Changing Protein Permeability with Nephron Loss: Evidence for a Human Remnant Nephron Effect.

BACKGROUND: If loss of functioning nephrons predisposes to glomerular barotrauma (a "remnant nephron" effect), then glomerular permeability should increase as glomerular filtration rate (GFR) falls, as is observed in animal models of nephron loss. METHODS: Changes in net renal protein permeability, defined as proteinuria or albuminuria per mL/min of GFR, were measured in the setting of nephron loss due to kidney donation (Assessing Long Term Outcomes in Living Kidney Donors cohort) or progressive chronic kidney disease (CKD; Modification of Diet in Renal Disease [MDRD], African American Study of Kidney Disease [AASK], and Chronic Renal insufficiency Cohort [CRIC] studies). RESULTS: Following kidney donation, renal albumin permeability increased by 31% from predonation levels (p < 0.001). With progression of CKD, a 50% loss of residual GFR was accompanied by increases in proteinuria per mL/min GFR of 1.8-, 2.1-, and 1.6-fold in the MDRD, AASK, and CRIC cohorts, respectively (p < 0.001 for all), independent of changes in systolic blood pressure and ACEi/ARB use. A 70% reduction in GFR was associated with permeability increases of 3.1-, 4.4-, and 2.6-fold in the same cohorts. Among MDRD participants with progression of nonglomerular primary disease, the 75th percentile of final permeability was 141 mg/24 h proteinuria per mL/min GFR. This degree of permeability would have resulted in nephrotic range proteinuria had it been present at the baseline mean GFR of 40 mL/min, implying the development of de novo glomerular pathology as GFR fell. Increasing permeability also accompanied CKD progression in participants with nephrotic syndrome at baseline. Consequently, these participants had little improvement in 24 h proteinuria or serum albumin, despite substantial loss of functioning nephron mass across which the protein leak occurred. In the absence of a fall in GFR, there was no increase in permeability in any cohort. CONCLUSION: Nephron loss is accompanied by an increase in renal protein permeability, even in the absence of a primary glomerular disease. This is consistent with a remnant nephron effect in human CKD.

A survey on the methodological processes and policies of renal guideline groups as a first step to harmonize renal guidelines.

BACKGROUND: Worldwide, several bodies produce renal guidelines, potentially leading to duplication of effort while other topics may remain uncovered. A collaborative work plan could improve efficiency and impact, but requires a common approved methodology. The aim of this study was to identify organizational and methodological similarities and differences among seven major renal guideline bodies to identify methodological barriers to a collaborative effort. METHODS: An electronic 62-item survey with questions based on the Institute of Medicine standards for guidelines was completed by representatives of seven major organizations producing renal guidelines: the Canadian Society of Nephrology (CSN), European Renal Best Practice (ERBP), Kidney Disease Improving Global Outcome (KDIGO), Kidney Health Australia-Caring for Australians with Renal Insufficiency (KHA-CARI), Kidney Disease Outcome Quality Initiative (KDOQI), Sociedad Latino-Americano de Nefrologia e Hipertension (SLANH) and United Kingdom Renal Association (UK-RA). RESULTS: Five of the seven groups conduct systematic searches for evidence, two include detailed critical appraisal and all use the GRADE framework. Five have public review of the guideline draft. Guidelines are updated as new evidence comes up in all, and/or after a specified time frame has passed (N = 3). Commentaries or position statements on guidelines published by other groups are produced by five, with the ADAPTE framework (N = 1) and the AGREEII (N = 2) used by some. Funding is from their parent organizations (N = 5) or directly from industry (N = 2). None allow funders to influence topic selection or guideline content. The budgets to develop a full guideline vary from $2000 to $500 000. Guideline development groups vary in size from <5 (N = 1) to 13-20 persons (N = 3). Three explicitly seek patient perspectives, for example, by involving patients in the scoping process, and four incorporate health economic considerations. All provide training in methodology for guideline development groups and six make their methods public. All try to avoid overlapping topics already planned or published by others. There is no common conflict of interest policy. CONCLUSIONS: Overall, there is considerable commonality in methods and approaches in renal guideline development by the different organizations, although some procedural differences remain. As the financial and human resource costs of guideline production are high, a collaborative approach is required to maximize impact and develop a sustainable work plan. Coming to consensus on methods and procedures is the first step and appears feasible.

Shared decision making: a personal view from two kidney doctors and a patient.

Shared decision making (SDM) combines the clinician's expertise in the treatment of disease with the patient's expertise in their lived experience and what is important to them. All decisions made in the care of patients with kidney disease can potentially be explored through SDM. Adoption of SDM in routine kidney care faces numerous institutional and practical barriers. Patients with chronic disease who have become accustomed to paternalistic care may need support to engage in SDM-even though most patients actively want more involvement in decisions about their care. Nephrologists often underestimate the risks and overestimate the benefits of investigations and treatments and often default to recommending burdensome treatments rather than discussing prognosis openly. Guideline bodies continue to issue recommendations written for healthcare professionals without providing patient decision aids. To mitigate health inequalities, care needs to be taken to provide SDM to all patients, not just the highly health-literate patients least likely to need additional support in decision making. Kidney doctors spend much of their time in the consulting room, and it is unjustifiable that so little attention is paid to the teaching, audit and maintenance of consultation skills. Writing letters to the patient to summarise the consultation rather than sending them a copy of a letter between health professionals sets the tone for a consultation in which the patient is an active partner. Adoption of SDM will require nephrologists to relinquish long-established paternalistic models of care and restructure care around the values and preferences of patients.

Patterns and effects of missing comorbidity data for patients starting renal replacement therapy in England, Wales and Northern Ireland.

BACKGROUND: Renal Registries play a key role in assessing quality of care and outcomes of renal replacement therapy and comparisons of outcomes between groups should adjust for differences in comorbidities. This study aimed to describe patterns of missing comorbidity data and differences in survival between patients with comorbidity data returned and those with missing comorbidity data. METHODS: Trends in comorbidity data returns by year (1998-2006) and within centres were examined using descriptive statistics. Survival of patients was described using Kaplan-Meier graphs (log-rank tests) and hazard ratios were calculated using Cox proportional hazard models. Last follow-up was at 31 December 2007. A range of sensitivity analyses were carried out, including multiple imputation. RESULTS: Among 34,059 patients, there were 62% who had no comorbidity data. The completeness of comorbidity data increased markedly from 17% in 1998 to 47% in 2003, but had fallen back to 37% by the year 2006. Those with a missing comorbidity generally do considerably worse than those without the comorbidity and in most cases more closely follow the survival curve of those with the comorbidity. Multiple imputation analysis suggested that those with missing information on comorbidity have higher prevalence of comorbidity than seen in those with available data. Treating missing comorbidity entries as indication of absent comorbidity (i.e. a tick only if yes policy) would lead to an attenuation of the effect of comorbidity on survival. CONCLUSIONS: Missing data lead to difficulties in performing between centre comparisons. A 'tick if present policy' in comorbidity data collection should be discouraged. Much more work is needed to fully understand why levels of missing comorbidity data are so high and to identify strategies to improve recording.

Guidance for post-discharge care following acute kidney injury: an appropriateness ratings evaluation.

BACKGROUND: Acute kidney injury (AKI) is associated with poor health outcomes, including increased mortality and rehospitalisation. National policy and patient safety drivers have targeted AKI as an example to ensure safer transitions of care. AIM: To establish guidance to promote high-quality transitions of care for adults following episodes of illness complicated by AKI. DESIGN & SETTING: An appropriateness ratings evaluation was undertaken using the RAND/UCLA Appropriateness Method (RAM). The Royal College of General Practitioners (RCGP) AKI working group developed a range of clinical scenarios to help identify the necessary steps to be taken following discharge of a patient from secondary care into primary care in the UK. METHOD: A 10-person expert panel was convened to rate 819 clinical scenarios, testing the most appropriate time and action following hospital discharge. Specifically, the scenarios focused on determining the appropriateness and urgency for planning: an initial medication review; monitoring of kidney function; and assessment for albuminuria. RESULTS: Taking no action (that is, no medication review; no kidney monitoring; or no albuminuria testing) was rated inappropriate in all cases. In most scenarios, there was consensus that both the initial medication review and kidney function monitoring should take place within 1-2 weeks or 1 month, depending on clinical context. However, patients with heart failure and poor kidney recovery were rated to require expedited review. There was consensus that assessment for albuminuria should take place at 3 months after discharge following AKI. CONCLUSION: Systems to support tailored and timely post-AKI discharge care are required, especially in high-risk populations, such as people with heart failure.

Effect of change in renal replacement therapy modality on laboratory variables: a cohort study from the UK Renal Registry.

BACKGROUND: Although previous comparisons have shown differences in biochemical and haematological variables between patients on haemodialysis and peritoneal dialysis and those with functioning transplants, these could be due to case mix rather than being due to differences in the types of renal replacement therapy (RRT). The longitudinal follow-up of individual patients after the change in modality has not hitherto been described. METHODS: From the UK Renal Registry (UKRR) database of patients receiving RRT between 1 January 1997 and 31 December 2004, we identified two cohorts: 2033 patients who had been on either haemodialysis (HD) or peritoneal dialysis (PD) for at least a year and who subsequently underwent transplantation and then survived at least a year (PD + HD to Tp); and 892 patients who had been on PD for at least a year who changed to HD and then survived at least a year (PD to HD). In both cohorts, the following variables were studied for the four quarters before and after the change of modality: blood haemoglobin and serum, ferritin, albumin, bicarbonate, cholesterol, calcium, phosphate and parathyroid hormone (PTH) concentrations. No information on drug treatment was available. RESULTS: In the PD + HD to Tp cohort, transplantation was associated with a rise in haemoglobin, albumin and bicarbonate, a fall in ferritin and phosphate, no change in calcium, a fall (but not to normal) in PTH and a transient rise in cholesterol concentrations. In the PD to HD group, the change in modality was associated with a significant temporary fall in haemoglobin, a progressive rise in ferritin, albumin, phosphate and PTH, no change in calcium and fall in bicarbonate and cholesterol concentrations. CONCLUSION: The change from HD to PD is associated with a significant fall in the haemoglobin concentration; anticipation of this change might enable clinicians to ameliorate it. Persistent hyperparathyroidism is common after kidney transplantation.

Assessment of urea removal in haemodialysis and the impact of the European Best Practice Guidelines.

BACKGROUND: Dialysis adequacy, assessed by urea kinetics, is an important determinant of patient outcome, and is therefore an important clinical performance indicator. In this perspective, renal registry data may be useful to compare practices across countries. To serve that purpose available data should be comparable and preferably collected using a standardized procedure. The aim of this study, initiated by the European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA) QUality European STudies (QUEST) initiative, was to make an inventory of the different methods used to determine urea kinetic measurements in the light of the European Best Practice Guidelines. METHODS: Via their national and regional registries, European haemodialysis centres were invited to complete a questionnaire regarding their practice of measuring dialysis adequacy. RESULTS: Fourteen regional or national registries among 51 sent back 255 questionnaires. Great variability in the methodology to assess Kt/V was observed. The urea reduction ratio (URR) was used alone by 37% (in association 46%) of dialysis centres, spKt/V by 25% (35%) and on-line clearance by 4% (12%), whereas only 10% (13%) used eKt/V, as recommended by EBPG. Forty percent of centres measured urea removal less than once a month, 6% of which never measured urea removal and 9% only every 6 months or less frequently. CONCLUSION: Despite the fact that the use of URR is not recommended by EBPG, it was the most commonly used indicator to measure urea removal, whereas eKt/V was only used by a small minority of centres. This study allowed us to point out the need to standardize definitions and procedures and to develop an effective plan for implementation of the guidelines.

UK Renal Registry 11th Annual Report (December 2008): Chapter 7 Survival and causes of death of UK adult patients on renal replacement therapy in 2007: national and centre-specific analyses.

INTRODUCTION: These analyses examine survival from the start of renal replacement therapy (RRT), based on the total incident UK dialysis population reported to the Registry, including the 21% who started on PD and the 5% who received a pre-emptive transplant. Survival of prevalent patients and changes in survival between 1997-2006 are reported. The article includes a discussion on the technical definition for the date of start of both PD and HD. METHODS: Survival was calculated for both incident and prevalent patients on RRT and compared between the UK countries after adjustment for age. Survival of incident patients (starting during 2006) was calculated with and without a 90 day RRT start cut off. Survival of incident patients is shown with and without censoring at transplantation. Both the Kaplan-Meier and Cox adjusted models were used to calculate survival. Causes of death were analysed for both groups. Relative risk of death was calculated compared with the general UK population. RESULTS: The 2006 unadjusted 1 year after 90 day survival for patients starting RRT was 86%. In incident 18-64 year olds the unadjusted 1 year survival had risen from 85.9% in 1997 to 91.5% in 2006 and for those aged > or = 65 it had risen from 63.8% to 72.9%. The age adjusted survival of prevalent dialysis patients rose from 85% in 2000 to 89% in 2007. Diabetic patient survival rose from 76.6% in 2000 to 84.0% in 2007. The relative risk of death on RRT compared with the general population was 30 at age 30 years compared with 3 at age 80 years. In the prevalent RRT dialysis population, cardiovascular disease accounted for 34% of deaths, infection 20% and treatment withdrawal 14%. CONCLUSIONS: Incident and prevalent patient survival on RRT in all the UK countries for all age ranges and also for patients with diabetes continued to improve. The relative risk of death on RRT compared with the general population has fallen since 2001. Death rates on dialysis in the UK remained lower than when compared with a similar aged population on dialysis in the USA.

Introduction to the 2006 UK Renal Registry report (chapter 2).

The UK Renal Registry is part of the UK Renal Association and provides independent audit and analysis of renal replacement therapy in the UK. The Registry is funded directly by participating renal units through an annual fee per patient registered. The Registry is now collecting data on incidence and prevalence from 100% of UK renal units, with the five remaining non-linked sites in England providing summary data. Maintaining and enhancing Registry functionality will be an important touchstone for the Connecting for Health initiative. Collaboration with other formal agencies also promises an exciting prospect for future development. After a long proving period, the means, methods and roles have come together to complete an effective adjunct to clinical activity, planning, research and the performance of the renal community.

Comorbidities in UK patients at the start of renal replacement therapy (chapter 6).

Comorbidity returns have continued to improve, albeit slowly, with centres running Mediqal software having the highest rates of completeness. Diabetes as a primary renal diagnosis accounted for 20% of those starting RRT, but a further 7% had diabetes present as a comorbid condition. The incidence of smoking remained high at 17% of diabetic patients, which was similar to that found in non-diabetics. Twelve percent of the patients starting RRT had a previous myocardial infarction (MI) and 31% of those aged over 65 years starting RRT had ischaemic heart disease (IHD). Patients starting on peritoneal dialysis (PD) were on average 9 years younger than those on haemodialysis (HD) and had fewer comorbidities present. Patients starting RRT without any comorbidity present had a lower median estimated glomerular filtration rate (eGFR) than those with comorbid conditions. Patients with a previous MI or coronary artery bypass grafting (CABG), started RRT with slightly higher mean haemoglobin than those without comorbid conditions or other comorbid conditions. On univariate survival analysis, diabetes was not associated with an increased risk of death amongst patients aged over 65 years, possibly due to its close association with other comorbidities in this age group. In the multivariate survival analysis, the presence of ischaemic/neuropathic ulcers was the predictor of worst survival, followed by malignancy, previous MI and age per 10 year increment. Smoking was less common in both South Asian and black patients than whites (7 vs 17%) starting RRT. Twenty-three percent of both South Asian and white patients started RRT with IHD compared with only 12% of Black patients.

Survival of incident RRT patients in the UK (chapter 12).

This analysis presents the survival of patients starting renal replacement therapy (RRT) in UK renal units ('centres'), and includes an analysis of survival by centre. Data from 59 of the 70 UK centres are included. This is the first year that UK centre anonymity has been removed from analysis of patient survival by centre. Survival after adjustment for comorbidity is also reported for the first time although this analysis is restricted to those centres returning data on comorbidity in at least 85% of incident patients. The importance of adjusting for comorbidity can be seen in that for one centre, after adjustment of survival for age and diagnosis, the adjusted 1 year after 90 day survival was 84.6%. After adjusting to the average comorbidity present across centres, survival increased to 90.4%. Improved comorbidity data returns by renal units may require investment in informatics staff and creating structural process at renal unit level for clinicians to support these data returns. From the date of first RRT, the 1 year survival of all patients (unadjusted for age) is 79%. From the 90th day of RRT (to allow comparison with other countries' 1 year survival), the 1 year survival is 83%. The age adjusted (60 years) survival for the 1 year after 90 day period is 86%. There is a high death rate in the first 90 days on RRT (6% of all patients starting RRT), a period not included in reports by many registries and other studies. The 5 year survival (including deaths within the first 90 days) rates are 58, 53, 44, 28, 19 and 12%, respectively for patients aged 18-34, 35-44, 45-54, 55-64, 65-74 and >75 years. The 'vintage effect' of increasing hazard of death with length of time on RRT, prominent in data from the US, is only noted in older age groups (65-75 and 75+ years) at 5-6 years after starting RRT. Six centres had a figure for the 1 year after 90 day survival which was outside 2 SDs from the mean for the UK: in three cases this was better survival, and in three, poorer survival, than expected. Poor reporting by renal units of patient comorbidity makes interpretation of these apparent differences in patient survival between centres difficult and a relationship to clinical performance cannot yet be inferred.

Haemodialysis dose and serum bicarbonate (chapter 7).

Data from 21 renal units was insufficient to allow analyses of the dose of dialysis in those units. Amongst the remainder, there is evidence of a progressive increase in the proportion of patients meeting the Renal Association audit standard for urea reduction ratio (URR). In the UK as a whole, 81% of prevalent haemodialysis patients met the standard for URR in 2005. Greater achievement of the standard in a given unit is associated with a higher median URR in that unit, although there is some evidence that some units have been able to narrow the distribution of achieved URR values. Achievement of the standard remains, as in previous years' Reports, less common amongst patients recently established on haemodialysis compared with those established on haemodialysis for longer. Correction of acidosis, as measured by serum bicarbonate concentration remains highly variable, although there is continued uncertainty about the interpretation of routine measurements of venous serum bicarbonate concentration in haemodialysis patients. Overall, approximately 64% of UK haemodialysis patients, and 50% of peritoneal dialysis patients met the Renal Association standard for serum bicarbonate in 2005.

Management of anaemia in haemodialysis and peritoneal dialysis patients (chapter 8).

Forty-one percent of UK patients commence RRT with an Hb < 10.0 g/dl. The mean Hb at commencement of RRT is 10.3 g/dl. Eighty-five percent of patients on dialysis in the UK have an Hb > or = 10.0 g/dl by 6 months after commencement of RRT. The median Hb on haemodialysis in the UK is 11.8 g/dl with an IQR of 10.7-12.8 g/dl. Eighty-six percent of haemodialysis patients in the UK have a Hb > or = 10.0 g/dl. The median Hb on peritoneal dialysis in the UK is 12.0 g/dl with an IQR of 11.0-12.9 g/dl. Ninety percent of peritoneal dialysis patients in the UK have an Hb > or = 10.0 g/dl. In the UK, 49% of patients on PD and 48% of patients on haemodialysis have an Hb between 10.5-12.5 g/dl. The median ferritin in UK haemodialysis patients is 413 microg/l (IQR 262-623), 95% of UK haemodialysis patients have a ferritin > or =100 microg/l. The median ferritin in UK PD patients is 256 microg/l (IQR 147-421), 86% of UK peritoneal dialysis patients have a ferritin > or = 100 microg/l. A higher proportion of HD patients than PD patients receive ESA therapy (88% vs 76%). The ESA dose is higher for HD than PD patients (9204 vs 6080 IU/week).

Evidence for Reverse Causality in the Association Between Blood Pressure and Cardiovascular Risk in Patients With Chronic Kidney Disease.

Among those with moderate-to-advanced chronic kidney disease, the relationship between blood pressure (BP) and cardiovascular disease seems U shaped but is loglinear in apparently healthy adults. The SHARP (Study of Heart and Renal Protection) randomized 9270 patients with chronic kidney disease to ezetimibe/simvastatin versus matching placebo and measured BP at each follow-up visit. Cox regression was used to assess the association between BP and risk of cardiovascular disease among (1) those with a self-reported history of cardiovascular disease and (2) those with no such history and, based on plasma troponin-I concentration, a low probability of subclinical cardiac disease. A total of 8666 participants had a valid baseline BP and troponin-I measurement, and 2188 had at least 1 cardiovascular event during follow-up. After adjustment for relevant confounders, the association between systolic BP and cardiovascular events was U shaped, but among participants without evidence of previous cardiovascular disease, there was a positive loglinear association throughout the range of values studied. Among those with the lowest probability of subclinical cardiac disease, each 10 mm Hg higher systolic BP corresponded to a 27% increased risk of cardiovascular disease (hazard ratio, 1.27; 95% confidence interval, 1.11-1.44). In contrast, the relationship between diastolic BP and cardiovascular risk remained U shaped irrespective of cardiovascular disease history or risk of subclinical disease. In conclusion, the lack of a clear association between systolic BP and cardiovascular risk in this population seems attributable to confounding, suggesting that more intensive systolic BP reduction may be beneficial in such patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00125593.

Identification, management and referral of adults with chronic kidney disease: concise guidelines.

Chronic kidney disease (CKD) is often thought to be a relatively rare condition requiring specialist care. However, early CKD is common and referral of all patients would completely overwhelm existing specialist services. The purpose of this concise guidance is to inform general physicians and general practitioners about the identification and management of CKD, and who to refer for specialist care.

Reducing the carbon footprint of hospital-based care.

Climate change, driven by man-made greenhouse gas emissions, is a major threat to the health of this and future generations. Hospital-based healthcare generates large quantities of greenhouse gas emissions. Reducing the carbon footprint of healthcare requires direct action to reduce waste and energy use, but also requires radical reform of care pathways so that the only patients who come to or stay in hospital are people whose healthcare cannot safely be delivered closer to home. Achieving these reforms without major structural changes to the financial flows in the NHS will be extraordinarily difficult.

Vascular calcification in chronic renal failure.

The prevalence and extent of vascular calcification (VC) increases rapidly with time on dialysis. There is increasing evidence that medial calcification of conduit arteries, without intimal disease, is associated with important abnormalities of vascular compliance and increased risk of cardiovascular death. Coronary artery calcification is also common in end-stage renal disease, but further research is required to determine how much of this calcification is in the form of calcified intimal atherosclerotic plaque and how much in the tunica media. Calcific uraemic arteriolopathy causes a syndrome of ischaemic necrosis of the skin and subcutaneous tissue and appears to be increasing in incidence. At all sites, arterial calcification is a biologically controlled process, with expression in vascular smooth muscle cells of genes usually expressed in osteoblasts and the formation of hydroxyapatite. High extracellular phosphate concentration induces these phenotypic changes in vitro, and much of the clinical evidence supports hyperphosphataemia as the major driver of VC. Whether warfarin treatment plays a role, by inhibiting production of vitamin-K-dependent inhibitors of calcification in humans, remains uncertain but possible. High doses of prescribed calcium-based phosphate binders are associated with VC, whereas use of sevelamer to achieve the same serum phosphate level greatly retards progression of coronary and aortic calcification. The biological mechanism by which positive calcium balance and/or episodes of hypercalcaemia promotes VC remains unclear. Treatment of established calcific uraemic arteriolopathy consists of aggressive reduction of serum calcium x phosphate product; the roles of hyperbaric oxygen, steroid therapy, and non-warfarin anticoagulation remain uncertain.

Membranoproliferative glomerulonephritis associated with an Epstein-Barr virus infection.

Type 1 membranoproliferative glomerulonephritis (MPGN) is an immune complex-mediated disorder that has been associated with certain viral infections including hepatitis C, hepatitis B, hepatitis G, HIV and Hantavirus. We describe a patient with type 1 MPGN in native kidneys and nephrotic syndrome in whom there was strong evidence that a primary Epstein-Barr virus (EBV) infection played a causative role. This patient was treated with an angiotensin 2-receptor blocker and the nephrotic syndrome resolved within 6 months from presentation. Our case report suggests that MPGN presenting with nephrotic syndrome may have a relatively benign course when it is associated with an acute EBV infection.