needed, unless efforts to prevent the occurrence of ERF are successful.

Refinement of the gene locus for autosomal dominant medullary cystic kidney disease type 1 (MCKD1) and construction of a physical and partial transcriptional map of the region.

Autosomal dominant medullary cystic kidney disease (MCKD) is an adult onset tubulointerstitial nephropathy that leads to salt wasting and end-stage renal failure. A gene locus (MCKD1) has been mapped on chromosome 1q21. Here we report on a large MCKD1 family of British origin linked to the MCKD1 locus. Haplotype analysis performed with markers spanning the previously reported critical MCKD1 region allowed for the refinement of this interval to 4 cM by definition of D1S305 as a new proximal flanking marker. Furthermore, we constructed a yeast artificial chromosome, P1-related artificial chromosome, and bacterial artificial chromosome contig of this region, which is only sparsely covered by the Human Genome Sequencing Project. This enabled us to map numerous expressed sequence tags within the critical interval. This physical and partial transcriptional map of the MCKD1 region is a powerful tool for the identification of positional and functional candidate genes for MCKD1 and will help to identify the disease-causing gene.

Management of anaemia in United Kingdom renal units: a report from the UK Renal Registry.

BACKGROUND: Morbidity and mortality of patients undergoing renal replacement therapy is influenced by the adequacy of correction of renal anaemia. The Renal Association has set standards for attainment of a target haemoglobin of 10 g/dl. This study compared the management of anaemia in dialysis patients in nine renal units in the UK. METHODS: A cross-sectional analysis was carried out on data submitted electronically to the UK Renal Registry. There were 1449 haemodialysis patients and 741 peritoneal dialysis patients in the nine renal centres analysed. Individual patient data were collected on haemoglobin, ferritin, erythropoietin prescription, and pre- and post-dialysis urea concentrations. RESULTS: None of the centres achieved the standard of more than 80% of haemodialysis patients with a haemoglobin of greater than 10 g/dl. Three centres achieved this standard for peritoneal dialysis. There was wide variation between centres in the percentage reaching the target. Differences in ferritin, erythropoietin prescription, and dialysis doses between centres could not entirely explain the variations between centres. Females had lower haemoglobin than males despite a greater proportion being treated with erythropoietin. There was a trend of increasing haemoglobin concentration during the study period in haemodialysis but not in peritoneal dialysis patients. CONCLUSIONS: The Renal Association standards for management of anaemia are not being met. The data allow renal centres to compare their practices with others to identify areas that might be improved. Further analysis may allow a benchmark to be determined of what it is possible to achieve by best practice.

Renal chloride channel, CLCN5, mutations in Dent's disease.

Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure. Patients with Dent's disease may also suffer from rickets and other features of the renal Fanconi Syndrome. Patients may have mutations in the X-linked renal chloride channel gene, CLCN5, which encodes a 746-amino-acid protein with 12-13 transmembrane domains. We have investigated the 11 coding exons of CLCN5 for mutations in eight unrelated patients with Dent's disease. Leukocyte DNA was used for the polymerase chain reaction amplification of CLCN5 and the products analyzed for single-stranded conformational polymorphisms (SSCPs). Abnormal SSCPs were sequenced and revealed eight mutations. These consisted of three nonsense mutations (Arg34Stop, Arg648Stop, Arg704Stop), four deletions involving codons 40, 86, 157, and 241, and one acceptor splice consensus sequence mutation tgcag --> tgaag. The mutations were confirmed either by restriction endonuclease or sequence-specific oligonucleotide hybridization analysis. In addition, an analysis of 110 alleles from 74 unrelated normal individuals demonstrated that the DNA sequence changes were not common polymorphisms. All of the mutations predict truncated chloride channels that are likely to result in a functional loss. Thus, our findings expand the spectrum of CLCN5 mutations associated with Dent's disease and the results will help to elucidate further the functional domains of this novel chloride channel.

Can intensive treatment alter the progress of established diabetic nephropathy to end-stage renal failure?

Diabetic nephropathy is now the leading cause of end-stage renal disease in the Western world, and is associated with a higher patient morbidity and mortality than other causes of renal failure, largely because of associated cardiovascular disease. Numerous studies have elucidated the factors which influence its onset and progression. The St Vincent Declaration in 1994 proposed standards for the appropriate management of patients with diabetic nephropathy. We assessed whether referral to a nephrology clinic attempting to apply these standards influenced the progression of diabetic nephropathy. The results show a significant improvement in blood pressure, glycosylated haemoglobin and serum cholesterol following referral. There was a significant reduction in the rate of decline of renal function following referral in 39% of patients. With the possible exception of diabetic control there were no significant differences in the management of those that did and did not show improvement. The results show that with intensive out-patient clinic monitoring it is possible to improve the quality of patient care, and that even in established diabetic nephropathy it is possible to slow the rate of progression to end-stage renal failure.

The care of patients with diabetic nephropathy: audit, feedback, and improvement.

Diabetic nephropathy is the commonest cause of end-stage renal failure in the developed world. The quality of care of 152 patients with diabetic nephropathy was assessed at the time of referral to a single nephrologist. The type II diabetics (62%) were older than the type I diabetics (38%) (mean 65 years vs. 48 years). The mean duration of diabetes was 17 years. Significant cardiovascular disease was present in 52%. There was diabetic retinopathy in 84% of the type I diabetics and 53% of the type II diabetics. Overall, 63% had hypertension at referral (St Vincent Declaration criteria), untreated in 25%. ACE inhibitors were not prescribed in 48% when no contraindications to their use were present. Glycosylated haemoglobin was > 9.1% in 29%. Twenty were prescribed medications inappropriate to their renal function. Of patients with ischaemic heart disease and serum cholesterol > 5.5 mmol/l, 82% were untreated; 82% of patients with secondary hyperparathyroidism were also untreated. At initial referral, many patients' care was sub-optimal. Referral was too late for adequate preparation for renal replacement therapy in 33%. Following a process of education and feedback of the results to referring practitioners, the timing of referral improved. We emphasize the need for closer co-operation between those managing diabetic patients with nephropathy to optimize their care.

Autosomal dominant medullary cystic kidney disease: evidence of gene locus heterogeneity.

Autosomal dominant medullary cystic kidney disease (ADMCKD; synonym: medullary cystic disease, MCD) is an autosomal dominant kidney disorder, sharing morphological and clinical features with recessive juvenile nephronophthisis (NPH), such as reduced urinary concentration ability and multiple renal cysts at the corticomedullary junction. While in NPH end-stage renal disease (ESRD) occurs in adolescence, ADMCKD leads to ESRD in adulthood. Recently a gene locus for ADMCKD has been localized to chromosome 1q21 in two large Cypriot families. This prompted us to examine linkage in three ADMCKD-families, using the same set of polymorphic microsatellite markers spanning the critical region on chromosome 1q21. Haplotype analysis revealed that none of the three families showed linkage to this locus, thus demonstrating evidence for genetic locus heterogeneity. Additional linkage analysis studies need to be performed in order to identify further gene loci cosegregating with this autosomal dominant kidney disorder.

Dialysis decision making in Canada, the United Kingdom, and the United States.

This study was designed to determine the extent to which differences in criteria for dialysis patient selection and availability of financial resources cause the wide variation in acceptance rates for dialysis in Canada, the United Kingdom, and the United States. We also sought to determine whether there is agreement among nephrologists in the three countries on which patients should not be offered dialysis. We used a cross-sectional survey of all members of the Canadian Society of Nephrology and the Renal Association of Great Britain, and a randomized sample of 800 members of the American Society of Nephrology. Five case vignettes were presented asking for yes/no decisions on offering or not offering dialysis, together with ranking of factors considered important. We also inquired about dialysis resources and physician demographics. We compared responses by country. More nephrologists from the United Kingdom returned responses (83%) than Canadian (53%) or American (36%) nephrologists. American nephrologists offered dialysis more than Canadian or British nephrologists (three of five cases; P < 0.04 to P < 0.001) and ranked patient/family wishes (three of five cases; P < 0.057 to P < 0.0001) and fear of lawsuit (P < 0.04 to P = 0.0012) higher than British or Canadian nephrologists. Canadian and British nephrologists reported their perception of patients' quality of life as a reason to provide (P = 0.0019) or not provide (P = 0.068 to P = 0.0026) dialysis more often than their American counterparts. Despite these differences, nephrologists from each country did not differ by more than 30% on any decision and ranked factors almost identically. Ten percent and 12% of Canadian and British nephrologists, respectively, but only 2% of American nephrologists, reported refusing dialysis due to lack of resources (P < 0.0001). We conclude that the wide variation in dialysis acceptance rates in the three countries is somewhat influenced by differences in patient selection criteria and withholding of dialysis by nephrologists based on financial constraints, but that other factors, such as differences in rates of patient nonreferral for dialysis, contribute more significantly to the variation. Generally agreed on practice guidelines for dialysis patient selection appear possible.

The provision of renal replacement therapy for adults in England and Wales: recent trends and future directions.

We assessed the level of provision of renal replacement therapy for adults in England and Wales. All autonomous main renal units in England (n = 52) and Wales (n = 5) were surveyed in 1996. Data for England were compared to the 1993 National Renal Review. The acceptance rate in England 1995 was 82 (80-85) per million population (p.m.p.) compared with 67 (65-70) p.m.p. in 1991-2. The rate in 1995 in Wales was 109 (98-122) p.m.p. The prevalence rate in England was 476 p.m.p. at end-1995 compared to 393 p.m.p. in 1993, in Wales it was 487 p.m.p. The number of main renal units in England did not rise between 1993 and 1995; capacity was increased by use of more treatment shifts and temporary haemodialysis stations, and by opening more satellite units. The main growth was in hospital haemodialysis. There was an uneven geographical distribution of services. Patients accepted were older with more comorbidity. The use of better-quality processes of dialysis increased. The steady-state position for RRT will not be reached for over a decade. Health authorities will face continued pressure to fund increases in quantity and quality improvements. A stronger evidence base of the effectiveness of therapies, and a national registry to monitor the equity and cost-effectiveness of services are needed.

Modified cytotoxic T lymphocyte precursor frequency assay by measuring released europium in a time resolved fluorometer.

The frequency of cytotoxic T lymphocyte precursors (CTLpf) can be quantified by using the principle of limiting dilution analysis (LDA). Chromium 51 (51Cr) and europium (Eu) release assays are based on the measurement of marker release after lysis of targets by the effector cells. Although, 51Cr release has been widely used to quantify cell lysis since its introduction, it has several disadvantages such as handling and disposal of radioisotopes as well as health risk to personnel involved performing the assay. This situation has led us to adopt a non-radioactive cytotoxicity assay. After 7 days culture the PHA-stimulated targets are labeled with europium DTPA chelate. Lysis of labeled targets by effectors releases the Eu-DTPA complex in culture medium--a highly fluorescent substance. The amount of fluorescence can be measured in a time resolved fluorometer. We describe here some modifications of the original protocol which include optimising IL-2 requirements, reduction of incubation times, addition of an extra spin before 37 degrees C incubation, readjustment of target cells per volume of labeling buffer and other crucial parameters increasing the specificity and sensitivity of CTLpf assay. We are in agreement with others that the Eu-release assay is specific and reproducible. It can be used for the CTLpf estimation as well as other T cell and non-T cell cytotoxicity assays.

Carbamylated hemoglobin: a potential marker for the adequacy of hemodialysis therapy in end-stage renal failure.

Urea can dissociate in vivo to form isocyanic acid which can react with hemoglobin to form carbamylated hemoglobin. Previous work has shown that formation of carbamylated hemoglobin depends upon both the severity and the duration of renal failure. To determine whether carbamylated hemoglobin can be used as an assessment of the adequacy of hemodialysis treatment, we prospectively studied 55 stable patients who regularly attended our hospital dialysis program. Carbamylated hemoglobin was greater in those patients with a Kt/V of < or = 1.1 compared to those with a Kt/V of > 1.1 (120 +/- 8 micrograms VH/gHb versus 99 +/- 7, P < 0.01), and there was a negative correlation with Kt/V (r = -0.37, P = 0.007). There were positive correlations between carbamylated hemoglobin and the time-averaged urea concentration (r = 0.4, P = 0.004), and a negative correlation with the urea reduction ratio (r = -0.37, P = 0.01). Carbamylated hemoglobin may therefore be a useful marker of the degree of uremia, just as glycosylated hemoglobin is used in the assessment of patients with diabetes mellitus.