Current management of chronic kidney disease in type-2 diabetes-A tiered approach: An overview of the joint Association of British Clinical Diabetologists and UK Kidney association (ABCD-UKKA) guidelines.

A growing and significant number of people with diabetes develop chronic kidney disease (CKD). Diabetes-related CKD is a leading cause of end-stage kidney disease (ESKD) and people with diabetes and CKD have high morbidity and mortality, predominantly related to cardiovascular disease (CVD). Despite advances in care over the recent decades, most people with CKD and type 2 diabetes are likely to die of CVD before developing ESKD. Hyperglycaemia and hypertension are modifiable risk factors to prevent onset and progression of CKD and related CVD. People with type 2 diabetes often have dyslipidaemia and CKD per se is an independent risk factor for CVD, therefore people with CKD and type 2 diabetes require intensive lipid lowering to reduce burden of CVD. Recent clinical trials of people with type 2 diabetes and CKD have demonstrated a reduction in composite kidney end point events (significant decline in kidney function, need for kidney replacement therapy and kidney death) with sodium-glucose co-transporter-2 (SGLT-2) inhibitors, non-steroidal mineralocorticoid receptor antagonist finerenone and glucagon-like peptide 1 receptor agonists. The Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) Diabetic Kidney Disease Clinical Speciality Group have previously undertaken a narrative review and critical appraisal of the available evidence to inform clinical practice guidelines for the management of hyperglycaemia, hyperlipidaemia and hypertension in adults with type 2 diabetes and CKD. This 2024 abbreviated updated guidance summarises the recommendations and the implications for clinical practice for healthcare professionals who treat people with diabetes and CKD in primary, community and secondary care settings.

Development and validation of a chronic kidney disease progression model using patient-level simulations.

Chronic disease progression models are available for several highly prevalent conditions. For chronic kidney disease (CKD), the scope of existing progression models is limited to the risk of kidney failure and major cardiovascular (CV) events. The aim of this project was to develop a comprehensive CKD progression model (CKD-PM) that simulates the risk of CKD progression and a broad range of complications in patients with CKD. A series of literature reviews informed the selection of risk factors and identified existing risk equations/algorithms for kidney replacement therapy (KRT), CV events, other CKD-related complications, and mortality. Risk equations and transition probabilities were primarily sourced from publications produced by large US and international CKD registries. A patient-level, state-transition model was developed with health states defined by the Kidney Disease Improving Global Outcomes categories. Model validation was performed by comparing predicted outcomes with observed outcomes in the source cohorts used in model development (internal validation) and other cohorts (external validation). The CKD-PM demonstrated satisfactory modeling properties. Accurate prediction of all-cause and CV mortality was achieved without calibration, while prediction of CV events through CKD-specific equations required implementation of a calibration factor to balance time-dependent versus baseline risk. Predicted annual changes in estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio were acceptable in comparison to external values. A flexible eGFR threshold for KRT equations enabled accurate prediction of these events. This CKD-PM demonstrated reliable modeling properties. Both internal and external validation revealed robust outcomes.

Management of adults with diabetes on dialysis: Summary of recommendations of the Joint British Diabetes Societies guidelines 2022.

Diabetes is the commonest cause of end-stage kidney disease in many parts of the world, and many people on dialysis programmes live with diabetes. Such people are vulnerable to complications from their diabetes, and their care may be fragmented due to the many specialists involved. This updated guidance from the Joint British Diabetes Societies aims to review and update the 2016 guidance, with particular emphasis on glycaemic monitoring in the light of recent advances in this area. In addition, the guidance covers clinical issues related to the management of diabetes in people on peritoneal dialysis, along with acute complications such as hypoglycaemia and ketoacidosis, and chronic complications such as foot and eye disease.

UK Kidney Association Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease 2023 UPDATE.

Large placebo-controlled trials have demonstrated kidney and cardiovascular clinical benefits of SGLT-2 inhibitors. Data from the EMPA-KIDNEY and DELIVER trials and associated meta-analyses triggered an update to the UK Kidney Association Clinical Practice Guideline on Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease. We provide a summary of the full guideline and highlight the rationale for recent updates. The use of SGLT-2 inhibitors in people with specific medical conditions, including type 1 diabetes, kidney transplants, and people admitted to hospital with heart failure is also considered, along with Recommendations for future research and Recommendations for implementation. A full "lay" summary of the guidelines is provided as an appendix to ensure that these guidelines are accessible and understandable to people who are not medical professionals.

Clinical practice guidelines for management of hyperglycaemia in adults with diabetic kidney disease.

A significant percentage of people with diabetes develop chronic kidney disease and diabetes is also a leading cause of end-stage kidney disease (ESKD). The term diabetic kidney disease (DKD) includes both diabetic nephropathy (DN) and diabetes mellitus and chronic kidney disease (DM CKD). DKD is associated with high morbidity and mortality, which are predominantly related to cardiovascular disease. Hyperglycaemia is a modifiable risk factor for cardiovascular complications and progression of DKD. Recent clinical trials of people with DKD have demonstrated improvement in clinical outcomes with sodium glucose co-transporter-2 (SGLT-2) inhibitors. SGLT-2 inhibitors have significantly reduced progression of DKD and onset of ESKD and these reno-protective effects are independent of glucose lowering. At the time of this update Canagliflozin and Dapagliflozin have been approved for delaying the progression of DKD. The Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) Diabetic Kidney Disease Clinical Speciality Group have undertaken a literature review and critical appraisal of the available evidence to inform clinical practice guidelines for management of hyperglycaemia in adults with DKD. This 2021 guidance is for the variety of clinicians who treat people with DKD, including GPs and specialists in diabetes, cardiology and nephrology.

Measurement of glomerular filtration rate in patients undergoing obesity surgery.

BACKGROUND: Most studies on obesity surgery have measured renal function using the estimated GFR. However, due to the reduction of muscle mass, and therefore creatinine that accompanies weight loss, such measures can falsely suggest an improvement in renal function. To balance the risks of surgery versus any potential benefits on renal function, we need to be able to determine renal function using valid and reliable methodologies. In this pilot study we aimed to measure renal function in patients with CKD undergoing obesity surgery using the gold standard 51Cr-EDTA GFR clearance methodology which is independent of measures of muscle mass. METHODS: Nine consecutive obese patients with CKD underwent obesity surgery. Their renal function was assessed using 51Cr-EDTA GFR, cystatin C and serum creatinine as well as using eGFR equations including MDRD CKD Epi, Cockcroft Gault and CKD Epi cystatin before and 12 months after surgery. RESULTS: Renal function using the 51Cr-EDTA measured GFR did not change significantly after surgery. Similar results were obtained when Cystatin C, CKD Epi cystatin, CKD Epi cystatin creatinine and adjusted Cockcroft Gault Creatinine clearance methods were used. In contrast there were either trends or significant improvements in renal function measured using the MDRD and CKD Epi equations. CONCLUSIONS: In this pilot study using the gold standard 51Cr-EDTA method we found stabilisation in renal function after obesity surgery. Until further definitive data emerge it is critical to balance the risk and benefits of surgery, especially if renal function may not improve as often as previously suggested. TRIAL REGISTRATION: ClinicalTrials.gov NCT01507350 . Registered June 2011.

CCL18 synergises with high concentrations of glucose in stimulating fibronectin production in human renal tubuloepithelial cells.

BACKGROUND: Diabetic nephropathy is the leading cause of end stage kidney disease worldwide. The pathogenesis of this disease remains elusive and multiple factors have been implicated. These include the effects of hyperglycaemia, haemodynamic and metabolic factors, and an inflammatory process that stimulates cellular signalling pathways leading to disease progression and severe fibrosis. Fibronectin (Fn) is an important protein of the extracellular matrix that is essential in fibrosis and its presence in increased amounts has been identified in the kidney in diabetic nephropathy. METHODS: Proximal tubuloepithelial (HK-2) cells were stimulated with high glucose (30 mM D-glucose) or glycated albumin (500 µg/mmol) + 4 mM D-glucose or their controls, Mannitol (26 mM + 4 mM D-glucose) and 4 mM D-glucose, respectively. Following 48 h of stimulation the supernatant was collected and MTT [3-(4,5-dimethylthiazole-2,5-diphenyltetrazolium bromide] assay performed to assess cell viability. HK-2 cells were also stimulated in the above environments with recombinant CCL18 (rCCL18) or MCP-1 (rMCP-1) for 48 h with quantification of Fn levels using ELISA. RESULTS: Co-stimulation of HK-2 cells with high concentrations of glucose and rCCL18 significantly increased Fn (p < 0.001), in comparison to high concentrations of glucose alone. HK-2 cells stimulated with glycated albumin consistently produced Fn and this did not alter following co-stimulation with rCCL18 or rMCP-1. CONCLUSION: This study demonstrates how stimulation with a specific chemokine CCL18 in high glucose upregulates the production of Fn from proximal tubuloepithelial cells. This may be relevant to the development of renal fibrosis in diabetic nephropathy.

Cost-effectiveness of empagliflozin as add-on to standard of care for chronic kidney disease management in the United Kingdom.

OBJECTIVE: The sodium-glucose co-transporter-2 inhibitor empagliflozin was approved for treatment of adults with chronic kidney disease (CKD) on the basis of its demonstrated ability to slow CKD progression and reduce the risk of cardiovascular death. This analysis was performed to assess the cost-effectiveness of empagliflozin plus standard of care (SoC) vs SoC alone in the treatment of CKD in the UK. METHODS: A comprehensive, patient-level CKD progression model that simulates the evolution of risk factors for disease progression based on CKD-specific equations and clinical data was used to project a broad range of CKD-related complications. Patient baseline characteristics, distribution across Kidney Disease Improving Global Outcomes (KDIGO) health states, and changes in estimated glomerular filtration rate (eGFR), urine albumin-creatinine ratio (uACR), and other parameters while on treatment were derived from the EMPA-KIDNEY trial. UK cost and utilities/disutilities were sourced from the literature. Univariate and probabilistic sensitivity analyses were conducted. Annual discounting of 3.5% was applied on costs and outcomes. RESULTS: Over a 50-year horizon, SoC resulted in per-patient costs, life years, and QALYs of £95,930, 8.55, and 6.28, respectively. Empagliflozin plus SoC resulted in an incremental gain in life years (+1.04) and QALYs (+0.84), while decreasing per-patient costs by £6,019. Empagliflozin was more effective and less costly (dominant) with a net monetary benefit of £22,849 at the willingness-to-pay threshold of £20,000. Although treatment cost was higher for empagliflozin, this was more than offset by savings in kidney replacement therapy. Empagliflozin remained highly cost-effective in patients with and without diabetes, and across scenario and sensitivity analyses. LIMITATIONS: This analysis is limited by reliance on short-term clinical trial data and by uncertainties in modelling CKD progression. CONCLUSIONS: Empagliflozin as an add-on to SoC for treatment of adults with CKD represents cost-effective use of UK National Health Service (NHS) resources.

Best practice for the selection, design and implementation of UK Kidney Association guidelines: a modified Delphi consensus approach.

BACKGROUND: Despite research into how to effectively implement evidence-based recommendations into clinical practice, a lack of standardisation in the commissioning and development of clinical practice guidelines can lead to inconsistencies and gaps in implementation. This research aimed to ascertain how topics in kidney care worthy of guideline development within the UK should be chosen, prioritised, designed and implemented. METHODS: Following a modified Delphi methodology, a multi-disciplinary panel of experts in kidney healthcare from across the UK developed 35 statements on the issues surrounding the selection, development and implementation of nephrology guidelines. Consensus with these statements was determined by agreement using an online survey; the consensus threshold was defined as 75% agreement. RESULTS: 419 responses were received. Of the 364 healthcare practitioners (HCPs), the majority had over 20 years of experience in their role (n=123) and most respondents were nephrologists (n=95). Of the 55 non-clinical respondents, the majority were people with kidney disease (n=41) and the rest were their carers or family. Participants were from across England, Northern Ireland, Scotland and Wales. Consensus between HCPs was achieved in 32/35 statements, with 28 statements reaching ≥90% agreement. Consensus between patients and patient representatives was achieved across all 20 statements, with 13/20 reaching ≥90% agreement. CONCLUSIONS: The current results have provided the basis for six recommendations to improve the selection, design and implementation of guidelines. Actioning these recommendations will help improve the accessibility of, and engagement with, clinical guidelines, contributing to the continuing development of best practice in UK kidney care.

The effect of bariatric surgery on renal function and disease: a focus on outcomes and inflammation.

Renal dysfunction and disease, including hyperfiltration, proteinuria and hypofiltration, are commonly associated with obesity. Diabetic kidney disease is also common in obese cohorts. Weight loss interventions, including bariatric surgery, can effectively reduce weight and improve renal outcomes. Some of this effect may be due to the remission of Type 2 diabetes and hypertension. However, other mechanisms, including the resolution of inflammatory processes, may also contribute. The effect of bariatric surgery on renal function has only recently become a focus of particular investigation. In this study, we will review the effects of bariatric surgery on obesity-associated kidney disease. We will discuss the pitfalls in assessing renal function in obese cohorts and will examine the effect of bariatric surgery on renal function and urinary protein excretion using different mechanisms. We will give particular attention to the evidence for bariatric surgery in cohorts with established renal disease and suggest future directions. In particular, we will outline the evidence for inflammation as an important therapeutic target, and the emerging medical therapies being considered to exploit this target in obesity- and diabetes-related kidney disease.

The Accuracy of Continuous Glucose Sensors in People with Diabetes Undergoing Hemodialysis (ALPHA Study).

Objectives: Real-time and intermittently scanned continuous glucose monitoring are increasingly used for glucose monitoring in people with diabetes requiring renal replacement therapy, with limited data reporting their accuracy in this cohort. We evaluated the accuracy of Dexcom G6 and Abbott Freestyle Libre 1 glucose monitoring systems in people with diabetes undergoing hemodialysis. Methods: Participants on hemodialysis with diabetes (on insulin or sulfonylureas) were recruited. Paired sensor glucose from Dexcom G6 and Freestyle Libre 1 were recorded with plasma glucose analyzed using the Yellow Springs Instrument (YSI) method at frequent intervals during hemodialysis. Analysis of accuracy metrics included mean absolute relative difference (MARD), Clarke error grid (CEG) analysis and proportion of CGM values within 15% and 20% or 15 and 20 mg/dL of YSI reference values for blood glucose >100 or ≤100 mg/dL, respectively (% 15/15, % 20/20). Results: Forty adults (median age 64.7 [60.2-74.4] years) were recruited. Overall MARD for Dexcom G6 was 22.7% (2656 matched glucose pairs), and 11.3% for Libre 1 (n = 2785). The proportions of readings meeting %15/15 and %20/20 were 29.1% and 45.4% for Dexcom G6, respectively, and 73.5% and 85.6% for Libre 1. CEG analysis showed 98.9% of all values in zones A and B for Dexcom G6 and 99.8% for Libre 1. Conclusions: Our results indicate Freestyle Libre 1 is a reliable tool for glucose monitoring in adults on hemodialysis. Further studies are required to evaluate Dexcom G6 accuracy in people on hemodialysis.

Narrative Review of Glycemic Management in People With Diabetes on Peritoneal Dialysis.

There is an increasing number of people with diabetes on peritoneal dialysis (PD) worldwide. However, there is a lack of guidelines and clinical recommendations for managing glucose control in people with diabetes on PD. The aim of this review is to provide a summary of the relevant literature and highlight key clinical considerations with practical aspects in the management of diabetes in people undergoing PD. A formal systematic review was not conducted because of the lack of sufficient and suitable clinical studies. A literature search was performed using PubMed, MEDLINE, Central, Google Scholar and ClinicalTrials.gov., from 1980 through February 2022. The search was limited to publications in English. This narrative review and related guidance have been developed jointly by diabetologists and nephrologists, who reviewed all available current global evidence regarding the management of diabetes in people on PD.We focus on the importance of individualized care for people with diabetes on PD, the burden of hypoglycemia, glycemic variability in the context of PD and treatment choices for optimizing glucose control. In this review, we have summarized the clinical considerations to guide and inform clinicians providing care for people with diabetes on PD.

Association and progression of multi-morbidity with Chronic Kidney Disease stage 3a secondary to Type 2 Diabetes Mellitus, grouped by albuminuria status in the multi-ethnic population of Northwest London: A real-world study.

INTRODUCTION: The prevalence of Diabetic Kidney Disease (DKD) secondary to Type 2 Diabetes Mellitus (T2DM) is rising worldwide. However, real-world data linking glomerular function and albuminuria to the degree of multi-morbidity is lacking. We thus utilised the Discover dataset, to determine this association. METHOD: Patients with T2DM diagnosed prior to 1st January 2015 with no available biochemical evidence of CKD were included. Patients subsequently diagnosed and coded for CKD3a in 2015, were grouped by the degree of albuminuria. Baseline and 5-year co-morbidity was determined, as were prescribing practices with regards to prognostically beneficial medication. RESULTS: We identified 56,261 patients with T2DM, of which 1082 had CKD stage 3a diagnosed in 2015 (224-CKD3aA1,154-CKD3aA2,93-CKD3aA1; 611 patients with CKD3a but no uACR available in 2015 were excluded from follow up). No statistically significant difference was observed in the degree of co-morbidities at baseline. A significant difference in the degree of hypertension, retinopathy, ischaemic heart disease and vascular disease from baseline compared to study end point was observed for all 3 study groups. Comparing co-morbidities developed at study end point, highlighted a statistical difference between CKD3aA1 Vs CKD3aA3 for retinopathy alone and for hypertension and heart failure between CKD3aA2 Vs CKD3aA3. 40.8% of patients with CKD3aA2 or A3 were prescribed Renin Angiotensin Aldosterone inhibitors (RAASi) therapy between June-December 2021. Survival analysis showed 15% of patients with CKD3aA3 developed CKD stage 5 within 5 years of diagnosis. DISCUSSION: CKD3a secondary to DKD is associated with significant multimorbidity at baseline and 5 years post diagnosis, with CKD3aA3 most strongly associated with CKD progression to CKD 5, heart failure, hypertension and retinopathy compared to CKD3aA1 or CKD3aA2 at 5 years post diagnosis. The lack of uACR testing upon diagnosis and poor prescribing of RAASi, in those with CKD3aA2/A3, raises significant cause for concern. CONCLUSION: DKD is associated with significant multimorbidity. Significant work is needed to be done to ensure patients undergo testing for uACR, to allow for future risk stratification and ability to be started on prognostically beneficial medication.

Oral cholecalciferol decreases albuminuria and urinary TGF-ß1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition.

The anti-inflammatory, antifibrotic, and antiproteinuric properties of vitamin D have been defined in studies using active vitamin D analogs. In this prospective observational study we determined whether nutritional vitamin D repletion can have additional beneficial effects in patients with type 2 diabetic nephropathy already established on renin-angiotensin-aldosterone system inhibition. During a 7-month period, 63 patients were enrolled and those with low levels of 25(OH)D were treated with oral cholecalciferol for 4 months. Baseline serum 25(OH)D and 1,25(OH)(2)D showed no significant correlation with baseline urinary MCP-1, TGF-ß1, or albuminuria measured as the urinary albumin-to-creatinine ratio. Of the 63 patients, 54 had insufficient or deficient levels of serum 25(OH)D and 49 complied with cholecalciferol therapy and follow-up. Both 25(OH)D and 1,25(OH)(2)D were significantly increased at 2 and 4 months of treatment. Albuminuria and urinary TGF-ß1 decreased significantly at both time points compared to their baseline values, while urinary MCP-1 did not change. Thus, in the short term, dietary vitamin D repletion with cholecalciferol had a beneficial effect in delaying the progression of diabetic nephropathy above that due to established renin-angiotensin-aldosterone system inhibition.

Urine proteomics and biomarkers in renal disease.

The application of urine proteomics is a useful approach to the study of the proteins involved in healthy and diseased kidneys and may provide a noninvasive approach to assess disease activity and to monitor clinical response in patients with renal diseases. This technique may provide an additional tool in clinical trials and for the assessment of prognosis for patients. Both soluble proteins and membrane-bound (exosomal) proteins may be studied, and multiple approaches are available. Discovery proteomics is an unbiased approach to detect novel proteins in urine samples. Mass spectrometry (MS) is often needed to identify specific protein fragments. Targeted proteomics often involves specific immunoassays or modified MS, which enables a hypothesis-based design. These approaches may be integrated. For example, specific proteins may be identified by the discovery approach or laboratory study of disease mechanisms. These proteins will then be studied further by targeted proteomics. In order to translate to clinical practice, the specific assays need vigorous validation by means of sufficiently statistically powered clinical trials.

Urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers for progression of diabetic nephropathy.

Profibrotic growth factors and inflammatory chemokines have been implicated in the pathogenesis of diabetic nephropathy (DN). However, measurement of urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers has not previously been reported, and neither have two such molecules in urine been examined in a single study of DN. In this prospective observational study, 43 adult diabetic patients were studied, 40 were followed up for 6years. Urinary MCP-1/creatinine ratios were found to be significantly higher in patients with macroalbuminuria (3.3- and 2.1-fold higher (p<0.01) than normoalbuminuric and microalbuminuric patients, respectively). CCN2 exhibited a pattern different from that of urinary MCP-1. Urinary CCN2/creatinine ratios were greatly elevated in both microalbuminuric and macroalbuminuric patients (125- and 74-fold higher than normoalbuminuric patients, respectively, p<0.01 and p<0.05, respectively). Further, urinary CCN2, but not MCP-1, correlated with progression of microalbuminuria (R=0.49, p<0.05). In contrast, MCP-1, but not CCN2, correlated with the rate of eGFR decline for all patients (R=0.61, p<0.0001), reflective of its predictive value in patients with macroalbuminuria, but not for patients with microalbuminuria or normoalbuminuria. In conclusion, increased urinary CCN2 is associated with the early progression of DN, whereas MCP-1 is associated with later stage disease.

Predictors of renal outcome in HIV-associated nephropathy.

BACKGROUND: Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is an important cause of end-stage renal disease among African American patients. This study was performed to study the epidemiology of HIVAN in a predominantly black African population and the impact of highly active antiretroviral therapy and other factors on the development of end-stage renal disease. METHODS: We retrospectively identified all patients with HIVAN, defined by biopsy or strict clinical criteria, in 8 clinics in the United Kingdom. Baseline renal function, HIV parameters, renal pathological index of chronic damage, and responses to highly active antiretroviral therapy were analyzed, and factors associated with adverse renal outcome were identified. RESULTS: From 1998 through 2004, we studied 16,834 patients, 61 of whom had HIVAN. HIVAN prevalence in black patients was 0.93%, and HIVAN incidence in those without renal disease at baseline was 0.61 per 1000 person-years. After a median of 4.2 years, 34 patients (56%) had developed end-stage renal disease. There were no significant differences in renal function and HIV parameters at baseline, time to initiation of highly active antiretroviral therapy, and rates of HIV RNA suppression between the 20 patients who developed end-stage renal disease >3 months after receiving the HIVAN diagnosis and the 23 patients who maintained stable renal function. However, the index of chronic damage score was significantly higher in those who developed end-stage renal disease (P < .001), and an index of chronic damage score >75 was associated with shorter renal survival (P < .001). CONCLUSIONS: Whereas overall patient survival suggested an important benefit of highly active antiretroviral therapy, no additional renal benefit of early initiation of highly active antiretroviral therapy or viral suppression could be demonstrated in this large cohort of patients with established HIVAN. Severity of chronic kidney damage, as quantified by biopsy, was the strongest predictor of renal outcome.

BK virus nephropathy in renal transplant patients in London.

BACKGROUND: BK nephropathy (BKN) is an important cause of renal transplant dysfunction, believed to be associated with higher levels of immunosuppression. We assessed the experience of BKN in renal transplant patients in the London region. METHODS: All six London transplant centers participated and case notes of patients with BKN in 2004 to 2005 were reviewed. RESULTS: There were 17 cases of BKN, giving an incidence of 2.1%. Median time to diagnosis was 9 months. Median baseline creatinine rose from 150 to 196 mumol/L. At diagnosis, 16 patients were on tacrolimus, 15 on mycophenolate mofetil, and 10 on triple therapy with tacrolimus, mycophenolate mofetil, and prednisolone. Management of BKN involved reducing immunosuppression; cidofovir was used in two patients and methylprednisolone in five for acute rejection. Median follow-up time was 29.2 months. Creatinine returned to baseline in four patients, remained elevated in 12 and one patient lost his graft. The new median baseline creatinine was 216 mumol/L. Eight patients underwent repeat biopsies of which four became negative for BKV and three subsequently cleared the virus on blood and urine polymerase chain reaction and urine decoy cells. Overall, eight patients cleared the virus. None of age, sex, viral load, or biopsy characteristics (Banff ct score, Drachenberg grade, and number of BKV positive cells) were associated with poorer outcome when patients with increase in creatinine of less than 30% (n=7) or more than 30% (n=10) from baseline were compared. CONCLUSION: The incidence of BKN in this study is comparable with previous studies, with more favorable outcomes. It supports the association of BKN with potent immunosuppression.

Defining Phenotypes in Diabetic Nephropathy: a novel approach using a cross-sectional analysis of a single centre cohort.

The global increase in Diabetes Mellitus (DM) has led to an increase in DM-Chronic Kidney Disease (DM-CKD). In this cross-sectional observational study we aimed to define phenotypes for patients with DM-CKD that in future may be used to individualise treatment We report 4 DM-CKD phenotypes in 220 patients recruited from Imperial College NHS Trust clinics from 2004-2012. A robust principal component analysis (PCA) was used to statistically determine clusters with phenotypically different patients. 163 patients with complete data sets were analysed: 77 with CKD and 86 with DM-CKD. Four different clusters were identified. Phenotypes 1 and 2 are entirely composed of patients with DM-CKD and phenotypes 3 and 4 are predominantly CKD (non-DM-CKD). Phenotype 1 depicts a cardiovascular phenotype; phenotype 2: microvascular complications with advanced DM-CKD; phenotype 3: advanced CKD with less anaemia, lower weight and HbA1c; phenotype 4: hypercholesteraemic, younger, less severe CKD. We are the first group to describe different phenotypes in DM-CKD using a PCA approach. Identification of phenotypic groups illustrates the differences and similarities that occur under the umbrella term of DM-CKD providing an opportunity to study phenotypes within these groups thereby facilitating development of precision/personalised targeted medicine.

Early detection of subclinical left ventricular myocardial dysfunction in patients with chronic kidney disease.

AIMS: To identify subclinical left ventricular (LV) myocardial dysfunction using speckle tracking echocardiography (STE) in patients with chronic kidney disease (CKD), preserved LV ejection fraction (LVEF), and no cardiovascular history or symptoms. METHODS AND RESULTS: Cross-sectional comparisons of conventional and STE parameters were performed between controls and patients with different stages of CKD. CKD patients were followed up for major adverse cardiovascular events (MACEs). We recruited 106 CKD patients and 38 controls. Mean age was 54.4 ± 15.1 and 36.9 ± 11.5 years, respectively (P < 0.001), with 49.1 vs. 52.6% being female (P = 0.705). There were 29 (27.4%) patients with CKD stages 1/2, 38 (35.8%) with stage 3, and 39 (36.8%) with stages 4/5. Global longitudinal strain (GLS) was more impaired when moving from controls to CKD stages 4/5 (-20.67 ± 3.06, -20.39 ± 2.29, -18.33 ± 3.81, -18.01 ± 2.64, controls vs. CKD stages 1/2, vs. CKD stage 3, vs. CKD stages 4/5, respectively, Padjusted = 0.016), whereas LV twist (16.2 ± 4.8, 18.51 ± 4.36, 19.91 ± 5.35, 24.6 ± 5.35, Padjusted < 0.001) and LV twist rate (101.7 ± 30.3, 110.4 ± 30.1, 121 ± 31.4, 154.8 ± 36.7, Padjusted < 0.001) increased. Risk factor-adjusted GLS (standardized beta ß = -0.245, P = 0.025), strain rate (SR) [global longitudinal strain rates (GLSRs); ß = -0.236, P = 0.019], and early diastolic longitudinal strain rate (GLSRe; ß = 0.247, P = 0.019) were significantly associated with estimated glomerular filtration rate (eGFR), whereas LV twist (ß = -0.432, P < 0.001), LV twist rate (ß = -0.433, P < 0.001), and number of segments with diastolic dysfunction (ß = -340, P < 0.001) were inversely and independently associated with eGFR. Impaired GLS (more than -16%) was observed in almost a quarter of CKD patients and associated with a reduced estimated MACE-free survival at 12-month follow-up (88.5 vs 93.7%, Plogrank = 0.038). CONCLUSION: In CKD patients with no cardiovascular symptoms or history and preserved LVEF, STE can identify subclinical abnormalities of both systolic (decreased GLS and GLSR, increased LV twist, and twist rate) and diastolic (decreased GLSRe and increased number of segments with diastolic dysfunction) LV function.